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                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                UNITED STATES FOOD AND DRUG ADMINISTRATION

 

                 CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

                PULMONARY-ALLERGY DRUGS ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

                           Monday, June 6, 2005

 

                                8:00 a.m.

 

 

 

 

 

 

 

                            5600 Fishers Lane

                                Room 1066

                           Rockville, Maryland
 

 

 

 

 

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                         P A R T I C I P A N T S

 

       Erik R. Swenson, M.D., Chairman

       Teresa Watkins, R.Ph., Executive Secretary

 

       MEMBERS:

 

       Mark L. Brantly, M.D.

       Steven E. Gay, M.D., M.S.

       I. Marc Moss, M.D.

       Calman P. Prussin, M.D.

       Theodore F. Reiss, M.D., Industry Representative

       Karen Schell, RRT, Consumer Representative

       David A. Schoenfeld, Ph.D.

 

       SGE CONSULTANTS AND GUESTS (VOTING):

 

       Jeffrey S. Barrett, Ph.D.

       Lawrence Hunsicker, M.D.

       Allan R. Sampson, Ph.D.

       Jurgen Venitz, M.D., Ph.D.

       Mary Lou Drittler, SGE Patient Representative

 

       GOVERNMENT EMPLOYEES (VOTING):

 

       James Burdick, M.D.

       Roslyn B. Mannon, M.D.

       Michael A. Proschan, Ph.D.

       John Tisdale, M.D.

 

       FDA STAFF:

 

       Mark J. Goldberger, M.D., M.P.H.

       Renata Albrecht, M.D.

       Marc Cavaille-Coll, Ph.D.

       Arturo Hernandez, M.D.

       Jyoti Zalkikar, Ph.D.
 

 

 

 

 

                                                                  3

 

                             C O N T E N T S

 

       Call to Order and Opening Remarks,

         Erik R. Swenson, M.D.                                    4

 

       Conflict of Interest Statement,

         Teresa A. Watkins, R.Ph.                                 7

 

       FDA Introductory Remarks,

         Renata Albrecht, M.D.                                    8

 

       Sponsor Presentation:

 

          Introduction, Michael Scaife, Ph.D.                    14

 

          Current State of Lung Transplantation,

            Jeffrey Golden, M.D., University of

            California, San Francisco                            20

 

          Clinical Evidence of Efficacy and Safety,

            Sarah Noonberg, M.D., Ph.D.                          28

 

          Statistical Considerations,

            Ronald W. Helms, Ph.D.,

          Rho, Inc.; University of North Carolina                59

 

          Safety and Benefit-Risk,

            Stephen Dilly, M.D., Ph.D.                           65

 

       Questions from the Panel                                  70

 

       FDA Presentation:

 

          Overview of Clinical Trial Efficacy and

            Safety Evaluation Discussion of Analysis,

            Arturo Hernandez, M.D.                               88

 

          Safety Considerations and Conclusions,

          Marc Cavaille-Coll, M.D., Ph.D.                       105

 

          Statistical Evaluation,

            Jyoti Zalkikar, Ph.D.                               111

 

       Questions from the Panel (Continued)                     121
 

 

 

 

 

                                                                  4

 

                       C O N T E N T S (Continued)

 

       Open Public Hearing:

 

          Esther Suss, Ph.D.                                    151

          John C. Sullivan                                      156

          Bill Stein                                            158

          Renee Moeller                                         162

 

       Charge to the Committee, Renata Albrecht, M.D.           163

 

       Committee Discussion and Vote                            168
 

 

 

 

 

                                                                  5

 

                          P R O C E E D I N G S

 

                              Call to Order

 

                 DR. SWENSON:  Good morning, everyone.  I

 

       am Dr. Erik Swenson, from the University of

 

       Washington, and I will be chairing this session.

 

       This is the meeting of the Pulmonary and Allergy

 

       Drugs Advisory Committee and today we are going to

 

       be discussing inhaled cyclosporine, a product to be

 

       presented by Chiron.

 

                 Let me begin with just a few items to keep

 

       us on schedule and for organizational purposes.

 

       One, I would request that everyone with cell

 

       phones, please turn them off or at least down to

 

       some vibrating or some innocuous mode.  Then, we

 

       will go around and introduce everyone here at the

 

       table.  I would ask that when you are questioning

 

       anything during this meeting to please identify

 

       yourself first.  The transcriber will need to know

 

       who is speaking.  We have microphones here.  All

 

       you need to do is simply push down "talk" to go

 

       ahead and be heard but, please, turn it off when

 

       you have finished.  If we get more than three
 

 

 

 

 

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       microphones on at one time things get confusing.

 

                 Without any further ado, I am going to

 

       turn the meeting over to Dr. Teresa Watkins for

 

       some introductory comments.

 

                      Introduction of the Committee

 

                 DR. WATKINS:  Let's first go around the

 

       table, starting with Dr. Reiss, if you will

 

       introduce yourself and your affiliations, please?

 

                 DR. REISS:  My name is Ted Reiss.  I am

 

       vice president of clinical research at Merck

 

       Research Labs.  I am the non-voting industry

 

       representative.

 

                 DR. BRANTLY:  My name is Mark Brantly.  I

 

       am from the University of Florida.  I am a

 

       professor of medicine.

 

                 DR. TISDALE:  My name is John Tisdale and

 

       I am in the intramural program of NIDDK.

 

                 DR. PRUSSIN:  My name is Calman Prussin.

 

       I am a clinical investigator with National

 

       Institute of Allergy and Infectious Diseases.

 

                 DR. MANNON:  I am Roslyn Mannon and I am a

 

       transplant nephrologist and medical director of the
 

 

 

 

 

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       intramural solid organ transplant program at NIDDK.

 

                 DR. GAY:  I am Steven Gay, assistant

 

       professor at the University of Michigan, associate

 

       director of the lung transplant program and

 

       director of clinical support services.

 

                 DR. HUNSICKER:  I am Larry Hunsicker, from

 

       the University of Iowa.  I am a transplant

 

       nephrologist and professor of medicine, and I am a

 

       member of the Chemical Immunosuppression Advisory

 

       Committee but guesting on this one.

 

                 DR. VENITZ:  I am Jurgen Venitz.  I am a

 

       clinical pharmacologist and associate professor at

 

       Virginia Commonwealth University.

 

                 MS. DRITTLER:  I am Mary Lou Drittler.  I

 

       am a  lung transplant recipient and I am a patient

 

       representative from here, in Silver Spring.

 

                 DR. BURDICK:  I am Jim Burdick.  I am

 

       director of the Division of Transplantation and

 

       Healthcare System, HRSA and a transplant surgeon.

 

                 DR. MOSS:  I am Mark Moss.  I am an

 

       associate professor of medicine at Emory University

 

       and section chief at Grady Memorial Hospital.
 

 

 

 

 

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                 DR. BARRETT:  I am Jeff Barrett.  I am a

 

       clinical pharmacologist from the University of

 

       Pennsylvania and Children's Hospital of

 

       Philadelphia.

 

                 DR. PROSCHAN:  I am Mike Proschan and I am

 

       a statistician from the National Heart, Lung and

 

       Blood Institute.

 

                 DR. SCHOENFELD:  I am David Schoenfeld.  I

 

       am a biostatistician and professor of medicine at

 

       Harvard Medical School and Massachusetts General

 

       Hospital.

 

                 DR. SAMPSON:  I am Allan Sampson,

 

       professor of statistics, Department of Statistics

 

       at the University of Pittsburgh.

 

                 MS. SCHELL:  I am Karen Schell.  I am a

 

       respiratory therapist from Emporia Kansas, and I am

 

       the consumer representative.

 

                 DR. CAVAILLE-COLL:  I am Marc

 

       Cavaille-Coll, medical team leader, Division of

 

       Special Pathogen and Immunologic Drug Products.

 

                 DR. ALBRECHT:  I am Renata Albrecht,

 

       director, Division of Special Pathogen and
 

 

 

 

 

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       Immunologic Drug Products.

 

                 DR. HERNANDEZ:  I am Arturo Hernandez, a

 

       medical reviewer for FDA, Division of Special

 

       Pathogens and Immunologic Drug Products, and I am a

 

       transplant surgeon.

 

                      Conflict of Interest Statement

 

                 DR. WATKINS:  With that, thank you.

 

       Welcome everyone.  I am now going to now read the

 

       conflict of interest statement.

 

                 The following announcement addresses the

 

       issue of conflict of interest with regard to this

 

       meeting and is made a part of the record to

 

       preclude even the appearance of such at this

 

       meeting.

 

                 Based on the submitted agenda for the

 

       meeting and all financial interests reported by the

 

       committee participants, it has been determined that

 

       all interests in firms regulated by the Center for

 

       Drug Evaluation and Research present no potential

 

       for an appearance of a conflict of interest at this

 

       meeting.

 

                 With respect to FDA's invited industry
 

 

 

 

 

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       representative, we would like to disclose that Dr.

 

       Theodore Reiss is participating in this meeting as

 

       a non-voting industry representative acting on

 

       behalf of regulated industry.  Dr. Reiss' role on

 

       this committee is to represent industry interests

 

       in general and not any one particular company.  Dr.

 

       Reiss is employed by Merck.

 

                 In the event that the discussions involve

 

       any other products or firms not already on the

 

       agenda for which an FDA participant has a financial

 

       interest, the participants are aware of the need to

 

       exclude themselves from such involvement and their

 

       exclusion will be noted for the record.

 

                 With respect to all other participants, we

 

       ask in the interest of fairness that they address

 

       any current or previous financial involvement with

 

       any firms whose products they may wish to comment

 

       upon.  Thank you.  With that, we will have opening

 

       remarks from Dr. Albrecht.

 

                         FDA Introductory Remarks

 

                 DR. ALBRECHT:  Thank you, Dr. Watkins.

 

       Good morning, everybody.  On behalf of the Division
 

 

 

 

 

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       of Special Pathogen and Immunologic Drug Products

 

       and the Office of Drug Evaluation IV, I would like

 

       to welcome everyone to today's meeting.

 

                 We wish to thank the members of the

 

       Pulmonary Advisory Committee, the Chair, Dr.

 

       Swenson, and our consultants for taking the time

 

       out of their schedules to come to Rockville and

 

       join us here to discuss this application.  I also

 

       wish to express our appreciation to Chiron and the

 

       investigators for the time and effort that they

 

       have put into developing this drug product and to

 

       the Chiron staff for their willingness and

 

       preparation for this advisory committee meeting.  I

 

       would also like to recognize the dedication of the

 

       Division staff and the long hours they have put in

 

       for reviewing this application.

 

                 Let me speak briefly about this new drug

 

       application for cyclosporine inhalational solution

 

       and why we are bringing this application to the

 

       advisory committee.  Could I have someone run the

 

       slides?  I apologize, there are some slides that go

 

       with this presentation so that you may follow
 

 

 

 

 

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       along.

 

                 Let me continue.  There are currently no

 

       FDA-approved products for the prevention of chronic

 

       rejection in patients with lung allografts.  There

 

       are approximately 1100 transplants done in the U.S.

 

       annually and the survival at five years is lower

 

       than survival in other organ transplants such as

 

       heart, kidney or liver transplants.  Prevention of

 

       rejection and increase in survival are critical

 

       and, therefore, there is a clear need for safe and

 

       effective therapy.

 

                 Next slide.  Chiron has submitted the NDA

 

       for Pulminiq and requested that the cyclosporine

 

       inhalational solution be approved for the increase

 

       in survival and prevention of chronic rejection in

 

       lung transplant patients. The drug development

 

       program and the NDA for this product are not

 

       conventional.  Unlike applications for

 

       immunosuppressants in kidney, heart of liver

 

       transplants for example, this NDA contained results

 

       from one single Phase II study conducted at one

 

       center.  This trial enrolled 66 patients out of a
 

 

 

 

 

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       planned 136 patients.  However, we learned that

 

       there was a survival advantage, 88 percent survival

 

       in patients who received aerosolized cyclosporine

 

       plus a tacrolimus-based systemic immunosuppressive

 

       regimen compared to 53 percent survival in patients

 

       receiving aerosolized propylene glycol vehicle in

 

       addition to a tacrolimus-based systemic

 

       immunosuppressive regimen.

 

                 Therefore, the agency agreed to file and

 

       review this NDA application.  Based on the NDA

 

       review of the information in the application, we

 

       were unable to conclude that the observed

 

       difference in survival and chronic rejection was

 

       due to study drug.  Therefore, we determined it was

 

       important to bring this application to the advisory

 

       committee for the following reasons:

 

                 This would represent the first drug for

 

       immunosuppression in patients with lung

 

       transplantation to garner FDA approval.  This is a

 

       new drug application.  Although oral and systemic

 

       cyclosporine are well characterized, cyclosporine

 

       inhalational solution is a new formulation of
 

 

 

 

 

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       cyclosporine.  It is seeking a new indication.  It

 

       is administered by a new route and it requests a

 

       new dosage regimen.  As I mentioned, we weren't

 

       able to conclude that the differences in chronic

 

       rejection and survival were due to the study drug.

 

       For these reasons, we determined it was important

 

       to have this application discussed in an open

 

       public forum.

 

                 We have asked the help of the pulmonary

 

       product advisory committee because it is a standing

 

       committee with expertise in pulmonary disease.  We

 

       have invited experts in statistics and

 

       transplantation to help with the deliberation, and

 

       we are very much interested in the committee's

 

       input regarding the adequacy of the clinical and

 

       statistical evidence whether aerosolized

 

       cyclosporine is safe and effective for the proposed

 

       indication.

 

                 This morning Chiron will present most of

 

       the background information, starting with Dr.

 

       Michael Scaife's presentation on the drug

 

       development program.  Then Dr. Jeff Golden will
 

 

 

 

 

                                                                 15

 

       provide an overview of lung transplantation.  Dr.

 

       Sarah Noonberg will discuss the results of the

 

       efficacy study, followed by Dr. Steven Dilly's

 

       presentation and Dr. Ron Helms' views.

 

                 The FDA presentation will follow the

 

       Chiron presentations and we will focus on those

 

       areas that proved challenging during the course of

 

       the review.  Dr. Arturo Hernandez will discuss the

 

       study design, various clinical issues and outcome

 

       demographic characteristics and dosing.  Dr. Marc

 

       Cavaille-Coll will provide a summary of the safety

 

       issues and Dr. Jyoti Zalkikar will give the

 

       statistical presentation.

 

                 Then, in the afternoon, we would like you

 

       to discuss, give advice and vote on a few

 

       questions.  So, as you listen to the presentations

 

       this morning, please keep these questions in mind

 

       for later discussion.  The first question:  Is

 

       there sufficient information to make the

 

       determination whether the observed survival

 

       difference in study ACS001 is due to study

 

       treatment or some other factors?
 

 

 

 

 

                                                                 16

 

                 In your deliberations, we will ask you to

 

       recall the statistical issues that were raised by

 

       the application; differences in baseline donor and

 

       recipient characteristics; whether the product

 

       demonstrated an effect on various clinical outcomes

 

       or things such as acute rejection, bronchiolitis

 

       obliterans syndrome, obliterative bronchiolitis.

 

                 Depending on whether you conclude that the

 

       answer is yes or no, we have a few additional

 

       questions, namely, if the answer is yes we would

 

       like you to talk about the generalizability or,

 

       more specifically, the labeling issues that you

 

       would recommend be put into a product label.  If

 

       the answer is no we would like you to consider what

 

       additional studies you would recommend be

 

       conducted.  In these discussions we would also like

 

       you to give us some suggestions regarding patient

 

       population, drug dosing regimen, as well as

 

       efficacy and endpoints that could be included in

 

       such studies.

 

                 The next question would be whether the

 

       safety of the product has been adequately
 

 

 

 

 

                                                                 17

 

       characterized for its intended use.  Again, in this

 

       particular question we would like you to also

 

       consider the amount of preclinical and clinical

 

       information that is available in this application;

 

       infection about the cyclosporine and the vehicle,

 

       as well as the number of patients who have been

 

       exposed to the proposed dosage regimen.

 

                 If the answer to this question as well as

 

       the preceding one is yes, then we would like you to

 

       give us suggestions about what population the

 

       product should be labeled for; what information we

 

       should include in labeling on dosing regimen, dose

 

       preparation and administration, dosing intervals

 

       and duration of treatment.  In addition, if you

 

       could give us guidance on what should be included

 

       in the labeling regarding the expected benefit on

 

       acute rejection, BOS, OB and so forth.  If your

 

       answer to the latter question is no, then we would

 

       like you to give us some advice about what

 

       preclinical and clinical information would be

 

       needed.

 

                 With that, thank you and I will turn it
 

 

 

 

 

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       back to Dr. Swenson.

 

                 DR. SWENSON:  Thank you, Dr. Albrecht.  We

 

       will proceed now with the sponsor presentation and

 

       I would like Dr. Michael Scaife to go ahead and

 

       begin this, and I will let him introduce his

 

       colleagues and their different presentations.

 

                           Sponsor Presentation

 

                               Introduction

 

                 DR. SCAIFE:  First of all, good morning,

 

       ladies and gentlemen.  My name is Michael Scaife.

 

       On behalf of Chiron, I would like to thank the FDA

 

       as well as members of the advisory panel for this

 

       opportunity today to present to you on the safety

 

       and efficacy of an inhalable form of cyclosporine

 

       that will be referred to throughout the talk as

 

       either CyIS or the product's trade name, Pulminiq.

 

                 The first point I would like to make is

 

       that currently in the United States there are no

 

       drugs or combination of drug therapies approved for

 

       the treatment of chronic rejection following lung

 

       transplantation.  The prognosis for these patients

 

       is really poor.  Despite aggressive care, only 45
 

 

 

 

 

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       percent of lung transplant recipients will be alive

 

       five years following transplantation.  This is much

 

       worse than for other solid organ transplant

 

       recipients.  This is an orphan population in the

 

       U.S.  On average less than 1100 lung transplants

 

       are performed each year.

 

                 We are here today to talk about certain

 

       aspects of Pulminiq, a medication that is an

 

       aerosolized form of cyclosporine dissolved in an

 

       inert vehicle, propylene glycol.  As you all know,

 

       cyclosporine is not a new chemical entity.

 

       Cyclosporine was approved by the FDA in 1983 and

 

       currently has been approved in most countries of

 

       the world.  It is available in oral, IV and ocular

 

       forms.  In the U.S. it has been approved for the

 

       prophylaxis of allogeneic heart, liver and kidney

 

       graft rejection, and for the treatment of

 

       refractory rheumatoid arthritis and plaque

 

       psoriasis.  In Europe cyclosporine is also approved

 

       for use following bone marrow and pancreatic

 

       transplantation, as well as for a variety of

 

       immune-modulated pathologies such as nephrotic
 

 

 

 

 

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       syndrome, atopic dermatitis and Bessay syndrome.

