Monday, June 6, 2005


                                8:00 a.m.








                            5600 Fishers Lane

                                Room 1066

                           Rockville, Maryland







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


       Erik R. Swenson, M.D., Chairman

       Teresa Watkins, R.Ph., Executive Secretary




       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.




       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




       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.







                             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







                       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







                          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







       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




                 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







       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.







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


       clinical pharmacologist from the University of


       Pennsylvania and Children's Hospital of




                 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




                 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







       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




                 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




                 With respect to FDA's invited industry







       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







       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









                 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







       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







       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




                 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







       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?







                 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







       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




                 With that, thank you and I will turn it







       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




                 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







       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







       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




                 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







       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







       studies will form the discussion of today's




                 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







       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







       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




                 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.







                 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




                 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







       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







                 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




                 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







       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







       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







       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







       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




                 The registry for transplant would say that


       somewhere around 5 years the percent of patients







       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







       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







       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




                 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







       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







       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







       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,







       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




                 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







       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









                 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




                 In the next set of protocols patients with


       refractory acute rejection, defined as acute


       rejection that failed to respond to


       immunosuppressive intensification--this represents







       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







       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







       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




                 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







       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







       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







       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




                 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,







       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




                 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







       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







       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




                 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. 







       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




                 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







       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




                 This graph illustrates the relative risk


       of death and 95 confidence intervals when the







       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







       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







       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




                 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







       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







       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




                 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







       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. 







       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









                 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







       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




                 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







       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




                 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







       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







       model has essentially no real impact on the


       treatment effect of the confidence intervals and


       the p values remain highly statistically




                 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




                 This slide illustrates the Kaplan-Meier


       estimate of time to chronic rejection with deaths







       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




                 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







       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







       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







       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.







                 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.







                 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




                 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







       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







       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







       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. 







       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







       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







       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




                 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







       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







       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




                 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,







       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







       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.




                 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







       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




                 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







       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







       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









                 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,







       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







       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







       everyone on the DSMBs in which I participated would


       have stopped this study to protect placebo


       patients, the results of the study are that




                 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









                 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.







                 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







       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




                 Of course, some questions remain open


       because of the nature of the clinical program


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







       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




                 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







       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







       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







       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




                 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 from the Panel


                 DR. SWENSON:  Go ahead.


                 DR. SCHOENFELD:  I just had a few


       questions on acute rejection since that endpoint







       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?







                 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







       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




                 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









                 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







       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




                 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







       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







       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







       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"







       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







       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




                 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,







       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







       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









                 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?







                 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







       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









                 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







       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







       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







       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







       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




                 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







       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




                 DR. HUNSICKER:  So, all of those patients







       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.







                 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









                 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







       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







       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







       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




                 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







       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







       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




                 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







       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




                 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







       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







       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







       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







       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




                 Complete FEV1 values were not available so







       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"







       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







       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




                 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







       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




                 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







       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







       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







       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.







                 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







       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







       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




                 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




                 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.







                 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







       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







       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







       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







       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







       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




                 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







       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







       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







       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