 

                 Pulminiq is simply an inhalable form of

 

       cyclosporine so, in essence, we are here today to

 

       talk about a well-known drug given by a new route

 

       of administration to enable delivery to the

 

       required site of action.  As I mentioned, Pulminiq

 

       is a simple formulation consisting of cyclosporine

 

       dissolved in propylene glycol, with no other

 

       ingredients.  Propylene glycol is also not new to

 

       pharmaceutics.  Since the initial inhalation tox

 

       studies of propylene glycol in the '40s it has been

 

       widely used as a compounding agent for intravenous

 

       and oral pharmaceuticals, as well as foods.  In

 

       fact, it is currently listed by the FDA as an

 

       approved inactive ingredient for use in inhalation

 

       products.

 

                 Several preclinical inhalation studies

 

       have been performed both with Pulminiq as well as

 

       with the vehicle alone.  Specifically, you will see

 

       in the briefing book that we make mention of two

 

       one-month studies in the rat and the dog and a

 

       three-month study in the rat.  I won't go into the
 

 

 

 

 

                                                                 21

 

       specific details but, as you will see, doses given

 

       in those animals were in multiples 15, 17 times the

 

       dose that we expected in man.  The

 

       histopathological findings again are detailed in

 

       the book.  You will find that aside from some small

 

       punctate findings in the larynx in a few of the

 

       animals, there were no long-lasting changes and, in

 

       our view, the results are not significant.

 

                 How did Chiron first become aware of the

 

       work on inhalable cyclosporine at the University of

 

       Pittsburgh Medical Center, which we will refer to

 

       from now on as UPMC?  Well, in fact, from a sales

 

       rep who was detailing our inhalable topromycine

 

       product, TOBI, which is used for the treatment of

 

       pseudomonas infections in cystic fibrosis patients.

 

                 The slide here details the development

 

       activities at UPMC.  The preclinical study started

 

       in '88, followed in '91 by human studies in lung

 

       transplant patients with chronic rejection.  In '97

 

       UPMC started a randomized, double-blind,

 

       placebo-controlled study of cyclosporine that ended

 

       in August, 2003.  The results of this and other
 

 

 

 

 

                                                                 22

 

       studies will form the discussion of today's

 

       meeting.

 

                 You may ask why did Chiron want to acquire

 

       the rights to develop this product.  Well, we

 

       looked at the results of 15 years of work at one of

 

       the largest lung transplant centers in the U.S.  We

 

       asked ourselves the same questions, frankly, and

 

       had the same concerns as anyone would have had.  It

 

       is a single-center study.  It was being conducted

 

       by a single lead investigator.  Has the study been

 

       conducted appropriately?  Are the data robust?  Are

 

       the striking effects seen on survival benefit real?

 

       And, if so, are they due to cyclosporine or some

 

       other factor or factors?

 

                 We did our initial due diligence of the

 

       data and how it had been collected and we concluded

 

       that the effect is real.  Based upon our

 

       conviction, we acquired the right to file an NDA

 

       for the product.  As you know, the FDA encourages

 

       the filing of applications for products that

 

       address a clear unmet medical need with a

 

       demonstrated significant clinical benefit and an
 

 

 

 

 

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       acceptable safety profile.  We went to UPMC and we

 

       extensively audited the hospital records.  We went

 

       in and we collected all of these data on

 

       standardized forms, and we analyzed the data in

 

       every possible manner, as you will hear later.

 

                 In may, 2004 we met with the FDA.  We

 

       posed a very simple question, would the agency

 

       consider the positive findings from one clinical

 

       study, conducted by one principal investigator to

 

       be registerable?  The FDA response, and I think Dr.

 

       Albrecht referred to it so she will forgive me for

 

       paraphrasing I hope, was assuming that the data are

 

       robust--and I happily stress the word "robust"--we

 

       encourage you to file.  It is rare for us at the

 

       FDA to be provided with significant survival data

 

       for such a product.  Based upon this positive

 

       meeting, Chiron filed an NDA for Pulminiq in

 

       October, 2004.

 

                 I would like to acknowledge the

 

       collaborative position taken by the FDA throughout

 

       the NDA process.  We have been encouraged to

 

       maintain a dialogue with the reviewers and it is in
 

 

 

 

 

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       this spirit that we are here today.

 

                 The finding was accepted by the FDA and

 

       priority review status was granted in December,

 

       2004.  Ladies and gentlemen, Chiron is here today

 

       because we believe the data on survival benefit are

 

       real and clinically relevant, as well as

 

       statistically significant.  We will present data

 

       that confirm that CyIS is safe and efficacious for

 

       the requested indication, which is to increase the

 

       survival and prevent chronic rejection in patients

 

       receiving allogeneic lung transplants in

 

       combination with standard chronic immunosuppressive

 

       therapy.

 

                 With that, I would like to introduce to

 

       the panel and the audience the agenda for the

 

       Chiron presentation as well as the speakers, their

 

       background and affiliation.  The first speaker is

 

       Dr. Jeff Golden who is professor of clinical

 

       medicine and surgery at the University of

 

       California in San Francisco.  Dr. Golden is also

 

       the medical director of the lung transplant program

 

       at UCSF.
 

 

 

 

 

                                                                 25

 

                 We have asked Dr. Golden to speak to you

 

       today for two main reasons, firstly, because he is

 

       an eminent practicing physician and scientist who

 

       actually treats and cares for lung transplant

 

       patients, as well as being an active researcher

 

       into the mechanisms of acute and chronic lung

 

       rejection phenomena.  Secondly, because he was not

 

       involved in the study and we wanted his independent

 

       views on the clinical findings.  Dr. Golden will

 

       address the current status of lung transplantation.

 

                 He will be followed by Dr. Sarah Noonberg

 

       who is the clinical leader at Chiron for this

 

       project.  Dr. Noonberg will present to you the

 

       clinical evidence for the efficacy and safety of

 

       CyIS.

 

                 Dr. Noonberg will be followed by Dr. Ron

 

       Helms, an emeritus professor of statistics at the

 

       University of North Carolina.  Why did we ask him

 

       to be here today?  As statisticians and physicians

 

       have analyzed the data from every possible angle

 

       and found the positive effect of Pulminiq on

 

       survival to be clinically as well as statistically
 

 

 

 

 

                                                                 26

 

       robust, the  FDA statisticians expressed some

 

       concerns about our analyses and so we asked Prof.

 

       Helms to look at our approaches, assumptions and

 

       methodologies, as well as those of the FDA

 

       reviewers, and to let us have his candid opinion.

 

       He will share those views with you today.

 

                 The final presentation by Chiron will be

 

       given by Dr. Stephen Dilly.  He is the chief

 

       medical officer for Chiron BioPharmaceuticals.  He

 

       will review the case for approval of Pulminiq

 

       including a discussion of our proposed postapproval

 

       study.  We will then hand over the meeting to the

 

       Q&A session that will be moderated by myself.

 

                 Finally, we have a list of additional

 

       experts, both internal and external.  I would like

 

       to make the special point that we have the pleasure

 

       of having Dr. Trulock here who is a world renowned

 

       expert on lung transplantation and, again, as you

 

       know, you are free to ask any of our experts for

 

       additional information.  With that, I would like to

 

       hand over to Dr. Golden.  Thank you very much.

 

                  Current State of Lung Transplantation
 

 

 

 

 

                                                                 27

 

                 DR. GOLDEN:  Thanks.  I am extremely

 

       delighted to be here as somebody who takes care of

 

       patients after transplantation.  I am here really

 

       to give an overview of the current state of lung

 

       transplant.

 

                 Just a brief statement about myself, about

 

       15 years ago I helped start a lung transplant

 

       program at the University of California in San

 

       Francisco.  In the past few years we have been

 

       doing about 30 transplants a year, and this year we

 

       are on a pace for 40 transplants.  Just to give you

 

       a perspective, this puts us in about the top 10

 

       percent in terms of volume of annual transplants in

 

       the world.

 

                 About two years ago I was asked to visit

 

       Chiron and give a review of lung transplant.  At

 

       that time I was first shown some data from the

 

       University of Pittsburgh on aerosolized

 

       cyclosporine.  Subsequently, as some of you may

 

       know, I did attend the first FDA meeting in 2004

 

       where I similarly presented an overview of lung

 

       transplant.  Well, I am back and actually nothing
 

 

 

 

 

                                                                 28

 

       has changed.

 

                 I would like to summarize on the next

 

       slide the main points in terms of where we are in

 

       lung transplant.  First, the long-term survival of

 

       lung transplant is 50 percent by five years.  This

 

       is a poor survival.  Second, bronchiolitis

 

       obliterans, or chronic rejection, is the primary

 

       cause of this poor survival.  Third, the future of

 

       lung transplant really demands that we learn how to

 

       prevent bronchiolitis obliterans.

 

                 By way of history, before cyclosporine

 

       there had been approximately 40 lung transplants in

 

       the world.  Looking at their survival, the median

 

       survival was somewhere around 10 days.  One patient

 

       lived 10 months.  After the introduction of

 

       cyclosporine there were one-year survivals, such

 

       that eventually there was 75 percent one-year

 

       survival in lung transplant.  With this large

 

       improvement compared to the pre-cyclosporine era,

 

       the interest in lung transplant really took off.

 

                 As you can see from this slide, early on

 

       in 1985 there were about a dozen transplants and as
 

 

 

 

 

                                                                 29

 

       of 2003 there are somewhere around 1700 transplants

 

       in the world, about 1100 in the United States.

 

       These are done for various recipient categories you

 

       see listed here.  Approximately half are for

 

       emphysema or alpha-1 antitrypsin deficiency, cystic

 

       fibrosis, and another large area is idiopathic

 

       pulmonary fibrosis.  Although in this registry

 

       analysis it is 17 percent, at UCSF 60 percent of

 

       our lung transplant patients have idiopathic

 

       pulmonary fibrosis, a disease for which there is no

 

       therapy and a disease that has a five-year

 

       survival, somewhat similar to lung cancer.

 

                 However, despite this increased one-year

 

       survival and this tremendous increase in the number

 

       of transplants done around the world, we are,

 

       unfortunately, still stuck at a low 50 percent

 

       survival of around 4.5 to 5 years.  Although one

 

       might say emphysema has a slightly better outlook

 

       at 4 and 5 years than idiopathic pulmonary

 

       fibrosis, in general lung transplant survival is

 

       about 50 percent at 4.5 to 5 years.

 

                 To give you some perspective, if you look
 

 

 

 

 

                                                                 30

 

       at kidney transplant at that interval of 4.5 years

 

       after transplant there is 90 percent survival.  And

 

       if you look at heart and liver transplant it is

 

       about 75 percent survival.  Not only do we have

 

       this 50 percent survival at 4 to 5 years, but this

 

       has not changed in almost 20 years.  We have

 

       plateau'd in terms of poor survival in that period

 

       of time.

 

                 As I say, the problem responsible for this

 

       poor mortality clearly is bronchiolitis obliterans.

 

       In this histology section, with an artery here, the

 

       obliterative lesion that is established as a

 

       fibroplastic plug diminishes the airway diameter

 

       such that, instead of being this size, it is

 

       reduced and constricted down to this tiny lumen

 

       here secondary to this fibroproliferative process

 

       of the lesion of bronchiolitis obliterans.

 

                 Bronchiolitis obliterans or chronic

 

       rejection is diagnosed in two ways, histologically

 

       through a transbronchial biopsy or clinically.  The

 

       problem with the histologic diagnosis of a

 

       transbronchial biopsy is that it is a specific
 

 

 

 

 

                                                                 31

 

       finding but it is not very sensitive.

 

       Transbronchial biopsy is simply not sensitive

 

       sufficiently to diagnose this chronic airway

 

       process.  Therefore, over the years we have

 

       developed a clinical diagnosis in the absence of a

 

       histologic finding on the transbronchial biopsy

 

       such that we look at specific decrease in air flow

 

       when there is no alternative cause, and we label

 

       this bronchiolitis obliterans syndrome.

 

                 It is important to stress that

 

       obliterative bronchiolitis and bronchiolitis

 

       obliterans syndrome, or BOS, are really histologic

 

       and clinical manifestations of the same airway

 

       process.  Patients develop progressive shortness of

 

       breath with this graft failure, progressive airflow

 

       obstruction and recurrent pulmonary infections.

 

       Regrettably, once this chronic rejection develops

 

       the airway damage is progressive and irreversible

 

       and patients die of graft failure and related

 

       infections.

 

                 The registry for transplant would say that

 

       somewhere around 5 years the percent of patients
 

 

 

 

 

                                                                 32

 

       dying from different etiologies would be

 

       bronchiolitis obliterans about 30 percent, but

 

       actually you cannot separate this from infections

 

       which are always present in the setting of this

 

       airway damage.  Furthermore, in this registry

 

       setting where they describe organ failure, that is

 

       obviously bronchiolitis obliterans.  So, when you

 

       add up these categories of bronchiolitis obliterans

 

       organ failure and related airway infections,

 

       including pseudomonas, aspergillus, etc., let me

 

       simply state that bronchiolitis obliterans

 

       complications relate to the vast majority of deaths

 

       at 4.5 to 5 years after lung transplantation.

 

                 No matter what we have done in the last 18

 

       years, we have not prevented this development of

 

       chronic rejection, this airway process, whether we

 

       give tacrolimus, different combinations of

 

       cyclosporine, micofenolate, azathioprine,

 

       prednisone and, in fact, I could put rapomyacin up

 

       there and various other lytic therapies and various

 

       approaches to prednisone pulses for acute

 

       rejection, etc.  Despite all this systemic
 

 

 

 

 

                                                                 33

 

       immunosuppression, we really have not changed the

 

       incidence of chronic airway rejection closely

 

       related, unfortunately, to the poor survival at 4.5

 

       to 5 years.

 

                 We now appreciate that there are

 

       non-immune factors that relate to airway damage, be

 

       these infection or reflux disease.  These

 

       non-alloimmune factors clearly relate to immune

 

       activation.  In fact, I believe we are now

 

       understanding that when we see chronic airway

 

       rejection and we increase systemic

 

       immunosuppression we actually are helping to

 

       promote such non-alloimmune factors, especially

 

       infections which cause further airway immune

 

       activation and actually make the process worse.

 

                 We have always known that there are

 

       alloimmune factors such as acute rejection that

 

       relate to damage of the organ.  We are now

 

       appreciating these non-alloimmune factors, again,

 

       be it early airway damage with transplant, various

 

       infections, reflux disease which is a very new

 

       concept in terms of what injures the airway--that
 

 

 

 

 

                                                                 34

 

       these non-alloimmune stimuli, in consort with

 

       alloimmune rejection, together damage the graft

 

       leading to progressive, additive epithelial injury,

 

       inflammation and fibroblastic repair culminating in

 

       the picture I showed you of bronchiolitis

 

       obliterans.

 

                 One newer concept in terms of immune

 

       factors is called lymphocytic

 

       bronchitis/bronchiolitis.  One might call it airway

 

       rejection.  This histology reveals lymphocytic

 

       bronchitis/bronchiolitis and airway disease wherein

 

       you have submucosal lymphocytes working their way

 

       into the mucosa.  Let me point out that lymphocytic

 

       bronchitis/bronchiolitis has been highly related to

 

       the subsequent development of the more fibrotic

 

       bronchiolitis obliterans.  This concept of an

 

       airway inflammation based on immune reaction in the

 

       airway, lymphocytic bronchitis, was not on the

 

       radar screen 15 years ago when the concept of

 

       inhaled cyclosporine was conceived.

 

                 We have always known that acute rejection

 

       is one of the factors that relates to the
 

 

 

 

 

                                                                 35

 

       subsequent development of bronchiolitis obliterans.

 

       However, I want to separate out the airway process

 

       from acute rejection which is a perivascular

 

       process diagnosed by transbronchial biopsy.  I

 

       should emphasize that a transbronchial biopsy has

 

       variable adequacy for obtaining small airway

 

       samples to diagnose whether it is bronchiolitis

 

       obliterans or the early airway inflammation of

 

       lymphocytic bronchitis.

 

                 If I was designing a study today of any

 

       inhaled immunosuppressant therapy I would try to

 

       learn more about the biology of the airways.  We,

 

       at UCSF, and some other institutions have been

 

       doing endobronchial biopsy.  This is not standard

 

       but we are learning a lot more about the airway

 

       biology in terms of lung transplantation.

 

                 On my last slide I want to just emphasize

 

       that although I might expect systemic

 

       immunosuppression to clear up a perivascular

 

       process, I am suggesting that bronchiolitis

 

       obliterans, chronic rejection, is an airway process

 

       and it makes eminent sense to employ inhaled
 

 

 

 

 

                                                                 36

 

       cyclosporine to treat the epithelium.  It is clear

 

       now that the epithelium is key to the development

 

       of bronchiolitis obliterans.  Bronchiolitis

 

       obliterans is an airway disease.

 

                 Just to finish, my colleagues in the lung

 

       transplant world are very excited about the

 

       potential benefit of inhaled cyclosporine.  As I

 

       say, the epithelium is key and it makes eminent

 

       sense to develop a system of local immune

 

       suppression to the airway and the mucosa.  Frankly,

 

       given the poor survival of our transplant

 

       recipients which, as I already mentioned, has not

 

       changed in almost 20 years, I personally feel that

 

       inhaled cyclosporine fulfills an unmet need.

 

                 I questioned whether I was going to say

 

       the following but I think I will.  On a personal

 

       note, for people like myself who take care of these

 

       patients, who see them terribly short of breath in

 

       various diagnostic categories who go on to have a

 

       lung transplant and then regain a normal life,

 

       including family life, going back to work--to all

 

       of a sudden see these patients once again slowly
 

 

 

 

 

                                                                 37

 

       develop progressive airway rejection, chronic

 

       rejection and shortness of breath is extremely

 

       disheartening to the patients, to say the least,

 

       their family and, frankly, for their physicians.

 

       Thank you for your attention.

 

                 Clinical Evidence of Efficacy and Safety

 

                 DR. NOONBERG:  Good morning.  My name is

 

       Sarah Noonberg and I am the clinical leader for the

 

       inhaled cyclosporine project.  Over the next 45

 

       minutes I will be reviewing the clinical data

 

       supporting the use of inhaled cyclosporine in lung

 

       transplant recipients.

 

                 I will begin with a brief discussion of

 

       early preclinical and open-label clinical trials of

 

       inhaled cyclosporine at UPMC.  These trials

 

       generated a lot of interest in inhaled cyclosporine

 

       and really set the stage for the pivotal

 

       randomized, double-blind, placebo-controlled trial

 

       which we, at Chiron, refer to as ACS001.

 

                 I will then describe the study design and

 

       baseline characteristics of patients in ACS001

 

       before moving into a discussion of efficacy,
 

 

 

 

 

                                                                 38

 

       focusing primarily on the endpoints of survival and

 

       chronic rejection.  I will then switch gears and

 

       summarize the safety data that has been generated

 

       for inhaled cyclosporine from a safety database of

 

       102 patients.  Although the favorable safety

 

       profile is clearly an important aspect of the drug,

 

       I am going to be spending much less time reviewing

 

       safety listings as this is an area of general

 

       agreement with the FDA.

 

                 Finally, as with all studies, there are

 

       limitations to ACS001 both with respect to study

 

       design, as well as choice of the primary endpoint.

 

       I am going to end this presentation with a

 

       discussion of some of those limitations and how we

 

       view them in light of the clear strengths of the

 

       study.

 

                 As Dr. Golden has described, the

 

       introduction of cyclosporine as an

 

       immunosuppressant truly revolutionized lung

 

       transplantation and allowed for the possibility of

 

       long-term survival.  Within a few years of FDA

 

       approval investigators at UPMC began to develop an
 

 

 

 

 

                                                                 39

 

       aerosolized formulation, and within five years they

 

       initiated preclinical trials.

 

                 In the first set of experiments

 

       non-transplanted dogs were given a single dose of

 

       inhaled cyclosporine.  The dose was well tolerated

 

       and revealed that pulmonary concentrations were

 

       10- to 100-fold higher than concentrations in other

 

       tissues.  In addition, there was no change in lung

 

       function and no histologic abnormalities.

 

                 In a canine lung transplant model dogs

 

       were given single agent immunosuppression with

 

       inhaled cyclosporine and investigators reported a

 

       dose-dependent decrease in the frequency and

 

       severity of allograft rejection.

 

                 In a rat transplant model rats were given

 

       an identical dose of either inhaled cyclosporine or

 

       intramuscular cyclosporine.  Inhaled cyclosporine

 

       was found to be at least as effective as

 

       intramuscular cyclosporine in causing a

 

       dose-dependent decrease in proinflammatory cytokine

 

       production, as well as a decrease in allograft

 

       rejection but with far lower systemic exposure to
 

 

 

 

 

                                                                 40

 

       cyclosporine.

 

                 These encouraging preclinical results led

 

       to the development of a series of open-label

 

       non-comparative trials with inhaled cyclosporine at

 

       UPMC.  These trials enrolled two different groups

 

       of patients, both with established complications of

 

       lung transplantation.  In the first set of

 

       protocols lung transplant recipients with

 

       documented chronic rejection were given inhaled

 

       cyclosporine in addition to their standard

 

       immunosuppressive regimen.  Investigators reported

 

       improvement in rejection histology and

 

       stabilization of pulmonary function relative to

 

       pre-enrollment data.  But, more importantly, these

 

       patients had improved survival both compared to

 

       contemporary UPMC unenrolled controls as well as

 

       controls from a historical lung transplant

 

       registry.

 

                 In the next set of protocols patients with

 

       refractory acute rejection, defined as acute

 

       rejection that failed to respond to

 

       immunosuppressive intensification--this represents
 

 

 

 

 

                                                                 41

 

       a step earlier in the disease process as acute

 

       rejection--as a risk factor for the subsequent

 

       development of chronic rejection and was the

 

       logical next population to study.  When these

 

       patients were given inhaled cyclosporine, again, in

 

       addition to their standard immunosuppressive

 

       regimen, investigators reported an improvement in

 

       rejection histology, a reduction in proinflammatory

 

       cytokine production, and a dose-dependent increase

 

       in pulmonary function, all relative to

 

       re-enrollment data.  Once again, these patients had

 

       improved survival compared to contemporary UPMC

 

       unenrolled controls.

 

                 Despite the non-comparative nature of

 

       these trials and their inherent limitations, they

 

       made quite an impact in the transplant community,

 

       and have led to unregulated compounding of inhaled

 

       cyclosporine by a number of U.S. transplant

 

       centers.  In a survey of 2002, published in Chest,

 

       of transplant practices 10 percent of U.S.

 

       transplant centers already used inhaled

 

       cyclosporine.  They compound it in their pharmacies
 

 

 

 

 

                                                                 42

 

       and they give it to patients with progressive

 

       chronic rejection.

 

                 These open-label trials were clearly

 

       provocative but their interpretation is limited by

 

       the lack of an adequate control group.  However,

 

       they laid the framework for the very first and one

 

       of the only randomized, double-blind,

 

       placebo-controlled trials in the lung transplant

 

       population.  Unlike the previous protocols that

 

       enrolled patients with established complications of

 

       lung transplantation, this trial was designed to

 

       test the efficacy of inhaled cyclosporine in

 

       preventing rejection and improving outcomes when

 

       given prophylactically to patients shortly after

 

       their single or double lung transplant procedure.

 

                 The trial had two phases.  In a pilot

 

       phase, the first phase, 10 patients were given

 

       open-label inhaled cyclosporine and were followed

 

       prospectively.  They formed a cohort designed to

 

       test the safety and tolerability of the drug in

 

       this patient population.  In the second phase, the

 

       randomized phase, 58 patients were randomized and
 

 

 

 

 

                                                                 43

 

       56 were randomized and treated with either inhaled

 

       cyclosporine or placebo, which in this case was

 

       inhaled propylene glycol, the vehicle used to

 

       create the inhalation solution.  The primary

 

       endpoint of the study was rate of acute rejection,

 

       and secondary, prospectively defined endpoints of

 

       survival, rate of chronic rejection and pulmonary

 

       function.

 

                 The criteria for enrollment into ACS001

 

       were fairly straightforward.  To be included, you

 

       had to be a recipient of a single or double lung

 

       transplant and be 18 years of age or older.

 

       Exclusion criteria included the presence of active

 

       fungal or bacterial pneumonia or anastomotic

 

       infections prior to the initiation of appropriate

 

       antimicrobial therapy.  Patients with bronchial

 

       stenosis greater than 80 percent had to be treated

 

       with standard techniques prior to enrollment.

 

       Patients who failed to wean from mechanical

 

       ventilation and women of childbearing potential

 

       unwilling to use birth control were also excluded.

 

       It is important to note that all patients met study
 

 

 

 

 

                                                                 44

 

       inclusion and exclusion criteria.

 

                 All patients in ACS001 were treated with

 

       standard-of-care immunosuppressive therapy

 

       following transplantation, and all were randomized

 

       and enrolled within the first 7-42 days following

 

       their transplant surgery.  A total of 26 patients

 

       were treated with inhaled cyclosporine and 30 were

 

       treated with placebo.  All patients underwent an

 

       initial 10-day dose escalation period where they

 

       were initiated on low dose inhaled cyclosporine at

 

       100 mg, and that dose or equivalent volume of

 

       placebo was gradually increased to a maximally

 

       tolerated dose up to a protocol-specified maximum

 

       of 300 mg.  The dose or equivalent volume that they

 

       reached on day 10 was the dose that they continued

 

       3 times a week for a period of 2 years.

 

                 After completion of dosing patients

 

       continued to be followed for study endpoints up to

 

       the study end date of August 21, 2003.  This

 

       corresponded to 2 years after the last patient was

 

       enrolled and, therefore, could complete their

 

       2-year period of dosing.  Therefore, the total
 

 

 

 

 

                                                                 45

 

       length of follow-up per patient depended on the

 

       timing of enrollment and ranged from 24 months for

 

       the last patient enrolled up through 56 months for

 

       the first patient enrolled.

 

                 ACS001 was a randomized trial, and the

 

       randomization scheme was developed by the

 

       Department of Statistics at the University of

 

       Pittsburgh.  The randomization was stratified by

 

       CMV mismatch, defined as donor positive/recipient

 

       negative, versus all other combinations.  This was

 

       chosen because international registry data has

 

       demonstrated that patients with CMV mismatch have a

 

       32 percent increased relative risk of death in the

 

       first year compared with other combinations, with a

 

       p value of less than 0.0001.  Therefore, the

 

       assertion that the randomization was not stratified

 

       by any variables known to affect outcome is

 

       incorrect.  The randomization was also stratified

 

       by enrollment period and distinguishes patients who

 

       generally had a less complicated postoperative

 

       course, were stable and met exclusion criteria by

 

       7-21 days versus those that had a relatively more
 

 

 

 

 

                                                                 46

 

       complicated postoperative course and met exclusion

 

       criteria and were stable between 22 and 42 days

 

       after the surgery.  In line with ICH guidelines, it

 

       is impractical and often counterproductive to

 

       stratify by more than 2 factors in a study of this

 

       size.

 

                 This slide illustrates the baseline

 

       characteristics of patients enrolled in ACS001.

 

       Overall, the two groups were well matched with

 

       respect to the majority of relevant baseline

 

       demographic characteristics.  Donors were similarly

 

       well matched for clinically relevant variables.

 

       However, as can be expected from any randomized

 

       study, there were a few important imbalances.  The

 

       two variables where clinically relevant imbalances

 

       existed were with respect to primary diagnosis and

 

       transplant type.

 

                 As Dr. Golden has demonstrated, the

 

       primary diagnosis leading to transplantation can

 

       have an important impact on survival.  Patients

 

       with COPD have traditionally been associated with

 

       better outcomes, especially within the first year,
 

 

 

 

 

                                                                 47

 

       and this is statistically significant.  Nearly

 

       twice as many placebo patients had this more

 

       favorable diagnosis.  In addition, patients with

 

       idiopathic pulmonary fibrosis or IPF have

 

       historically had among the worst survival, both

 

       short-term and long-term, and this is statistically

 

       significant at one year and at five years, and

 

       there were far more patients with IPF in the

 

       inhaled cyclosporine group compared to placebo.

 

       Both of these factors together could potentially

 

       bias results for better outcomes in the placebo

 

       group.

 

                 By contrast, double lung transplant

 

       recipients have historically had marginally

 

       improved survival compared to single lung

 

       transplant recipients in the first several years,

 

       and this difference becomes increasingly pronounced

 

       with time but is not statistically significant at

 

       one year or at five years, the time period of

 

       interest for ACS001.  However, there were more

 

       double lung transplant recipients in the inhaled

 

       cyclosporine group and this could potentially bias
 

 

 

 

 

                                                                 48

 

       results towards better outcomes in the inhaled

 

       cyclosporine group.  Therefore, although imbalances

 

       exist, they are split between groups and would not

 

       be expected to strongly influence results in one

 

       direction or the other.

 

                 The protocol specified that patients were

 

       to continue study drug for a period of two years.

 

       However, due to the nature of the patient

 

       population with its high mortality rate, frequent

 

       complications and frequent hospitalizations, not

 

       all patients could complete the two-year period of

 

       dosing and this is not surprising.  Roughly

 

       two-thirds completed at least one year of therapy

 

       and roughly half completed the full two years of

 

       therapy.  As the protocol specified that dosing

 

       should be held temporarily in the presence of an

 

       infection not responding to treatment, not all

 

       patients had each and every one of their scheduled

 

       doses.  However, this just reflects the protocol

 

       rather than any lack of compliance.

 

                 The median duration of dosing was

 

       comparable among the two groups.  Of the patients
 

 

 

 

 

                                                                 49

 

       that did prematurely discontinue dosing, the

 

       primary reasons were adverse events in the placebo

 

       group and withdrawal of consent in the inhaled

 

       cyclosporine group.  Of the six who withdrew

 

       consent, two were due to early tolerability

 

       problems; two were primarily due to unrelated

 

       medical problems; and one was due primarily to an

 

       unrelated social problem and for one the reason was

 

       unknown.

 

                 Although no patients were lost to

 

       follow-up, five patients, three in the inhaled

 

       cyclosporine group and one in the placebo group,

 

       were taken off the study, the randomized trial, and

 

       crossed over into an open-label rescue protocol of

 

       inhaled cyclosporine.  Their data was censored at

 

       the time of crossover and the treatment groups

 

       remained blinded.  In both groups there were

 

       patients that were withdrawn due to protocol

 

       deviations and violations that largely included

 

       medical non-compliance and smoking.

 

                 This slide summarizes the important

 

       efficacy and safety results from study ACS001. 
 

 

 

 

 

                                                                 50

 

       Treatment with inhaled cyclosporine led to

 

       significantly improved survival and chronic

 

       rejection-free survival compared to placebo but did

 

       not affect the rate of acute rejection.  Treatment

 

       with inhaled cyclosporine was not associated with

 

       increased risk of nephrotoxicity, infections,

 

       malignancies or any systemic toxicities known to

 

       occur when cyclosporine is given orally or

 

       intravenously.  However, similar to other inhaled

 

       drugs, inhaled cyclosporine was associated with

 

       mild to moderate respiratory tract irritation and

 

       bronchospasm.

 

                 I will first discuss the effect of inhaled

 

       cyclosporine on survival.  Using an unadjusted

 

       analysis, inhaled cyclosporine was associated with

 

       a significant survival advantage compared to

 

       placebo, with a relative risk of death of 0.213 and

 

       a p value of 0.007.  This corresponds to a 79

 

       percent decreased risk of death in patients treated

 

       with inhaled cyclosporine compared to placebo.

 

       This slide is the Kaplan-Meier plot of survival

 

       duration from the time of transplantation to the
 

 

 

 

 

                                                                 51

 

       study end date, and is the primary reason that we

 

       are all here today.

 

                 During the period of the study there were

 

       3 deaths in the inhaled cyclosporine group compared

 

       to 14 deaths in the placebo group.  The results are

 

       not only highly statistically significant but also

 

       clinically very important.  This is the first time

 

       a cohort of lung transplant recipients has had

 

       survival comparable to recipients of other solid

 

       organ transplants and marks a major advance in

 

       outcomes for this patient population.

 

                 The importance of an unadjusted analysis

 

       rests on its robustness and how well it compares to

 

       analyses that control for other baseline

 

       characteristics that might affect outcome.

 

       Therefore, we performed univariate analyses

 

       adjusting for potential risk factors that might

 

       affect survival, and found that the relative risk

 

       of death and the p values were remarkably

 

       consistent.

 

                 This graph illustrates the relative risk

 

       of death and 95 confidence intervals when the
 

 

 

 

 

                                                                 52

 

       survival data is adjusted by a number of different

 

       factors that have been documented in the literature

 

       to potentially affect outcome.  We also include two

 

       factors suggested by the FDA, ICU time after

 

       transplantation and the use of donors who at some

 

       point during their hospitalization prior to

 

       harvesting were treated with an inotrope.  Neither

 

       of these two factors is supported by the literature

 

       or registry data as having an impact on survival.

 

       For the case of donor inotrope use, it is not

 

       considered in guidelines for optimal donors or

 

       marginal donors.  However, the key message is that

 

       regardless of the baseline characteristic none of

 

       these factors appreciably impacts the relative risk

 

       of death and lends strong support to the validity

 

       of the unadjusted analysis, and this is what is

 

       meant by a robust endpoint.

 

                 In order to further test the robustness of

 

       the survival endpoint, we performed multivariate

 

       analyses which adjust for clinically relevant

 

       baseline characteristics simultaneously.  As not

 

       all characteristics can ever be simultaneously
 

 

 

 

 

                                                                 53

 

       input into a single statistical model, the job of

 

       the clinician is to decide which of these are the

 

       most clinically relevant.

 

                 In order to determine the most clinically

 

       relevant factors we searched through the literature

 

       to determine those that had been documented to be

 

       short-term or long-term prognostic factors.  We

 

       then reviewed registry data to determine the level

 

       of significance and, finally, we discussed these

 

       factors with transplant physicians who care for

 

       these patients.  The general agreement was that the

 

       most clinically relevant factors were transplant

 

       type, CMV mismatch, primary diagnosis, early acute

 

       rejection--all shown in green.  We also include in

 

       our model the variable of enrollment period as this

 

       was a randomization stratification variable and it

 

       is in accordance with ICH guidelines.

 

                 This slide also illustrates the relative

 

       distribution of 16 different baseline

 

       characteristics that have been documented in the

 

       literature to potentially affect short-term or

 

       long-term outcome.  As is evident, the majority are
 

 

 

 

 

                                                                 54

 

       balanced or, if anything, would favor better

 

       outcomes in the placebo group.

 

                 This slide illustrates the results of the

 

       multivariate analyses when these factors are

 

       successively added into a Cox proportional hazards

 

       model.  The key point is the consistency of the

 

       treatment effect.  The addition of the five most

 

       clinically relevant factors into this study does

 

       not have any appreciable impact on the relative

 

       risk of death or the p values, and provides even

 

       further support for the robustness of the survival

 

       endpoint.

 

                 Robustness was further evaluated by

 

       performing a number of sensitivity analyses around

 

       the survival endpoint.  When we did so, we found

 

       that the relative risk of death remained

 

       consistent.  The top row illustrates the unadjusted

 

       analysis on the full data set.  When we include

 

       patients who were randomized and treated the

 

       results are essentially unchanged.  When we look at

 

       survival relative to first dose of study drug

 

       rather than time of transplantation, again the
 

 

 

 

 

                                                                 55

 

       results are essentially unchanged.  When we exclude

 

       three placebo patients who had early mortality and

 

       died within the first three months--when we just

 

       take them out of the analysis and we only analyze

 

       the remaining 27, it remains statistically

 

       significant.  When we take out 14 patients who did

 

       not receive at least 80 percent of the protocol

 

       maximum dosing adjusted for death, we lose 25

 

       percent of the sample size but still maintain

 

       statistical significance and the relative risk of

 

       death is barely altered.

 

                 The FDA has raised concern about the

 

       effects of early pneumonia.  So, if we remove from

 

       analysis 15 patients who had an episode of

 

       pneumonia within one month of initiation of study

 

       drug we have lost greater than 25 percent of the

 

       patient population and, therefore, expect that the

 

       p value is going to increase but the key point is

 

       that the relative risk of death, the treatment

 

       effect, is barely changed.

 

                 Questions have also been raised about the

 

       effects of ICU time after transplantation.  If five
 

 

 

 

 

                                                                 56

 

       patients who were in the ICU greater than 14 days

 

       were removed from analysis, the results are

 

       statistically significant and in favor of the

 

       inhaled cyclosporine group.  Therefore, we have

 

       looked at the survival data from a number of

 

       different angles and found the survival data to be

 

       robust.

 

                 To assess the duration of the survival

 

       benefit we collected additional survival data 10

 

       months after the study ended, and we found that the

 

       survival benefit persisted.  At that point there

 

       were 5 deaths in the inhaled cyclosporine group

 

       compared to 15 deaths in the placebo group, with a

 

       p value of 0.017.

 

                 This post-study follow-up is important and

 

       it is useful and supportive data.  However, it has

 

       its limitations.  The first is that the study had

 

       ended and it ended almost a year earlier.  The data

 

       was analyzed and patients were unblinded; treatment

 

       groups were known.  In addition, except for those

 

       patients who had crossed over into an open-label

 

       protocol, all patients were off study drug for a
 

 

 

 

 

                                                                 57

 

       substantial period of time, ranging anywhere from

 

       10 months to a maximum of 3.5 years.  When you

 

       consider that the median time to diagnosis of

 

       chronic rejection is 16-20 months, it is going to

 

       confound the results.  Also, there were placebo

 

       patients that had crossed over and were now

 

       receiving inhaled cyclosporine so the net effect,

 

       as expected, is that it is going to trend toward

 

       the null.

 

                 This is what the FDA refers to as the

 

       five-year data and believes that it is the most

 

       appropriate time point to analyze the survival

 

       data, but for the reasons that I have just

 

       described we disagree and we believe that the data

 

       is best analyzed at the prospectively defined study

 

       end date.

 

                 In order to verify that the placebo

 

       population was representative of what would be

 

       expected in a larger U.S. transplant population,

 

       the placebo survival curve was compared with data

 

       from the United Network for Organ Sharing, or UNOS,

 

       that maintains a large transplant registry. 
 

 

 

 

 

                                                                 58

 

       Placebo patients were matched with UNOS controls

 

       who were transplanted during the same period of

 

       enrollment as ACS001, and they were matched by the

 

       variables on the slide.  Matching also excluded

 

       patients who died before they could have possibly

 

       enrolled into ACS001.

 

                 This slide illustrates the results and

 

       shows that both early mortality and late mortality

 

       in the placebo group are extremely consistent with

 

       what is expected in a larger multicenter patient

 

       population.  Roughly 50 percent survival at 4.5

 

       years is exactly what has been documented in the

 

       literature for years.  Therefore, any analyses that

 

       exclude early deaths or late deaths or deaths due

 

       to particular causes have to be viewed with caution

 

       as they would no longer lead to a placebo group

 

       whose survival is representative.  By comparison,

 

       when the ACS001 inhaled cyclosporine group is

 

       compared to the UNOS controls the relative risk of

 

       death of 0.252 is very comparable to what was seen

 

       in ACS001 where the relative risk of death was

 

       0.213.
 

 

 

 

 

                                                                 59

 

                 This is a busy slide but it makes a very

 

       important point and brings us into our next topic,

 

       namely, the primary reason for the improved

 

       survival in patients treated with inhaled

 

       cyclosporine is that inhaled cyclosporine prevented

 

       chronic rejection.  This slide illustrates the

 

       timing and cause of death for both groups.  As

 

       expected, early deaths were predominantly due to

 

       infectious causes.  However, subsequently nearly

 

       all deaths are associated with chronic rejection.

 

       Of the five deaths that the agency calls attention

 

       to in the mid portion of the graph as driving the

 

       statistical significance, four out of the five had

 

       chronic rejection.  By contrast, in the inhaled

 

       cyclosporine group the curve becomes flat and late

 

       mortality is not occurring.

 

                 One question that has been raised is why

 

       is the survival difference statistically different

 

       at two years when all patients would have completed

 

       their study drug.  The reason, as evident from this

 

       graph, is that chronic rejection is the predominant

 

       cause of death in the first year so you wouldn't
 

 

 

 

 

                                                                 60

 

       expect to see early large separation of the two

 

       curves.  However, after a year it is the major

 

       contributor, as Dr. Golden has demonstrated, to

 

       mortality.

 

                 To review, chronic rejection is an

 

       umbrella term for patients with histologic evidence

 

       of bronchiolitis obliterans, or OB, documented by

 

       transbronchial biopsy.  It is also representative

 

       of patients with clinical evidence of bronchiolitis

 

       obliterans syndrome, or BOS, using a sustained and

 

       unexplained decline in FEV1 as a surrogate marker.

 

       It is not uncommon for patients to have

 

       bronchiolitis obliterans but, due to the

 

       progressive nature, they haven't met clinical

 

       criteria for BOS.  It is also not uncommon for

 

       patients to have BOS but, due to the insensitive

 

       nature of transbronchial biopsy in making the

 

       diagnosis they don't have OB.  So, these two

 

       groups, patients with OB and patients with BOS, are

 

       overlapping but they all represent patients with

 

       chronic rejection.  So, looking at each group

 

       individually may be informative but it has to be
 

 

 

 

 

                                                                 61

 

       viewed as a subset analysis.  Consistent with

 

       direct delivery to the airway epithelium, the site

 

       of chronic rejection, treatment with inhaled

 

       cyclosporine led to a 72 percent decrease in the

 

       risk of chronic rejection or death.  As you will

 

       see, when we performed the same univariate and

 

       multivariate analyses, the results are even more

 

       robust.

 

                 This slide illustrates the Kaplan-Meier

 

       estimate of chronic rejection-free survival and

 

       uses a composite endpoint of first diagnosis of OB,

 

       first diagnosis of BOS or death.  There are two

 

       important points here.  One is that there is

 

       general agreement with the FDA that the rate of

 

       biopsy and the rate of pulmonary function testing

 

       is comparable between the two groups so that the

 

       difference isn't driven by increased testing in one

 

       group or the other.

 

                 The second is that the use of a composite

 

       endpoint of chronic rejection and death implies

 

       that patients who die and, therefore, can't go on

 

       to be diagnosed with chronic rejection are counted
 

 

 

 

 

                                                                 62

 

       as events rather than censored in the statistical

 

       analysis.  To censor deaths in a statistical

 

       analysis of chronic rejection would require the

 

       assumption that there is no relationship between

 

       chronic rejection and death, an assumption that we

 

       know to be invalid.

 

                 The agency issued guidelines in April of

 

       2005 endorsing a progression-free survival analysis

 

       for similar oncology endpoints to avoid a type of

 

       bias known as informative censoring.  As with the

 

       survival endpoint, we found a remarkable

 

       consistency of the chronic rejection-free survival

 

       endpoint when we performed a series of univariate

 

       analyses.  None of these baseline characteristics

 

       had any appreciable impact on the treatment effect

 

       or its significance, which speaks to the robustness

 

       of this endpoint as well.

 

                 This slide illustrates the result of

 

       multivariate analyses on the chronic rejection-free

 

       survival endpoint.  Once again, the addition of the

 

       5 most clinically relevant factors in this

 

       study--adding them into a Cox proportional hazards
 

 

 

 

 

                                                                 63

 

       model has essentially no real impact on the

 

       treatment effect of the confidence intervals and

 

       the p values remain highly statistically

 

       significant.

 

                 Valid questions have been raised about

 

       whether the survival benefit is so strong that any

 

       composite endpoint that includes survival would be

 

       statistically significant.  Therefore, for

 

       exploratory reasons we performed an analysis of

 

       chronic rejection with death censored.  This

 

       clearly biases results against the inhaled

 

       cyclosporine group due to the larger number of

 

       deaths in the placebo group.  As mentioned, this is

 

       referred to as informative censoring.  However that

 

       said, when we performed the analysis the results

 

       were still statistically significant and in favor

 

       of the inhaled cyclosporine group.  Chronic

 

       rejection occurred in 50 percent of placebo

 

       patients and 27 percent of inhaled cyclosporine

 

       patients.

 

                 This slide illustrates the Kaplan-Meier

 

       estimate of time to chronic rejection with deaths
 

 

 

 

 

                                                                 64

 

       censored and clearly illustrates a statistically

 

       significant effect on chronic rejection independent

 

       of death despite the large bias inherent in the

 

       analysis.  This analysis is important because it

 

       leads to the conclusion that treatment with inhaled

 

       cyclosporine prevents chronic rejection, the

 

       leading cause of late mortality in lung transplant

 

       patients.

 

                 However, the primary endpoint of the study

 

       was not survival or chronic rejection but rate of

 

       acute rejection and this endpoint was not met.

 

       Approximately 70 percent of patients in both groups

 

       had at least 1 episode of documented grade 2 or

 

       higher acute rejection prior to study termination.

 

       After the start of dosing rates were comparable

 

       between the 2 groups, with a p value of 0.73.

 

                 Dr. Golden has explained the paradigm

 

       shift that has occurred in the transplant community

 

       in terms of how acute and chronic rejection are now

 

       understood.  Acute rejection is primarily a

 

       vascular process so an immunosuppressant with low

 

       vascular exposure would not be expected to have a
 

 

 

 

 

                                                                 65

 

       significant effect, and that is what we are seeing

 

       in ACS001.  By contrast, chronic rejection is an

 

       airway process.  It is mediated in the airway

 

       epithelium so an immunosuppressant delivered

 

       directly to the airway epithelium would be expected

 

       to have an effect, and that too is what we are

 

       seeing in ACS001.

 

                 Now I am going to switch gears and briefly

 

       discuss safety.  This slide illustrates the

 

       relative systemic exposure to cyclosporine when

 

       given by an inhalation route compared to an oral

 

       route.  A 300 mg dose of inhaled cyclosporine has

 

       been demonstrated to lead to a mean peak blood

 

       concentration of 206 ng/mL, roughly 11-14 percent

 

       of what you would expect in an oral dose.  the

 

       levels at 24 hours are barely detectable by

 

       standard assays, and these numbers are reflected in

 

       the mean AUC, or area under the curve, which

 

       suggests a roughly 8-fold lower systemic exposure

 

       to cyclosporine when it is given by an inhaled

 

       route compared to an oral route.  This low systemic

 

       exposure explains why no additional systemic
 

 

 

 

 

                                                                 66

 

       toxicities were seen in the inhaled cyclosporine

 

       group compared to placebo.

 

                 Data to support the safety of inhaled

 

       cyclosporine and propylene glycol come from

 

       multiple sources, and this is outlined in much

 

       further detail in the briefing book.  The first are

 

       preclinical toxicology studies in dogs and rats,

 

       performed both by Chiron as well as referenced in

 

       the literature.  These studies show that no

 

       unexpected toxicities were seen when animals were

 

       treated at many-fold higher doses than what would

 

       be used clinically.

 

                 The next source is the randomized,

 

       placebo-controlled ACS001 trial where safety data

 

       from 30 placebo patients were compared with safety

 

       data from 36 inhaled cyclosporine patients, the 26

 

       randomized and the 10 placebo.

 

                 The next source is ACS002, which was a

 

       retrospective safety analysis of 70 patients

 

       enrolled in 1/7 different open-label protocols of

 

       inhaled cyclosporine in patients with refractory

 

       acute and chronic rejection.  The ISS, or
 

 

 

 

 

                                                                 67

 

       integrated safety summary, is a combination of all

 

       patients treated with inhaled cyclosporine in

 

       either ACS001 or ACS002 and represents 102 unique

 

       patients in our safety database.

 

                 To summarize our clinical safety data,

 

       review of the adverse event listings in ACS001

 

       revealed that inhaled cyclosporine was safe.  There

 

       was no increased risk of nephrotoxicity,

 

       neurotoxicity, infections, malignancies or any

 

       other toxicities that occur with oral or

 

       intravenous cyclosporine.  In addition, there were

 

       no new or unexpected systemic toxicities.

 

                 So, the key point is that treatment with

 

       inhaled cyclosporine led to a 79 percent decreased

 

       risk of death compared to placebo, with no systemic

 

       toxicity.  However, inhaled cyclosporine was

 

       associated with respiratory tract irritation and

 

       bronchospasm and this will be discussed in the next

 

       slide.  Review of adverse event data in ACS002 and

 

       the ISS confirmed the safety findings of ACS001,

 

       and no new safety signals were seen after review of

 

       the serious adverse event data.
 

 

 

 

 

                                                                 68

 

                 After review of the ACS001 adverse event

 

       listings and case report forms, it became clear

 

       that there were two distinct but interrelated

 

       safety signals that appeared to be a direct result

 

       of inhaled cyclosporine.  The first was

 

       bronchospasm manifested primarily by cough,

 

       exacerbated dyspnea and wheezing.  The second was

 

       respiratory tract irritation manifested primarily

 

       by pharyngitis but also laryngitis and non-cardiac

 

       chest pain.  In general, these events were mild to

 

       moderate.  They occurred early in the patient's

 

       treatment course and diminished with time, and once

 

       they resolved it was rare for them to recur.  But,

 

       most importantly, there was no progression to more

 

       serious respiratory complications such as acute

 

       respiratory failure or ARDS.  The adverse event of

 

       lung consolidation was noted in higher frequency in

 

       the inhaled cyclosporine group but the clinical

 

       relevance of this finding is unclear as underlying

 

       causes such as pneumonia, lung mass, atelectases or

 

       other underlying causes were comparable between the

 

       2 groups.
 

 

 

 

 

                                                                 69

 

                 Having reviewed the most important

 

       clinical results for inhaled cyclosporine, it is

 

       appropriate to take a step back and take a look at

 

       some of the outstanding issues surrounding the

 

       data.  Study ACS001 was conducted at a single

 

       center, and this was discussed with the FDA well

 

       before Chiron decided to move ahead and file the

 

       NDA.  However, it is important to note that no

 

       other transplant studies or registry analyses have

 

       ever shown a survival benefit comparable to what

 

       was seen in the inhaled cyclosporine group of

 

       ACS001.

 

                 We also looked at the placebo group and

 

       found that survival was comparable to a multicenter

 

       matched database.  Single-center trials are not

 

       ideal.  However, they do have one important

 

       advantage.  Because confounding due to differences

 

       in patient care is minimized, single-center trials

 

       are actually better at determining a treatment

 

       effect than multicenter trials of the same size.

 

       Finally, Chiron has committed to a multicenter

 

       postapproval trial to further study the efficacy
 

 

 

 

 

                                                                 70

 

       and safety of inhaled cyclosporine.

 

                 The sample size of N equals 56 for

 

       efficacy and N equals 102 for safety is small.

 

       However, the lung transplant population is

 

       exceedingly small, with 1100 lung transplants

 

       performed in the United States each year.  Despite

 

       the small sample size, the survival and chronic

 

       rejection data are highly statistically significant

 

       so the sample size was sufficient to test the

 

       hypothesis that inhaled cyclosporine improves

 

       survival and chronic rejection-free survival.

 

                 Cyclosporine and propylene glycol are

 

       well-known and well-characterized, and the safety

 

       profile of inhales cyclosporine is extremely

 

       favorable, especially in light of the survival

 

       benefit.  Again, Chiron has committed to creating a

 

       larger efficacy and safety database through a

 

       postapproval trial.

 

                 The randomization code was susceptible to

 

       unblinding and CRF assembly was retrospective.  The

 

       randomization code used a patient subject number

 

       followed by an A, B, C or D designation, with A and
 

 

 

 

 

                                                                 71

 

       D referring to placebo patients, B and C referring

 

       to inhaled cyclosporine patients, and it is

 

       possible that the study could have become unblinded

 

       due to the simple nature of this designation.

 

       However, there are several factors that make this

 

       very unlikely.  First is that the principal

 

       investigator was never exposed to the subject

 

       numbers.  Second, the investigator removed 3

 

       inhaled cyclosporine patients from the inhaled

 

       cyclosporine arm only to cross over into an inhaled

 

       cyclosporine open-label rescue protocol.  In

 

       addition, the pathologist reading the

 

       transbronchial biopsies and making the

 

       determination of bronchiolitis obliterans was never

 

       exposed to study numbers.

 

                 The issue with retrospective CRF assembly

 

       is whether somehow in the retrospective nature of

 

       filling out these forms an assessment of an outcome

 

       is altered.  However, when the outcome is death, or

 

       the presence or absence of bronchiolitis obliterans

 

       on an original histopathology report, or whether

 

       FEV1 has declined by 20 percent or more from a
 

 

 

 

 

                                                                 72

 

       post-transplant maximum, these are hard endpoints

 

       and would not be expected to be altered by

 

       retrospective CRF assembly.

 

                 Treatment groups were not balanced on each

 

       and every baseline characteristic.  The purpose of

 

       randomization is not to eliminate all imbalances

 

       but, rather, to randomly distribute them between

 

       groups.  The two treatment groups are comparable,

 

       and of the clinically relevant baseline

 

       characteristics we examined the majority are

 

       balanced or, if anything, would favor better

 

       outcomes in the placebo group.

 

                 Finally, when imbalances do occur in

 

       clinically relevant variables statistical models

 

       can be used to adjust for these both in univariate

 

       or multivariate analyses, and we have presented

 

       such analyses that show that the data is robust.

 

       So, we feel extremely confident in saying that

 

       baseline imbalances did not explain the efficacy of

 

       inhaled cyclosporine.

 

                 The study did not meet its primary

 

       endpoint of decreased rate of acute rejection. 
 

 

 

 

 

                                                                 73

 

       However, scientific understanding has evolved since

 

       the design of ACS001 and the lack of an effect on

 

       acute rejection is consistent with low systemic

 

       exposure.  The design of the study doesn't impact

 

       the assessment of survival or chronic rejection or

 

       alter how the data is obtained.  It is also

 

       important to note that survival and chronic

 

       rejection were prospectively defined secondary

 

       endpoints.  These analyses are not post hoc nor do

 

       they constitute data mining.

 

                 Finally, the survival and chronic

 

       rejection data are clinically important,

 

       statistically significant and scientifically sound.

 

       Inhaled cyclosporine is delivered directly to the

 

       airways, the site of chronic rejection.  Inhaled

 

       cyclosporine prevented chronic rejection and, in

 

       doing so, markedly improved survival.  The

 

       importance of this data is illustrated by the fact

 

       that physicians from 30 different transplant

 

       centers in the United States, which represents

 

       almost half of all active lung transplant centers,

 

       have requested early access to inhaled cyclosporine
 

 

 

 

 

                                                                 74

 

       as part of our early access program.

 

                 We have been advised to make it clear to

 

       the advisory committee where there are differences

 

       of opinion between Chiron and the FDA, and that is

 

       really why we are here today.  So, this slide

 

       illustrates five of the most important areas where

 

       we disagree.

 

                 First, we believe that covariates in a

 

       statistical model should be chosen based on an

 

       association with the clinical outcome rather than

 

       because of an imbalance.  In the case of ICU time,

 

       the use of ICU time greater than ten days, there is

 

       an imbalance toward the placebo group.  However,

 

       this is not documented to be associated with

 

       survival.  If an ICU time greater than seven days

 

       is chosen that imbalance is minimized, and if an

 

       ICU time greater than four days is chosen the

 

       imbalance is reversed.  We believe that it is

 

       important to differentiate patients who had an

 

       earlier, easier postoperative course from those who

 

       had a harder postoperative course, but believe that

 

       this is best accomplished by the randomization
 

 

 

 

 

                                                                 75

 

       stratification variable enrollment period, early

 

       versus late.

 

                 In the case of donor inotropic support, we

 

       have yet to find a single reference that even

 

       considers this variable, much less finds it

 

       clinically relevant and the FDA has called this one

 

       of the most clinically relevant factors in the

 

       study.

 

                 We do have variables and we do have data

 

       on donor quality through other variables that have

 

       been documented in the literature to be clinically

 

       important, such as donor age, donor bacterial

 

       colonization, donor graft, ischemic time, and these

 

       are balanced between the two groups.  The important

 

       point is that the use of a covariate that is

 

       imbalanced but not clinically relevant will always

 

       cause results to trend toward the null and that is

 

       what we have seen with the FDA analyses.

 

                 Second, in analyses of survival we

 

       disagree that patients whose use of donor inotrope

 

       or the donor inotrope data is missing--we disagree

 

       that these patients should be excluded from
 

 

 

 

 

                                                                 76

 

       analyses.  In the FDA analysis, by excluding

 

       long-term survivors in the inhaled cyclosporine

 

       group, the treatment effect and p values are going

 

       to be altered inappropriately.

 

                 Three, we believe that survival is best

 

       analyzed at the prospectively defined study end

 

       date rather than one year after--or nearly a year

 

       after the study was over.  I have already discussed

 

       our reasons for this.

 

                 Four, we believe that patients with

 

       bronchiolitis obliterans, or OB, should be included

 

       in an analysis of chronic rejection.  The diagnosis

 

       of OB has a specificity of over 95 percent.

 

       Patients with BOS and OB represent overlapping

 

       subsets and, therefore, to look at either one

 

       alone, we believe, is a subset analysis.

 

                 Finally, five, analyses of BOS should not

 

       censor deaths.  This is clearly informative

 

       censoring, and when deaths are not censored and

 

       BOS-free survival is analyzed the results are

 

       statistically significant and remain so when

 

       controlled for by CMV mismatch, primary diagnosis
 

 

 

 

 

                                                                 77

 

       and early  acute rejection.  Analyses that censor

 

       death can be informative but we have shown in our

 

       chronic rejection that although they can be

 

       informative they shouldn't be used as the primary

 

       analysis.

 

                 So, I would like to end with a summary of

 

       the clinical data that I presented.  In the lung

 

       transplant population with no appropriate approved

 

       drugs, very few randomized clinical trials and a

 

       dismal prognosis that hasn't changed in almost 20

 

       years, treatment with inhaled cyclosporine was

 

       associated with a 79 percent decrease in the risk

 

       of death.  Treatment with inhaled cyclosporine was

 

       associated with a 72 percent decrease in the risk

 

       of chronic rejection or death.  We have

 

       demonstrated that our efficacy results are robust

 

       through a number of different analyses.  We have

 

       also demonstrated that the ACS001 placebo

 

       population is representative of a larger U.S.

 

       transplant population.  We have demonstrated that

 

       treatment with inhaled cyclosporine was not

 

       associated with any systemic toxicities.  Finally,
 

 

 

 

 

                                                                 78

 

       inhaled cyclosporine was associated with local

 

       respiratory tract irritation and bronchospasm, a

 

       relatively small price to pay in light of the

 

       profound survival benefit.

 

                 Thank you.  I would like to end and turn

 

       this presentation over to Dr. Ronald Helms,

 

       Professor Emeritus of Biostatistics of the

 

       University of North Carolina, who is going to spend

 

       a few minutes discussing the statistical

 

       considerations of the study.

 

                        Statistical Considerations

 

                 DR. HELMS:  Thank you, and thank you for

 

       the opportunity to come and address this group here

 

       this morning.  My time is short so I am going to

 

       dive right in, if I may.

 

                 Why are we here?  Well, this survival

 

       curve tells why we are here, the profound

 

       difference in survival in these two treatment arms,

 

       as has been discussed at length already.

 

                 A second reason I am here is that this is

 

       a very interesting project, a very interesting

 

       project.  Let me first establish a disclaimer and
 

 

 

 

 

                                                                 79

 

       my conflict of interest issue.  The views that are

 

       expressed in this presentation are mine alone and

 

       do not represent either the FDA or Chiron or Rho,

 

       my current employer, or the University of North

 

       Carolina, my former employer.  It is possible that

 

       these views may represent the best interests of

 

       future lung transplant patients.  In terms of

 

       financial conflict of interest, neither Rho nor I

 

       have any financial stake in the outcome of this

 

       submission.  Less than half a percent of Rho's

 

       total income this year will come from Chiron.

 

       Chiron pays Rho an hourly consulting fee for my

 

       time plus travel expenses and, in fact, my board of

 

       directors told me they would prefer that I work on

 

       other projects that are more financially rewarding

 

       to the company.

 

                 [Laughter]

 

                 So, I am here despite that.  Also, neither

 

       Rho nor Chiron has edited my presentation and I

 

       have reviewed the briefing documents that you have

 

       seen from both the FDA and Chiron, plus some other

 

       more comprehensive documentation.  So, I feel
 

 

 

 

 

                                                                 80

 

       unconflicted here.

 

                 So, why am I here?  Well, coming back to

 

       the results of this study and the fact that it is a

 

       very interesting project--it is a very interesting

 

       project and we have a problem.  By "we" I mean the

 

       professionals sitting here around the table, the

 

       FDA professionals, the Chiron staff--we have a

 

       problem.

 

                 This Kaplan-Meier graph tells that this

 

       product has the potential to save the lives of a

 

       statistical number of lung transplant patients.

 

       The NDA does not meet the usual regulatory

 

       requirements for approval.  Should it be approved?

 

                 Well, there are advantages and

 

       disadvantages to approval in this case.  The

 

       results indicate that if approved, widespread use

 

       of this product would probably save the lives of

 

       around 300 to 350 lung transplant patients a year.

 

       Now, I should just comment that my comments here

 

       are really aimed at the non-statisticians on this

 

       panel.  The statisticians know how to interpret

 

       relative risk and those kinds of things.  I thought
 

 

 

 

 

                                                                 81

 

       it would be useful to translate this into lives

 

       saved after a period of time when the product was

 

       in widespread use.  It appears to improve the

 

       survival probability by about 30 or 35 percentage

 

       points.  You see the numbers there, somewhere

 

       around 50-90 percent, and there are about 1000 or

 

       1100 transplant patients so if you do the

 

       arithmetic it comes out to around 300 to 350 lung

 

       transplant lives saved a year.

 

                 Another advantage is--and this is a

 

       practical advantage--if this product were approved

 

       FDA could require Chiron to conduct the

 

       sufficiently large follow-up study that Chiron has

 

       proposed.  If the study were negative the approval

 

       could be withdrawn and, as a practical matter,

 

       without approval the follow-up study will never be

 

       done.  Off-label use of the product would

 

       ultimately become a standard of care and failure to

 

       use it would be considered unethical and subject to

 

       lawsuits and those sorts of things.  And it is an

 

       interesting aside that we have a very closely

 

       related case.  Cyclosporine, which is used
 

 

 

 

 

                                                                 82

 

       universally in the treatment of lung transplants,

 

       is not approved for that indication; it is all

 

       off-label use.  The studies have never been done.

 

                 There are some obvious obstacles to

 

       approval.  We have the results of only one small

 

       unconfirmed study.  This is a serious problem.  It

 

       is a serious problem.  This one study has a number

 

       of flaws that have been noted by both Chiron and

 

       FDA.  Here are some opinions, one of these is very

 

       important; some are potentially important; and some

 

       really are inconsequential in my opinion.

 

                 The very important flaw in this clinical

 

       trial from a statistical perspective is that the

 

       stated primary outcome was acute rejection, not

 

       mortality or survival.  The statistical methods

 

       that we routinely use for Phase III confirmatory

 

       studies aren't very helpful with this problem, the

 

       problem of switching the primary endpoint from what

 

       was stated in the protocol to a secondary endpoint.

 

       But good, old-fashioned common sense can be

 

       helpful.  When you see that big an effect on

 

       survival you very likely made an important
 

 

 

 

 

                                                                 83

 

       discovery.

 

                 Now, we could use, as statisticians, a

 

       branch of statistics called decision theory for

 

       formal risk-benefit analyses here but the fact is

 

       that if we did that the analyses would be based on

 

       a number of assumptions and if you are strongly

 

       opposed to approval here you challenge the

 

       assumptions, and rightly so.  The result is so big,

 

       the difference in survival is so big here that we

 

       can tell what the outcome would be anyway, that it

 

       would lead to a decision in favor of the product.

 

                 Some potentially important flaws--let me

 

       address those.  My time is brief and I won't go

 

       into statistical details but there is an important

 

       side note here.  At least as of a few weeks ago,

 

       the FDA and  Chiron biostatisticians had confirmed

 

       each other's statistical calculations.  The point

 

       is that there is no issue about correctness of

 

       populations.  Now, you are going to hear different

 

       perspectives obviously from Chiron and FDA.  In my

 

       opinion, the issues here are about how to use and

 

       interpret the statistics, not the actual results,
 

 

 

 

 

                                                                 84

 

       and I think that is good to know.

 

                 There are some potentially important flaws

 

       that have already been mentioned and you will hear

 

       some more about that in the FDA presentation.  The

 

       randomization, if done improperly, could be an

 

       important flaw; the lack of balance with respect to

 

       important baseline characteristics; unmasking or

 

       unblinding--we used to call it unblinding but then

 

       I worked with some ophthalmologists and they taught

 

       me to use the word "unmasking."  The study was

 

       conducted in such a manner that the investigators

 

       could have been unmasked essentially, and the study

 

       was conducted at a single clinical center, not

 

       multiple centers.

 

                 I want to cut to the chase because my time

 

       is limited.  The bottom line is I reviewed each of

 

       the potentially important flaws and my conclusions

 

       for each one were that each was either not a flaw

 

       at all or was relatively unimportant.  For example,

 

       the randomization failed to balance with respect to

 

       all the baseline factors.  It rarely does in

 

       clinical trials, even large clinical trials.  It
 

 

 

 

 

                                                                 85

 

       has been my experience over the last 15 years since

 

       I began looking at this that only one out of

 

       hundreds of clinical trials was balanced with

 

       respect to all important baseline factors.  So, it

 

       is not a case of failure.  On request, on somebody

 

       else's time, I will be happy to talk about some of

 

       these issues.

 

                 There are some unimportant flaws in the

 

       clinical trial, and they are listed there.  We

 

       don't have to spend time on that.

 

                 Let me raise an important ethical point

 

       for the members of the panel.  Suppose the data

 

       from this study were the results of an interim

 

       analysis half way through the study, and suppose

 

       the members of this advisory panel were instead

 

       sitting as the study's data and safety monitoring

 

       board, would we be ethically bound to terminate the

 

       study to protect future patients who might be

 

       assigned to placebo?  I suspect that many of you

 

       have sat as members of data and safety monitoring

 

       boards and faced precisely this question in the

 

       middle of a study.  I have.  And I believe that
 

 

 

 

 

                                                                 86

 

       everyone on the DSMBs in which I participated would

 

       have stopped this study to protect placebo

 

       patients, the results of the study are that

 

       compelling.

 

                 I think there is another important ethical

 

       point.  I think the people in this room--again, the

 

       FDA staff, the advisory panel, the Chiron

 

       staff--are ethically bound to find a way to make

 

       this product available on-label to U.S. lung

 

       transplant patients.  It will be used off-label.

 

       It already is being used off-label but without

 

       approval for some years this product will only be

 

       available to people who can afford to pay for it

 

       from their own funds because it won't be covered by

 

       insurance.  So, we have a product that would be

 

       made available to wealthy people and not others.

 

                 We also, I think, are ethically bound to

 

       find a way to make it necessary for Chiron to

 

       conduct the proposed postapproval follow-up study.

 

       If we don't, it won't be done.  Realistically, it

 

       can only be done as a postapproval study for

 

       financial reasons that Chiron can talk to you
 

 

 

 

 

                                                                 87

 

       about.

 

                 What an interesting project!  Thank you

 

       for the opportunity to talk to you.

 

                         Safety and Benefit-Risk

 

                 DR. DILLY:  Thank you, Prof. Helms and

 

       thank you, everyone, for your patience in following

 

       through our presentation.  I am going to conclude

 

       with about five minutes of remarks to end the

 

       Chiron presentation.

 

                 What I would like to do is consider some

 

       of the issues relevant to the potential approval of

 

       Pulminiq.  Clearly, we believe the best way to help

 

       lung transplant patients now is to make CyIS

 

       available.  Lung transplant, as you heard, is in

 

       many ways the poster child of the orphan drug

 

       indication.  Despite the incentive provided by the

 

       orphan drug designation, no drugs have been

 

       developed for lung transplantation, probably

 

       because the economics simply don't work for a

 

       conventional development program.  So, if we are

 

       looking for new drugs, it is going to come from

 

       sources like this.
 

 

 

 

 

                                                                 88

 

                 Now, we are not suggesting for a moment

 

       that the burden of evidence is any different for an

 

       orphan indication.  Rather, what we are suggesting

 

       is that we must consider the evidence that exists

 

       on its merit and, in fact, the case for approval of

 

       this drug is very strong.

 

                 The scientific premise for inhaled

 

       cyclosporine is extremely straightforward.  We are

 

       giving an effective drug, with systemic toxicity,

 

       by inhalation to achieve higher lung levels.  This

 

       has been done, of course, successfully in asthma,

 

       in COPD, in cystic fibrosis.  It is a well

 

       precedented approach.  In fact, as you heard, the

 

       idea is so straightforward that many lung

 

       transplant centers were already using inhaled

 

       cyclosporine empirically before the clinical data

 

       of ACS001 were known.

 

                 Of course, these are the essential

 

       clinical data.  Patients who received inhaled

 

       cyclosporine in the pivotal trial lived

 

       significantly longer than those who did not.  You

 

       have heard compelling arguments that the difference
 

 

 

 

 

                                                                 89

 

       in survival was due to inhaled cyclosporine and

 

       that the benefit is highly likely to be

 

       generalizable to other patients in other treatment

 

       centers.  Publication of these data will rightly

 

       have a major impact on the treatment of lung

 

       transplantation with or without approval of

 

       Pulminiq.  The case for benefit is very strong.

 

       Also as you have heard, there is very little risk

 

       of harm.  This is a known drug.  Local toxicity in

 

       the lung is minor and systemic exposure is not

 

       clinically important.  Finally, this is a very

 

       small population with an entirely clear-cut

 

       diagnosis, lung transplantation.  So, the chances

 

       of a major public health problem from broad usage

 

       is very, very small.  In other words, the

 

       demonstrated benefit far outweighs the potential

 

       for harm.  The bottom line is patients will live

 

       longer if inhaled cyclosporine is made available to

 

       them.

 

                 Of course, some questions remain open

 

       because of the nature of the clinical program

 

       conducted to date.  So, the right thing to do for
 

 

 

 

 

                                                                 90

 

       patients is to approve inhaled cyclosporine now and

 

       conduct the appropriate postapproval study to

 

       address those outstanding questions.  So, I would

 

       like to finish the Chiron comments by considering

 

       what that postapproval study should look like.

 

                 The central question really is how to give

 

       inhaled cyclosporine.  We have seen benefits from

 

       therapy lasting for up to two years.  All logic

 

       dictates that for a chronic rejection endpoint

 

       chronic therapy should be better.  We need to study

 

       that.  We need to study dosing beyond two years.

 

       We need to work on making the first few doses as

 

       tolerable as possible so we can get as many

 

       patients as possible onto an effective dosing

 

       regimen.

 

                 We would also love to know more about the

 

       interplay of the key clinical endpoints, survival,

 

       rejection, lung function.  You can only interpret

 

       so far based on a single, relatively small study

 

       with such a bright line survival effect.  We

 

       believe that 300 mg of inhaled cyclosporine by

 

       nebulizer three times a week is a perfectly
 

 

 

 

 

                                                                 91

 

       appropriate inhaled regimen and the right thing to

 

       put in the label, but there are some questions we

 

       need a bigger study to answer.

 

                 How do patients do if they actually

 

       tolerate a dose below 300 mg--100 mg or 200 mg?  Is

 

       the need for systemic dose intensification reduced

 

       with effective long-term inhaled therapy?  What is

 

       the best way to deal with treatment interruptions,

 

       for instance during concomitant illnesses?  Of

 

       course, it will be informative to have a much

 

       bigger safety experience.

 

                 So, here is our proposal, essentially this

 

       is a very large single-arm study with external

 

       controls.  We believe that we could draw the

 

       control arm now from the UNOS database.  From the

 

       comments you heard from Dr. Golden and others, we

 

       know what happens to lung transplant patients

 

       treated with current standard of care.  So, 250

 

       patients will be treated with a labeled regimen of

 

       inhaled cyclosporine for 5 years.  A placebo group

 

       is not appropriate and not necessary given the

 

       robust survival advantage already demonstrated with
 

 

 

 

 

                                                                 92

 

       inhaled cyclosporine.  There will be 2 external

 

       controls, firstly, about a thousand matched

 

       patients with long-term follow-on data drawn from

 

       the UNOS database.  Secondly, a group of

 

       contemporaneous controls who will not receive

 

       inhaled cyclosporine.  The exact size of this

 

       group, of course, will be somewhat dependent on the

 

       rapidity of uptake of inhaled cyclosporine therapy.

 

       So, we would expect that the availability of those

 

       patients would go down over time.

 

                 What I am attempting to describe to you

 

       here is a study that is entirely doable in the

 

       postapproval context.  The primary endpoint will be

 

       chronic rejection-free survival, with all-cause

 

       mortality and lung function as secondary endpoints.

 

       We see three safety endpoints as particularly

 

       interesting:  Firstly, infections requiring

 

       hospitalization because we believe that that signal

 

       in favor of the lower incidence of pneumonia on the

 

       inhaled cyclosporine group in ACS001 is probably

 

       real and due to decreased lung damage from chronic

 

       rejection, making the lungs less susceptible to
 

 

 

 

 

                                                                 93

 

       infection.  Secondly, we want to look at renal

 

       dysfunction and malignancy as readouts of systemic

 

       immunosuppressive status, as well as diligent

 

       follow-up for the other safety events.  In fact,

 

       this will be the largest study ever done and the

 

       longest study ever done in the lung transplant

 

       setting.

 

                 In conclusion, based on what we know now

 

       lung transplant patients will clearly live longer

 

       with inhaled cyclosporine.  The outstanding

 

       questions can be addressed in a postapproval study

 

       and so we believe that inhaled cyclosporine should

 

       be approved now.

 

                 Now I would like to invite Dr. Scaife to

 

       the podium as well and we can take your questions.

 

                 DR. SCAIFE:  Thank you very much, Dr.

 

       Dilly.  We can open to the FDA and the panel for

 

       questions.

 

                         Questions from the Panel

 

                 DR. SWENSON:  Go ahead.

 

                 DR. SCHOENFELD:  I just had a few

 

       questions on acute rejection since that endpoint
 

 

 

 

 

                                                                 94

 

       wasn't exactly described.  How is that diagnosed?

 

                 DR. SCAIFE:  Dr. Sarah Noonberg?

 

                 DR. NOONBERG:  It is diagnosed by

 

       transbronchial biopsy and it is graded 0-4.  So, it

 

       is the same transbronchial biopsy that can be used

 

       to make the diagnosis of bronchiolitis obliterans.

 

                 DR. SCHOENFELD:  So, was there sort of a

 

       program of periodic transbronchial biopsies in

 

       these patients during the study?

 

                 DR. NOONBERG:  Yes, approximately the

 

       first month and then three to four months afterward

 

       for a period of two years and then as clinically

 

       relevant.  It should be noted that the mean greatly

 

       exceeded that.  All patients had the minimum and

 

       the mean was far higher.

 

                 DR. SCHOENFELD:  Another question about

 

       acute rejection, once a patient has bronchiolitis

 

       obliterans can they have acute rejection also?

 

                 DR. NOONBERG:  Yes.

 

                 DR. SCHOENFELD:  I see.  So, it can happen

 

       after the chronic rejection has begun.

 

                 DR. SWENSON:  Dr. Hunsicker?
 

 

 

 

 

                                                                 95

 

                 DR. HUNSICKER:  I would like to ask Dr.

 

       Golden if he would be willing to comment on this.

 

       Let me give perhaps a little bit of a setting for

 

       my concerns here.  We have a study in which the

 

       primary outcome was not met and the secondary

 

       outcome is met that at the time the study was

 

       conceived didn't correspond to biology that was

 

       understood.  The understanding of biology has

 

       changed but--I would like to say I am not a

 

       pulmonary person but I am a transplanter--is still

 

       not very well understood.  So, I think I need to

 

       have somebody who really understands the pulmonary

 

       rejection business to tell me a little bit about

 

       the preclinical information on the impact of local

 

       immunosuppression for chronic rejection in the

 

       lungs.  Right now the general assumption is that

 

       most of the effects of immunosuppression are

 

       central.  I grant you that there is some very real

 

       interest in the possibility of local immunocytes

 

       being locally immunosuppressed but this is not what

 

       I would call a robustly well understood part of

 

       science.  So, since we can't look at this really in
 

 

 

 

 

                                                                 96

 

       most of the forms of transplantation, it may be

 

       that we have some better understanding of this from

 

       the pulmonary point of view and I would like to get

 

       the best understanding I can have of what is

 

       currently understood about the impact of local

 

       immunosuppression for pulmonary rejection.

 

                 DR. GOLDEN:  First of all, nobody knows

 

       with precision exactly where you are treating

 

       locally along the airway.  I would infer, given

 

       that there is a difference in chronic rejection,

 

       that that is generally a more peripheral airway

 

       portion.

 

                 DR. HUNSICKER:  Let me clarify that.  I

 

       wasn't talking where along the airway, I was

 

       talking about central immunological events as

 

       opposed to peripheral immunological events.  Most

 

       of us have assumed that the primary effects of

 

       immunosuppression are central rather than in the

 

       peripheral organs, particularly of the calcineurin

 

       inhibitors.  So, what I want to know is, is it

 

       known what the effects of local immunosuppression

 

       in lung rejection are in experimental models for
 

 

 

 

 

                                                                 97

 

       instance?

 

                 DR. GOLDEN:  Let me make sure I understand

 

       the question.  You want to know when you give

 

       systemic immunosuppression centrally how that might

 

       affect the airway.

 

                 DR. HUNSICKER:  Actually, it is the other

 

       way around.  Let's assume that when cyclosporine

 

       gets into the body where it really is doing its

 

       thing is in the lymph nodes and the spleen, and

 

       stuff like that where the cells are being

 

       developed.  Then it doesn't make a whole lot of

 

       sense that local application should be effective.

 

       If, in fact, there is local effect on the lymphatic

 

       cells that are in the bronchi, then it might make

 

       sense.  Right now this is something that is not

 

       understood in other forms of rejection because we

 

       can't get at the local tissues quite so well.  What

 

       is known about this?

 

                 DR. GOLDEN:  I think this is a new area.

 

       To answer it the best I can, one would have to

 

       infer that systemic therapy does not reach a level

 

       of mucosal benefit, that applying the medicine
 

 

 

 

 

                                                                 98

 

       locally, as you say, must have some local immune

 

       benefit.  The slide I showed of the mucosa with

 

       lymphocytes moving into the submucosa--I can only

 

       infer that systemic therapy or having a central

 

       effect on lymph nodes, etc., as you say, is not

 

       reaching a level of immunosuppression along the

 

       airway that is benefitted by a direct local

 

       application to the epithelium of an

 

       immunosuppressant.

 

                 I must say that there are ongoing studies

 

       now with other agents, like inhaled rapomyacin, to

 

       also try and treat this.  That is an animal study,

 

       very preliminary.  So, the best answer is I really

 

       don't know.  I infer that there is a benefit

 

       locally to applying, as you can uniquely do in the

 

       lung as you said, to a mucosal process.

 

                 DR. PRUSSIN:  Calman Prussin, NIAID.  Just

 

       to follow-up, in all immunologic and allergic lung

 

       diseases I know T-cells are being activated in the

 

       lung locally and expressing cytokines locally.  So,

 

       if you are applying that drug locally you would

 

       expect that it would have an effect there as
 

 

 

 

 

                                                                 99

 

       opposed to cells that are in the spleen which are

 

       mostly resting and not producing cytokines.  So, it

 

       does make sense immunologically.

 

                 DR. SWENSON:  Dr. Gay?

 

                 DR. GAY:  Steve Gay, University of

 

       Michigan.  I had a question concerning the early

 

       stoppage of the trial.  Pittsburgh is a fairly

 

       aggressive transplant institution and it seems as

 

       if the study was initially powered for 120

 

       patients.  The study was stopped at 56 patients.  I

 

       was wondering what factors led to the early

 

       stoppage with the fact that the primary endpoint

 

       was clearly not achieved at that point.

 

                 DR. DILLY:  The original sample size

 

       estimate was based on the availability of patients

 

       during the predefined study duration, and the study

 

       ended on the day that the study was intended to

 

       end.  That was not influenced by the primary

 

       endpoint.  It was simply that there were

 

       approximately 120-odd patients during that period

 

       who were transplanted at Pittsburgh and around half

 

       of those patients went on to the study.  So, in
 

 

 

 

 

                                                                100

 

       fact, this was a pretty good enrollment of eligible

 

       patients at the site.

 

                 DR. SWENSON:  Dr. Proschan?

 

                 DR. PROSCHAN:  I also have a question

 

       about that because you say it was not influenced by

 

       the results.  Does that mean the results were not

 

       known at that time?

 

                 DR. DILLY:  The study was done blinded at

 

       that time so the results were not known and the

 

       blind was well preserved.  We really became aware

 

       of those results after the unblinding.

 

                 Another thing that we have looked at in

 

       some detail--and perhaps Dr. Noonberg or Dr. Capra

 

       would like to talk about this--is whether there was

 

       something special about the patients that went into

 

       the study.  Was there something about the placebo

 

       group and whether these were a selected group of

 

       patients?  All the evidence says is that these were

 

       the same kind of patients as were not enrolled in

 

       the study.

 

                 DR. NOONBERG:  When we compared the

 

       placebo and ACS001 to UPMC unenrolled controls we
 

 

 

 

 

                                                                101

 

       found that the survival curves were comparable,

 

       with a p value of 0.99, so these didn't represent a

 

       select group of patients.  One of the reasons for

 

       the poor enrollment is that there just simply

 

       weren't enough transplants performed during that

 

       period of time.  During those three years there was

 

       a far lower time for--I am just going to stop and

 

       show this slide quickly that demonstrate the

 

       survival of screen failures, so patients who were

 

       not enrolled in ACS001 and those that were enrolled

 

       into the placebo group.

 

                 But to go back to my previous thought, I

 

       mean, they couldn't have enrolled 136 patients.

 

       There were 105 transplants performed during the

 

       enrollment period.  The enrollment period didn't

 

       stop early; the enrollment period had a three-year

 

       duration and it stopped at that three-year

 

       duration.  It just didn't enroll the requisite

 

       number of patients that it anticipated.

 

                 DR. SWENSON:  I believe Dr. Proschan has

 

       another question, but for the members of the panel

 

       here, if you will just simply hit your "talk"
 

 

 

 

 

                                                                102

 

       button we will be able to see the light on and you

 

       needn't raise your hand.  That will probably be

 

       easier for us.  Dr. Proschan?

 

                 DR. PROSCHAN:  I guess I was just

 

       following up on that because, you know, usually

 

       even if it is the primary endpoint to stop early

 

       there are boundaries that you use and, you know,

 

       the commonly used boundary is called the

 

       O'Brien-Flemming type of boundary, and this trial

 

       would not have met that level of evidence.  But

 

       that is a concern, mainly motivated by my thinking

 

       that the results were known at the time you stopped

 

       and, therefore, the possibility on a random high.

 

                 DR. SWENSON:  Dr. Moss?

 

                 DR. MOSS:  I have a question I guess for

 

       Dr. Noonberg but you, guys, might answer it too.

 

       It has to do with the generalizability of your

 

       results and I think you showed it on that slide.

 

       Normally when you have figures on a study you say

 

       we screened this many people; these many were

 

       excluded and we were left with 10 percent of the

 

       population.  That wasn't included in any documents
 

 

 

 

 

                                                                103

 

       but I think you brought it out a little bit there

 

       so could you just go over that and say, you know,

 

       these many people were screened and these many were

 

       excluded and you were left with what percentage of

 

       the patients that were actually enrolled in the

 

       study, so we can get an idea about the

 

       generalizability of your data?

 

                 DR. SCAIFE:  Dr. Noonberg?

 

                 DR. NOONBERG:  You want to go back to that

 

       last slide?

 

                 DR. MOSS:  I think the data was there but

 

       you never mentioned it before.  You don't need the

 

       slide, just how many people were screened and how

 

       many were excluded and you were left with this many

 

       people so we can see how generalizable your data

 

       are.

 

                 DR. NOONBERG:  Right.  There were 105

 

       transplants performed during the roughly 3-year

 

       enrollment period and there were 68

 

       patients--actually, 58 patients enrolled during

 

       that 3-year period; 10 were enrolled the year

 

       previous.  So, approximately half and, as I say,
 

 

 

 

 

                                                                104

 

       the survival in the enrolled and the placebo

 

       survival in the unenrolled group is comparable,

 

       with a p value of 0.99.

 

                 DR. SWENSON:  Dr. Venitz?

 

                 DR. VENITZ:  I want to follow-up on Dr.

 

       Hunsicker's question in a different way.  He was

 

       questioning the biology supporting localized

 

       administration versus systemic administration.  You

 

       obviously looked at exposure to cyclosporine after

 

       inhalation relative to oral or systemic

 

       administration.  Did you look at exposure to the

 

       lung in either clinical or preclinical models and

 

       compare systemic administration to inhalation?

 

                 DR. DILLY:  We actually have access to

 

       data on a scintigraphy study looking at labeled

 

       inhaled cyclosporine, conducted by Dr. Corcoran at

 

       the University of Pittsburgh, and I think it would

 

       be extremely relevant to show you those data.  I

 

       will give you the editorial comment while Sarah

 

       retrieves the slide.

 

                 But with the 300 mg dose put into a

 

       nebulizer, what we have seen is that about 25 mg is
 

 

 

 

 

                                                                105

 

       the applied dose to the lung.  That is achieving

 

       dose levels in the lung that would require

 

       approximately doubling of the systemic

 

       immunosuppressive dose, and that is our central

 

       premise, which is that that is not something that

 

       you could routinely do in clinical practice because

 

       of the toxicities.

 

                 DR. NOONBERG:  Again, just going back to

 

       the first animal experiments in 1988 where they

 

       just gave single doses of inhaled cyclosporine,

 

       they found that pulmonary concentrations were

 

       10- to 100-fold higher than concentrations in other

 

       tissues.  In the rat model that I described

 

       pulmonary concentrations were at least 3-fold

 

       higher than systemic concentrations.  So, that is

 

       the data that we have for preclinical.

 

                 DR. VENITZ:  Again just to follow-up, how

 

       does that compare if you give cyclosporine

 

       systemically?  You are talking about what happens

 

       after inhalation.  Right?  The levels in the lung

 

       are higher than in other tissues, higher than in

 

       plasma?
 

 

 

 

 

                                                                106

 

                 DR. NOONBERG:  Right.

 

                 DR. VENITZ:  And I am wondering how would

 

       that compare if a dose of cyclosporine was given

 

       intravenously to those animals.  What lung

 

       concentrations would you be able to achieve?

 

                 DR. DILLY:  What we showed was a 25 mg

 

       dose applied to the lung through inhalation.  You

 

       have to remember that when you put 300 mg into a

 

       nebulizer an awful lot goes into the atmosphere and

 

       an awful lot doesn't get into the lung.  That 25 mg

 

       applied dose, in terms of mg/g lung weight, equates

 

       to approximately an 8-fold higher systemic dose.

 

       If you assume 100 percent bioavailability of the

 

       systemic dose you have given parenterally, that

 

       would mean that you are looking at something like a

 

       200 mg dose given orally to get to the same lung

 

       levels.  That is based on AUC calculations.  If you

 

       are thinking about peak levels, then the difference

 

       is far greater because, of course, you get the

 

       early distribution phenomenon into the lung.

 

                 DR. VENITZ:  And that is in humans?  Any

 

       preclinical data to back that up?
 

 

 

 

 

                                                                107

 

                 DR. DILLY:  Actually, that is in the

 

       briefing book.  The best data we got is in humans.

 

       It is actually in the briefing book.

 

                 DR. SWENSON:  Dr. Burdick?

 

                 DR. BARRETT:  In Dr. Golden's presentation

 

       he showed some data looking at BOS as a disease

 

       progression marker.  However, in the documentation

 

       provided both BOS and FEV1 were not determined to

 

       be significantly different between the two groups.

 

       So, assuming chronic rejection as the indication

 

       here for this product, can you give some reasons

 

       why you think that occurred?

 

                 DR. SCAIFE:  Dr. Bill Capra is the lead

 

       statistician for Chiron.

 

                 DR. CAPRA:  Actually, CyIS did show an

 

       effect on BOS, specifically BOS-free survival.  The

 

       reason why our results are different than the FDA's

 

       is that the FDA censors BOS in their analysis and

 

       this is informative censoring.  Because the reasons

 

       for death are disease related, it is invalid to

 

       censor deaths in a disease progression endpoint.

 

                 The FDA has recently issued a guidance on
 

 

 

 

 

                                                                108

 

       this type of endpoint for oncology studies where

 

       they recommend using a progression-free survival

 

       endpoint in such an analysis rather than time to

 

       progression analysis.  If you do such an analysis

 

       with this BOS what you see is an effect of

 

       cyclosporine on improving BOS-free survival with a

 

       p value of 0.99.

 

                 DR. BARRETT:  Could you comment on the

 

       FEV1 though?

 

                 DR. CAPRA:  Sure.  We looked at FEV1 in a

 

       number of ways.  We looked at change from baseline

 

       to the final value; change from post-transplant to

 

       the final value.  We looked at time adjusted area

 

       under the curves and we looked at slopes.  In none

 

       of these analyses did we see a statistical

 

       significance.  However, in each and every analysis

 

       the point estimate favored the active group.  As an

 

       example, up here I have the results of the change

 

       from baseline to the final value and we see that

 

       the placebo group increased by 0.15 L and the

 

       active group increased by 0.40 L.  So, there seemed

 

       to be a trend, however it was not statistically
 

 

 

 

 

                                                                109

 

       significant.

 

                 We think there are some limitations to the

 

       FEV1 analysis and we think one of the major

 

       limitations is the informed censoring.  Because

 

       there is such a large number of deaths and because

 

       the FEV1 values cannot be obtained from subjects

 

       after they die it goes against censoring.  Also,

 

       FEV1 itself is highly variable.  Any single subject

 

       might have short-term fluctuations and what BOS

 

       does is it basically ignores those short-term

 

       fluctuations and looks for a sustained 20 percent

 

       decrease.  So, when you look at BOS, removing some

 

       of that variability, and when you address the

 

       informed censoring by use of progression-free

 

       survival endpoint rather than time to progression

 

       endpoint, we see an effect of cyclosporine on lung

 

       function, namely, BOS-free survival with a p value

 

       of 0.019.

 

                 DR. DILLY:  Can I just add one

 

       supplementary comment?  This is exactly the kind of

 

       question that we need to nail down in the next

 

       study because what we want to do is take a large
 

 

 

 

 

                                                                110

 

       group of patients, enroll them, nail down what

 

       their lung function is and follow them over time

 

       because, remember, the objective of this treatment

 

       is to preserve the lungs in a good condition.  So,

 

       actually a no-effect on FEV1 in that context in a

 

       large group of patients would be a great outcome,

 

       and that is what we want to show next.

 

                 DR. SWENSON:  Dr. Gay?

 

                 DR. GAY:  My question is to follow Dr.

 

       Moss' question from a while ago.  I am still not

 

       clear on the number of patients, why the number is

 

       so small, the number of patients that were included

 

       in the study.  It is essentially a single-site

 

       study in which every therapy is an off-label one

 

       for the treatment of rejection in transplantation.

 

       I am trying to get a grasp of why there were so

 

       many screening failures, essentially 50 percent

 

       screening failures in the study over the course of

 

       the three years.  Why weren't more patients

 

       included or made available to be included in the

 

       study, and what were the reasons for that?

 

                 DR. DILLY:  In fact, what we would
 

 

 

 

 

                                                                111

 

       consider the 50 percent enrollment of eligible

 

       patients as quite good in a clinical study.  Our

 

       experience has been typically when we are trying to

 

       enroll clinical trials, which is what we do for a

 

       living, that we see something like 25-40 percent

 

       enrollment into the study.  So, when we went into

 

       Pittsburgh and we looked at this whole body of data

 

       we were quite reassured that the patients had gone

 

       to the study in an elegant way; that about half of

 

       them got into the study; and there was nothing

 

       particularly strange about the patients that did

 

       and the patients that didn't.  So, we did not see

 

       that as an issue and we came back to the fact that

 

       we saw the data as robust.

 

                 DR. SWENSON:  Dr. Prussin?

 

                 DR. PRUSSIN:  I was impressed by the

 

       heterogeneity in terms of the cyclosporine group in

 

       terms of the dose that they received.  You know,

 

       some of the subjects received all the doses for the

 

       full length of the study, and various documents

 

       suggest that something like 9/36 received 1 month

 

       or less.  So, my question is did you ever stratify
 

 

 

 

 

                                                                112

 

       the analysis for survival based on how much drug

 

       they received?  It is pretty impressive that 9 of

 

       these patients received only a month of drug and

 

       yet presumably had a fairly good survival.

 

                 DR. SCAIFE:  Dr. Noonberg?

 

                 DR. NOONBERG:  There are several responses

 

       to that question.  The first is that ACS001 wasn't

 

       a dose-response study and we don't have formal

 

       dose-response data.  However, in one of our

 

       sensitivity analyses we did exclude patients, 14,

 

       who didn't receive at least 80 percent of the

 

       protocol maximum dosing and they are excluded from

 

       analysis.  As would be expected, the p value is

 

       going to go up due to loss of power, however, the

 

       treatment effect is essentially unchanged.

 

                 DR. PRUSSIN:  But on the flip side, why

 

       did the patients who essentially didn't receive

 

       drug respond to a drug they didn't get?  That is

 

       what I am more concerned about, not the ones that

 

       did receive the drug.  Yes, they responded even if

 

       the p value is going to be higher, but the ones

 

       that essentially were on the active side of the
 

 

 

 

 

                                                                113

 

       protocol but who effectively did not receive drug

 

       still had an effect in their survival.  Correct?

 

                 DR. NOONBERG:  I mean, we used an

 

       intent-to-treat analysis so we include those

 

       patients, but there are placebo patients that have

 

       long-term survival too.  This isn't a uniformly

 

       fatal diagnosis so you would expect to see

 

       variability in survival.  But we include the

 

       intent-to-treat analysis in accordance with

 

       guidelines.

 

                 DR. SWENSON:  Dr. Noonberg, I have a

 

       question that somewhat follows up on that very same

 

       one but is occasioned by one of your graphs here,

 

       and that is you continue to see and, in fact, you

 

       even highlighted that more patients seemed to be

 

       prevented in their chronic rejection appearance

 

       following the cessation of their two-year therapy,

 

       if I read this graph correctly.  Can you explain

 

       why this drug may, in fact, have benefits beyond

 

       its cessation?

 

                 DR. NOONBERG:  The CR that is in green on

 

       this graph doesn't represent new diagnoses of
 

 

 

 

 

                                                                114

 

       chronic rejection but, rather, deaths associated

 

       with chronic rejection.  So, they are not

 

       necessarily new rejection episodes.  So, this just

 

       highlights the strong association of chronic

 

       rejection with death and the fact that you don't

 

       see that in the inhaled cyclosporine group.  But

 

       the chronic rejection episodes are actually

 

       occurring throughout the process.

 

                 DR. SWENSON:  Okay.  Dr. Hunsicker?

 

                 DR. HUNSICKER:  On that same graph, it was

 

       not clear to me when you put that up--you don't

 

       have to put it back up again, I think we have all

 

       seen it--how you made the diagnosis of chronic

 

       rejection in those cases.  Was that either well

 

       defined BOS or a biopsy, or was that a clinical

 

       definition of chronic rejection based on the fact

 

       the patient had died with lung disease?

 

                 DR. NOONBERG:  It is either by

 

       transbronchial biopsy with histologic proof of the

 

       lesion of bronchiolitis obliterans or clinical

 

       BOS--

 

                 DR. HUNSICKER:  So, all of those patients
 

 

 

 

 

                                                                115

 

       that had the CR in green there either had one or

 

       the other?

 

                 DR. NOONBERG:  Correct.

 

                 DR. HUNSICKER:  I have a couple of other

 

       questions just to be sure I am correct on this, you

 

       referred to the analysis plan.  First of all, there

 

       was a prospective analysis plan that specified that

 

       the total survival at the end of the study was to

 

       be used as the primary outcome rather than the data

 

       at the end of two years of treatment?  I wasn't

 

       quite sure.  There were three or more different

 

       types of analysis that were discussed in the

 

       briefing books.  What did the original prospective

 

       analysis plan say was to be used as the primary

 

       evaluation?  Was it total survival at March 31, or

 

       whatever it was, or was it supposed to be at the

 

       end of the two years of treatment?

 

                 DR. NOONBERG:  It should have been at the

 

       end of the study.  Dr. Aldo Iacona, the principal

 

       investigator is nodding his head so, yes.

 

                 DR. PROSCHAN:  But it was not survival; it

 

       was acute rejection.
 

 

 

 

 

                                                                116

 

                 DR. HUNSICKER:  Well, I understand--

 

                 DR. NOONBERG:  Right, but the survival is

 

       the secondary endpoint--

 

                 DR. PROSCHAN:  We have so many secondary

 

       endpoints to look at, we have to figure out which

 

       endpoint we are looking at.

 

                 DR. HUNSICKER:  And the second question I

 

       have is that I thought I found in the briefing book

 

       that of the ten patients who were put into the

 

       so-called pilot thing, five of them had eventually

 

       died.  Is this correct?

 

                 DR. NOONBERG:  That is correct.

 

                 DR. HUNSICKER:  So, five out or ten

 

       patients, and they received treatment for the full

 

       two years or at least as much of the two full years

 

       as one would have expected them to get?

 

                 DR. NOONBERG:  Correct.  When those

 

       patients are included in the statistical analysis,

 

       and that was one of the sensitivity analyses that

 

       we performed, the results were still statistically

 

       significant.  They died but the timing of death is

 

       very important, as well as the fact that they
 

 

 

 

 

                                                                117

 

       died--

 

                 DR. HUNSICKER:  Sure.

 

                 DR. NOONBERG:  Here is a Kaplan-Meier of

 

       survival from time of transplantation to study end

 

       date including the randomized and the pilot, with a

 

       p value of 0.018.

 

                 DR. SWENSON:  At this time we should

 

       break.  I know there are more questions and they

 

       can be taken up in our other discussion sessions

 

       later today.  We will reconvene at 10:15.

 

                 [Brief recess.]

 

                 DR. SWENSON:  We should make a start on

 

       the next session, and Dr. Hernandez, of the FDA,

 

       will lead the discussion.

 

                             FDA Presentation

 

                   Overview of Clinical Trial Efficacy

 

                          and Safety Evaluation

 

                          Discussion of Analysis

 

                 DR. HERNANDEZ:  Thank you.  Good morning.

 

       During this presentation I will describe the

 

       Division's perspective on the application for

 

       cyclosporine inhalation solution.  I will start by
 

 

 

 

 

                                                                118

 

       saying that this is not a regular NDA application.

 

       The study, submitted to support the proposed

 

       indication, is a small Phase II study that failed

 

       to meet its primary endpoint for the prevention of

 

       acute rejection.  However, the potential for the

 

       prevention of chronic rejection and improved

 

       survival are very important aspects for the lung

 

       transplant population for which long-term survival

 

       is mostly limited by chronic rejection.

 

                 The agency considered that the potential

 

       survival benefit in this specific transplant

 

       population was reason enough to accept this new

 

       drug application for review.  The proposed

 

       indication for cyclosporine inhalation solution

 

       requested by Chiron is for increase in survival and

 

       prevention of chronic rejection in patients who

 

       receive allogeneic lung transplantation, in

 

       combination with standard immunosuppression.

 

                 In my presentation I will give an overview

 

       of the data submitted in this NDA.  Then I will

 

       summarize study ACS001 objectives, outcomes and

 

       limitations.  I will describe the FDA review which
 

 

 

 

 

                                                                119

 

       will address the following subjects:  Acute

 

       rejection, obliterative bronchiolitis,

 

       bronchiolitis obliterans syndrome and FEV1 data,

 

       and survival.  Then I will discuss the recipient

 

       and baseline characteristics, donor baseline

 

       characteristics, the primary causes of death,

 

       available autopsy results, dosing information and

 

       related outcomes and, finally, Dr. Cavaille-Coll

 

       will give you a summary of the safety

 

       considerations and our summary conclusions.

 

                 The data submitted to support this

 

       application was derived from two reports generated

 

       by Chiron Corp.  That report was referred to as

 

       ACS001 and ACS002.  The study ACS001 is actually

 

       the name given by Chiron to the study report that

 

       summarizes the findings from the University of

 

       Pittsburgh Medical Center, protocol 003.  In this

 

       protocol a total of 68 patients were studied in two

 

       phases.  First, 10 patients were enrolled in an

 

       open phase and treated with cyclosporine inhalation

 

       solution.  Then the total of 58 patients were

 

       randomized to cyclosporine inhalation solution
 

 

 

 

 

                                                                120

 

       which contains propylene glycol as a vehicle or

 

       propylene glycol vehicle alone.

 

                 From here I will refer to these groups as

 

       cyclosporine inhalation solution as CyIS or

 

       propylene glycol group as PG.  Twenty-six patients

 

       received CyIS and 30 patients received propylene

 

       glycol vehicle.  This was administered by

 

       inhalation with a nebulizer.  It should be noted

 

       that all patients received concurrent

 

       tacrolimus-based systemic immunosuppressive

 

       therapy.

 

                 Study ACS002 was the name that Chiron

 

       Corp. gave to the study report that summarizes the

 

       findings on adverse events in 70 patients selected

 

       from seven open-label studies conducted at UPMC.  I

 

       will refer to these study reports later.  Also, I

 

       will refer to the ACS001 study and study ACS002 to

 

       avoid confusion.

 

                 The rest of my discussion will focus on

 

       study ACS001, and the primary objective of this

 

       study was to determine if cyclosporine delivered to

 

       the lung allograft by inhalation prevents the
 

 

 

 

 

                                                                121

 

       development of acute cellular rejection.

 

                 As you can see from this slide, the study

 

       failed to show superiority of cyclosporine

 

       inhalation solution over PG vehicle.  The mean

 

       number of acute rejections of grade 2 or higher per

 

       patient was 1.3 in the cyclosporine arm and 1.2 in

 

       the PG arm.  The median number of acute rejections

 

       grade 2 or higher was 1 in both arms.  Therefore,

 

       the study failed the primary endpoint.

 

                 However, we noted that the sponsor

 

       reported a difference in mortality and obliterative

 

       bronchiolitis between the two arms.  In the study

 

       report and database OB was reported as 1 for its

 

       presence or 0 for its absence.  No additional

 

       histopathology information was provided.  The

 

       specimens for diagnosis of OB were obtained by

 

       transbronchial biopsies.

 

                 The reporting mortality was 12 percent in

 

       the CyIS arm and 40 percent in the PG arm.  The

 

       applicant noted that this represents a 79 percent

 

       decrease in risk for mortality in this specific

 

       population.  The reported rate of bronchiolitis
 

 

 

 

 

                                                                122

 

       obliterans or death was 19 percent in the CyIS arm

 

       and 60 percent in the PG arm, with a reported p

 

       value of 0.003.  It should be noted that this

 

       difference is mostly driven by the difference in

 

       mortality.

 

                 In study ACS001 all patients were followed

 

       up for three years after enrollment, and thereafter

 

       were followed up to document mortality.  At the

 

       time of the study end when the last patient

 

       completed two years of aerosolized treatment in

 

       August, 2003, the mortality was 12 percent in the

 

       cyclosporine arm and 40 percent in the PG arm.

 

       Follow-up data obtained through July, 2004 was

 

       submitted in the NDA and it showed mortality of 19

 

       percent in the cyclosporine arm and 50 percent in

 

       the PG arm.  Additional information submitted in

 

       the safety update in May, 2005 showed a mortality

 

       rate of 31 percent in the CyIS arm and 50 percent

 

       in the PG arm.

 

                 At the time the NDA was submitted to the

 

       agency, the limitations of the study were known to

 

       us.  These included the following:  This was a
 

 

 

 

 

                                                                123

 

       single-center Phase II study.  There was a small

 

       sample size.  The study intended to enroll 136

 

       patients.  The case report forms were created

 

       retrospectively.  Therefore, some important

 

       recipient and donor implementation was not

 

       captured.  Some data were not systematically

 

       collected, for example, prospective routine

 

       transbronchial biopsies.  Some data were not

 

       available, for example, some donor characteristics

 

       or information on management on acute rejection

 

       episodes grade 2 or higher that appeared prior to

 

       enrollment.

 

                 FDA concerns included the lack of effect

 

       on the primary endpoint.  We also shared the

 

       sponsor's concerns that the study may have become

 

       unblinded.  For example, patients at UPMC with

 

       identification numbers ending in letters B or C

 

       received cyclosporine inhalation solution, while

 

       those patients with numbers ending in A or D

 

       received PG.  This may have allowed the

 

       investigators to identify if a given patient was

 

       receiving propylene glycol or cyclosporine
 

 

 

 

 

                                                                124

 

       inhalation solution.

 

                 Protocol documentation was limited.

 

       Chronic rejection or survival were not designed as

 

       the primary endpoints.  Furthermore, the protocol

 

       for this study did not specify how secondary

 

       endpoints would be analyzed, and there was no

 

       pre-specified statistical analysis plan.

 

                 There were nine protocol amendments.  The

 

       study was stopped before completing enrollment.

 

       There were various protocol violations and there

 

       was no stratification by risk factors important for

 

       chronic rejection or mortality.  We can give an

 

       example such as double lung versus single lung.

 

       Despite randomization, there were imbalances in

 

       baseline characteristics.

 

                 Now I would like to describe our approach

 

       to the analysis of chronic rejection and mortality

 

       in study ACS001.  Acute rejection is considered a

 

       major risk factor for the development of chronic

 

       rejection or obliterative bronchiolitis, and a

 

       number of acute rejection episodes experienced

 

       early after transplantation are considered to have
 

 

 

 

 

                                                                125

 

       a significant impact on the subsequent development

 

       of OB.

 

                 Even though acute and chronic rejection

 

       represent different histopathology and

 

       pathophysiology, there is general consensus that

 

       the frequency, intensity and duration of acute

 

       rejection episodes are correlated with subsequent

 

       development of obliterative bronchiolitis.

 

                 Strong evidence suggests that acute

 

       rejection is the principal cause of chronic

 

       allograft dysfunction.  However, the role of other

 

       immunologic and non-immunological factors have to

 

       be considered.  Therefore, we examined the

 

       following data on acute rejection, obliterative

 

       bronchiolitis histological findings, FEV1 and BOS

 

       clinical manifestations of the disease, and

 

       mortality as a clinical outcome.

 

                 Obliterative bronchiolitis is an important

 

       cause of mortality after the first year from

 

       transplantation, accounting approximately for 30

 

       percent of deaths.  FEV1 is the best surrogate

 

       marker available for OB, and has been proven
 

 

 

 

 

                                                                126

 

       successful in describing--very important--the

 

       pattern of lung function decline, described as

 

       acute or chronic BOS onset; the identification of

 

       the main risk factors for BOS; and the extent and

 

       the rate of progression of OB.

 

                 The International Society of Heart and

 

       Lung Transplantation subcommittee has recommended

 

       that the slope of serial FEV1 measurements over

 

       time, before and after a therapeutic intervention,

 

       should be used to compare treatment responses.

 

                 Therefore, if chronic rejection is

 

       effectively prevented, we should expect to observe

 

       an evident therapeutic effect on FEV1 and BOS.

 

       Obliterative bronchiolitis, as defined in the study

 

       report, was documented by transbronchial biopsies

 

       and was found in 12 percent of the CyIS patients

 

       and 30 percent of the propylene glycol patients.

 

                 Now there are three points that I would

 

       like to make regarding FEV1.  First, as you can

 

       see, FEV1 values pre-enrollment, that is, after the

 

       transplantation but before randomization to the

 

       cyclosporine or PG arms, were not available in 40
 

 

 

 

 

                                                                127

 

       percent if the patients.  This data is shown in the

 

       first row.  Second, by 3 months there is FEV1 data

 

       on essentially all patients, all 26 patients in the

 

       CyIS arm and 26/30 in the PG patients.  Third, you

 

       will notice that there is a difference in mean FEV1

 

       values between the 2 groups.  At all point times

 

       the mean FEV1 values are higher for the CyIS group

 

       as compared to the PG group.  Even before treatment

 

       assignment higher mean FEV1 values were observed in

 

       the cyclosporine inhalation group.  This difference

 

       may be attributable to the greater number of double

 

       lung transplants that were performed in this group,

 

       which we will discuss later in greater detail.

 

                 Here is a graphical presentation of the

 

       data shown in the previous slide.  You can see that

 

       even though the FEV1 values in the cyclosporine

 

       inhalation group are higher than the PG group, the

 

       yellow line below, the two curves are essentially

 

       parallel.  Therefore, it does not appear that

 

       cyclosporine inhalation solution has an effect on

 

       FEV1.

 

                 Complete FEV1 values were not available so
 

 

 

 

 

                                                                128

 

       BOS, bronchiolitis obliterans syndrome, as defined

 

       by the International Society of Heart and Lung

 

       Transplantation could not be calculated using these

 

       criteria.  Therefore, an alternative definition of

 

       BOS, defined by the sponsor and qualified by an

 

       independent investigator was used.

 

                 As seen in this graph, the time to BOS

 

       between the 2 arms is similar, and the log-rank b

 

       value is 0.214.  This also indicates that the

 

       cyclosporine inhalation solution has no effect on

 

       BOS.  Patients who died without double-blind of

 

       BOS, as defined by the applicant, were censored at

 

       the time of the last follow-up for BOS.

 

                 We observed a difference in OB and

 

       mortality at the end of the study in August, 2003.

 

       OB was present in 12 percent in the cyclosporine

 

       inhalation solution versus 30 percent in the PG

 

       group.  Mortality was 12 percent in the CyIS arm

 

       versus 47 percent in the PG group.  No difference

 

       was observed in acute rejection, FEV1 or BOS.  As a

 

       clinician, FEV1 values are really, really

 

       important.  Questions like "how are you breathing"
 

 

 

 

 

                                                                129

 

       are really important questions.

 

                 The association between acute rejection

 

       and chronic rejection and the effect on patients

 

       and graft survival is well documented in registry

 

       and published literature.  Acute rejection is a

 

       major risk factor for the development of chronic

 

       rejection or obliterative bronchiolitis.  In light

 

       of the strong association between acute rejection

 

       and chronic rejection, the difference observed in

 

       OB was not expected in the absence of differences

 

       in acute rejection, FEV1 or BOS, and this warrants

 

       further exploration.

 

                 Therefore, we asked the question is the

 

       mortality difference between cyclosporine

 

       inhalation solution and PG in the absence of

 

       differences in acute rejection, FEV1 or BOS due to

 

       treatment effect or could other factors account for

 

       this difference?  For example, difference in

 

       baseline characteristics of donors and recipients

 

       between the study arms, or other factors such as

 

       study conduct.

 

                 I want to remind you that there was no
 

 

 

 

 

                                                                130

 

       difference in acute rejection grade 2 or higher at

 

       randomization to the drug or to the placebo arm.

 

       In contrast, there is a clinical and meaningful

 

       difference in acute rejection grade 2 or higher

 

       before treatment assignment.  Thirty-one percent in

 

       the CyIS arm and 42 percent in the PG patients had

 

       grade 2 or higher acute rejection prior to

 

       enrollment.  Although data were incomplete,

 

       approximately 40 percent of the CyIS allografts and

 

       50 percent of the PG allografts were colonized with

 

       bacteria or fungi.  So, this data is incomplete but

 

       I still think it is worth mentioning it.  So, if we

 

       assume that patients who had acute rejection grade

 

       2 or higher prior to enrollment received some type

 

       of steroid treatment or any other treatment

 

       augmentation, they could be predisposed to

 

       infectious complications such as pneumonia or

 

       sepsis.

 

                 Now I will discuss other imbalances in

 

       patient characteristics.  There is well documented

 

       association between the type of lung transplant and

 

       survival.  In this study there is an imbalance in
 

 

 

 

 

                                                                131

 

       the number of single lung and double lung

 

       transplants between the two arms.  Single lung

 

       transplants were done in 58 percent in the CyIS arm

 

       and 80 percent of the PG patients.  Conversely,

 

       double lung transplants were done in 42 percent of

 

       the CyIS patients and 20 percent of the PG

 

       patients.  This difference is statistically

 

       significant at a level of 10 percent.  FEV1

 

       pre-enrollment was lower in the PG arm and may be a

 

       reflection of more single lung transplants in this

 

       group.

 

                 The imbalance between single and double

 

       lung transplant is important.  The literature and

 

       registry data show an advantage for long-term

 

       survival and freedom from BOS in double versus

 

       single lung transplants.  Single lung

 

       transplantation is associated with lower exercise

 

       tolerance, poorer pulmonary mechanics, and higher

 

       infectious complications such as pneumonia.

 

                 The International Society of Heart and

 

       Lung Transplant registry data show that the there

 

       is a difference in survival between single and
 

 

 

 

 

                                                                132

 

       double lung transplant patients.  The half-life of

 

       double lung transplant patients is 5.3 years, as

 

       shown in the top line, while the half-life for

 

       single lung transplants is 3.9 years.  The average

 

       survival is shown in green in this graph.

 

                 As noted before, the information on donor

 

       characteristics was incomplete.  Therefore, we

 

       examined the data available that was informative

 

       about the state of the donor lung, and we noted a

 

       difference in donor inotropic support.  Fifty

 

       percent of the donor lung transplantations to the

 

       CyIS patients and 83 percent of the donor lung

 

       transplantations to the PG arm came from donors

 

       that received inotropic support.

 

                 PaO2/FiO2 ratio is an indicator of the

 

       severity of acute lung injury and it is useful to

 

       indirectly assess the degree of ischemic

 

       re-perfusion injury sustained by an allograft.

 

       PaO2/FiO2 ratio of greater than 200 percent

 

       indicates limited alveolar damage and gas exchange.

 

                 Another difference between the two arms

 

       was the time in the ICU.  While most of the
 

 

 

 

 

                                                                133

 

       patients stayed in the ICU for less than 10 days, 4

 

       percent in the cyclosporine arm patients and 20

 

       percent in the PG patients were in the ICU for more

 

       than 10 days, and this is kind of important in a

 

       single center where the criteria for keeping the

 

       patients in the ICU pretty much remained the same

 

       The other important thing is that it will reflect

 

       how the patients are in terms of degree of severity

 

       of the disease.  Patients are not allowed to go out

 

       of the ICU if there is something that still needs

 

       to be taken care of.  So, it is a good reflection

 

       of the degree of sickness that these patients have.

 

                 PaO1/FiO2 ratio is an indicator of the

 

       ability of the lung to perform adequate gas

 

       exchange, and it is useful to indirectly assess the

 

       severity of acute allograft injury.  The baseline

 

       PaO2/FiO2 ratio on ICU admission was worse in the

 

       PG group, suggesting a major degree of ischemic

 

       re-perfusion injury in these allografts.  Also,

 

       perioperative renal dysfunction was in 4 percent in

 

       the cyclosporine inhalation solution and 13 percent

 

       in the PG patients.  Prolonged ICU stay, inadequate
 

 

 

 

 

                                                                134

 

       gas exchange and perioperative renal dysfunction

 

       are factors that reflect a more severe condition

 

       after surgery.

 

                 We also looked at the time to the first

 

       pneumonia.  As noted, there were more cases of

 

       pneumonia in the PG arm and this was within the

 

       first one to two months of the study.  The outcome

 

       in patients with these pneumonias is summarized in

 

       the next slide.

 

                 A large number of patients in the PG arm

 

       had early pneumonias and there was a strong

 

       relationship between pneumonia and death.  The

 

       relationship is not surprising given what we know

 

       about the causes of death after lung

 

       transplantation.  The occurrence of these early

 

       pneumonias is not likely to be related to any

 

       treatment effect but may be related to baseline

 

       donor and recipient characteristics or other events

 

       which occurred prior to enrollment.  These events

 

       include but are not limited to episodes of acute

 

       rejection requiring additional immunosuppressive

 

       therapy or microbial colonization of the graft.
 

 

 

 

 

                                                                135

 

                 I would like to underline that early

 

       pneumonia may lead to histopathological findings

 

       compatible with obliterative bronchiolitis.  This

 

       has been documented to be a risk factor for the

 

       development of obliterative bronchiolitis.  There

 

       were five patients in cyclosporine inhalation

 

       solution arm and two patients in the PG arm who

 

       developed pneumonia in the first month.  By two

 

       months there were an additional three PG patients

 

       with pneumonia.  Of these patients that developed

 

       pneumonia, 2/5 died in the cyclosporine arm and

 

       7/13 in the PG arm; 1/5 developed OB in the

 

       cyclosporine inhalation solution and 7/13 in the PG

 

       group; and BOS was observed in 3/5 in the CyIS arm

 

       and 3/13 in the PG arm.

 

                 I want to make two observations.  There is

 

       a strong association between early pneumonia and

 

       risk of death.  Second, early pulmonary infections

 

       and early acute rejection episodes are well

 

       recognized risk factors for the subsequent

 

       development of chronic rejection.

 

                 This table show the primary causes of
 

 

 

 

 

                                                                136

 

       death by July, 2004.  Three patients in the

 

       cyclosporine inhalation solution arm and seven

 

       patients in the PG group died of infections,

 

       pneumonia or sepsis.  In the CyIS arm one patient

 

       died of graft failure and in one patient the cause

 

       was unknown.  In the PG group two patients died of

 

       OB; one patient died of pulmonary embolism and

 

       another from congestive heart failure, and one from

 

       lung cancer.  There were three patients in which

 

       the cause of death was unknown.  The distribution

 

       of causes of death is consistent with registry data

 

       where infections remain the major cause of death

 

       during the first year after transplantation while

 

       chronic rejection begins to become an important

 

       cause of death after one year, as seen in table 3,

 

       reference 1 in your background package.

 

                 Autopsy results--from the available data

 

       in the application CRFs, narratives and data sets

 

       we learned that some patients who died had autopsy

 

       performed.  In the cyclosporine inhalation solution

 

       arm one patient had autopsy and OB was not

 

       reported.  In the propylene glycol arm 15 patients
 

 

 

 

 

                                                                137

 

       died and there were six autopsies.  In two of these

 

       OB was reported and four of them died of infection,

 

       and there was no OB reported out of the six

 

       reports.

 

                 The protocol specified that patients

 

       should receive treatment for two years.  The dose

 

       should be titrated from 100 mg to 300 mg for the

 

       first three days of treatment, then daily dosing up

 

       to three consecutive days with the maximum

 

       tolerated dose, and thereafter three times weekly

 

       dosing for two years.  There was a lot of

 

       variability in individual patient dosing in this

 

       trial.

 

                 This table shows the number of doses

 

       received by patients.  The protocol dosing schedule

 

       was not followed in many patients.  In fact, six

 

       CyIS and five PG patients received less than 25

 

       doses, as you can see circled in this slide.  The

 

       large variation in the number of doses received

 

       makes it difficult to establish a relationship

 

       between the specific treatment regimen and the

 

       improvement in survival.
 

 

 

 

 

                                                                138

 

                 Six cyclosporine inhalation solution

 

       patients who received less than 25 doses are shown

 

       on this table.  Two patients received a single

 

       dose; others received 3, 12, 13 and 24 doses

 

       respectively.  The doses show that not all patients

 

       succeeded in titrating up to 300 mg.  Five out of

 

       these six patients experienced adverse events

 

       directly related to the administration of the

 

       cyclosporine inhalation solution, and three

 

       patients discontinued due to adverse events, and

 

       three additional patients withdrew consent.  We

 

       noted, however, that all six patients survived and

 

       all are included in the mortality calculations as

 

       cyclosporine inhalation solution successes.

 

                 There were five patients in the PG arm who

 

       received less than 25 doses and, as can be seen,

 

       four/five died.  Could these be attributable to the

 

       lack of cyclosporine inhalation solution?  All

 

       these deaths are included in the mortality

 

       calculation as PG failures.

 

                 In addition to the 3 cyclosporine

 

       inhalation solution who withdrew consent after
 

 

 

 

 

                                                                139

 

       receiving 1, 3 and 13 doses, 3 additional patients

 

       withdrew consent--these are the last 3 rows in this

 

       slide--1 at 4 months and 2 others at 20 months.

 

       The right-hand column shows that 2 of these 3

 

       additional patients survived.

 

                 At this point I would like to turn the

 

       podium over to Dr. Cavaille-Coll to discuss our

 

       safety considerations and give our conclusions.

 

                  Safety Considerations and Conclusions

 

                 DR. CAVAILLE-COLL:  Good morning.  We are

 

       in general agreement with the applicant that the

 

       systemic safety profile of cyclosporine after oral

 

       or intravenous administration is well characterized

 

       and that the amount of systemic exposure to

 

       cyclosporine, meaning what was deposited in the

 

       lung and entered in the bloodstream before being

 

       eliminated, was not associated with detectable

 

       increases in systemic toxicity.  There is more

 

       limited information on the safety of cyclosporine

 

       when administered by inhalation in a propylene

 

       glycol solution.

 

                 As you have heard, propylene glycol is
 

 

 

 

 

                                                                140

 

       classified as an additive that is generally

 

       recognized as safe for use in food, mainly through

 

       studies using oral and dermal exposure.  It is used

 

       to absorb extra water and maintain moisture in

 

       certain medicines, cosmetics or food products.  It

 

       is a solvent for food colors and flavors.  However,

 

       information on the inhalation toxicity of propylene

 

       glycol is more limited.  There is no approved

 

       product for inhalation containing nearly 100

 

       percent propylene glycol such as this product.

 

                 The applicant has submitted some

 

       preclinical safety data, including a 28-day study

 

       in dogs and a 28-day inhalation study in rats.  The

 

       28-day inhalation study in dogs demonstrated lung

 

       irritation, alveolar and interstitial inflammation

 

       in all cyclosporine dose groups and the vehicle

 

       control.  Laryngeal inflammation with ulceration

 

       was seen in the mid-dose group males.  Inflammatory

 

       cell infiltrates, lymphocytes, plasma cells,

 

       monocytes were seen in the control and treated

 

       group as well.  The dog studies did not contain a

 

       sham control.  Thus, this confounded the separation
 

 

 

 

 

                                                                141

 

       of the extent of pulmonary toxicity due to

 

       cyclosporine versus that of the propylene glycol

 

       vehicle.  No additional cyclosporine inhalation

 

       toxicity was observed in the animals.  Dose levels

 

       in the dogs were limited, however, by the maximum

 

       feasible dose.  However, serum cyclosporine levels

 

       in the high dose group exceeded the human exposure

 

       by 2.5-fold.

 

                 Again, there were also studies that were

 

       done in rats which showed similar findings, except

 

       that the doses in rats did exceed about 80-fold the

 

       human exposure and there was evidence of increasing

 

       toxicity with increasing doses of cyclosporine.

 

       The rat studies did include an air control and did

 

       show that even in the propylene glycol group there

 

       were findings that were not present in the sham

 

       control animals.

 

                 I would like to address now the clinical

 

       safety.  In the usual safety review we would look

 

       at the rates of adverse events, the grade of

 

       severity, the duration of the events and their

 

       reversibility, as well as the temporal relationship
 

 

 

 

 

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       to dosing with the study drug.  Collection of such

 

       information is facilitated by the use of

 

       prospectively designed case report forms.  The

 

       latter often provide another very useful source of

 

       safety information in the form of handwritten

 

       comments by the investigators on the margins of the

 

       pages of the case report forms.  Such forms and

 

       comments were not available and it is in the

 

       context of these limitations that we must evaluate

 

       the safety of this product.  Evaluation of safety

 

       in this fragile population receiving systemic

 

       immunosuppression and numerous medications is

 

       admittedly complicated.

 

                 There are no prospectively designed case

 

       report forms to guide the systematic collection of

 

       safety data throughout the conduct of the study

 

       including but not limited to the use of concomitant

 

       medications used to prevent or treat the

 

       complications associated with the administration of

 

       study drug.  Clinical safety data was collected

 

       retrospectively from source materials from one

 

       double-blind, controlled study and a number of
 

 

 

 

 

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       small open-label, uncontrolled studies at the

 

       University of Pittsburgh Medical Center.

 

       Comparative safety data is available on only 26

 

       randomized subjects in study ACS001, or 36 subjects

 

       that include the first 10 non-randomized subjects

 

       from the study.  Additional non-comparative safety

 

       data was obtained in report ACS002 by pooling data

 

       from seven open-label, uncontrolled studies that

 

       enrolled 70 lung transplant recipients who were

 

       receiving similar tacrolimus-based systemic

 

       immunosuppression.

 

                 Subjects in study ACS001 were titrated in

 

       a double-blind fashion to a maximum tolerated dose

 

       not to exceed 300 mg or the propylene glycol

 

       control equivalent.  That dose was then to be

 

       administered three times a week for up to two

 

       years.  As mentioned earlier, there was a great

 

       variation in dose, 100 mg to 300 mg per day, the

 

       number of doses administered and, consequently,

 

       duration of exposure.  I think we have seen those

 

       slides before.  Subjects also received per protocol

 

       premedication with aerosolized lidocaine and
 

 

 

 

 

                                                                144

 

       bronchodilators to improve tolerance.

 

                 This slide comes from the integrated

 

       summary of safety and lists basically the adverse

 

       events that occurred with a statistical

 

       significance of greater than 10 percent.  I think

 

       we are in general agreement with the applicant's

 

       description of the safety data they were able to

 

       collect.  We do note that there seemed to have been

 

       more respiratory, and thoracic adverse events in

 

       the cyclosporine group compared to the propylene

 

       glycol group.  In all these categories, of course,

 

       as I mentioned before, the significance was greater

 

       than 10 percent.  As in the 28-day preclinical

 

       animal studies, there was a sham treatment group to

 

       help discern the potential contribution of inhaled

 

       propylene glycol to the respiratory tolerability in

 

       both treatment groups.  Here we do see that more

 

       events occurred in the cyclosporine group.  These

 

       findings in general are consistent with the

 

       respiratory safety findings that were found in the

 

       28-day preclinical animal studies.

 

                 Another thing we look at when we are
 

 

 

 

 

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       evaluating safety is the discontinuations and

 

       withdrawal of consent.  Although a greater

 

       proportion of subjects in the propylene glycol

 

       group, 33 percent, were reported to discontinue

 

       study drug due to an adverse event, other than

 

       death, than in the cyclosporine group, 15 percent,

 

       this comparison must be interpreted with caution.

 

                 Six patients in the cyclosporine group, or

 

       23 percent, were reported to have discontinued due

 

       to withdrawal consent compared to none in the

 

       propylene glycol group.  Further examination of the

 

       individual case report forms revealed a number of

 

       respiratory adverse events associated with the

 

       study drug administration which could have

 

       influenced their continued willingness to

 

       participate in the study.  Taken together, a

 

       similar proportion of subjects discontinued study

 

       drug due to adverse events or tolerability in the

 

       propylene glycol group and the cyclosporine group.

 

                 We also have some non-comparative data

 

       that was presented in report ACS002 from a pool of

 

       70 lung transplant recipients.  Again, these
 

 

 

 

 

                                                                146

 

       represent a variety of lung transplant types,

 

       mostly patients with refractory acute rejection

 

       and/or OB who were treated with cyclosporine

 

       inhalation solution in seven open-label,

 

       uncontrolled studies at UPMC.  They were also

 

       receiving systemic tacrolimus-based

 

       immunosuppression.  These, again, represent an

 

       experience of a wide range of dosing and duration

 

       of treatment, which is really very difficult to

 

       interpret.  Patients were generally administered

 

       the maximum tolerated dose which was individualized

 

       and depended on the characteristics of the patients

 

       and their response to medication.

 

                 In summary, the overall safety database is

 

       smaller than usually expected in a commercial

 

       application.  Respiratory adverse events were

 

       common despite premedication and limited the

 

       maximum doses used and the durations of the