UNITED STATES OF AMERICA
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FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
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ANTIVIRAL DRUGS ADVISORY COMMITTEE
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THURSDAY
NOVEMBER 14, 2002
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The Advisory Committee met in the Versailles Room in the Holiday Inn Bethesda, 8120 Wisconsin Avenue, Bethesda, Maryland, 15 8:30 a.m., Roy Gulick, M.D., M.P.H., Chair, presiding
PRESENT:
ROY M. GULICK, M.D., M.P.H., Chair
TARA P. TURNER, Pharm. D., Executive Secretary
JANET A. ENGLUND, M.D., Committee Member
COURTNEY V. FLETCHER, Pharm. D., Committee Member
PRINCY N. KUMAR, M.D., Committee Member
SHARILYN K. STANLEY, M.D. (by phone), Committee Member
LAUREN V. WOOD, M.D., Committee Member
EUGENE SUN, M.D., Acting Industry Representative (non-voting)
MIRIAM J. ALTER, Ph.D., Consultant
THOMAS R. FLEMING, Ph.D., Consultant
VICTORIA A. JOHNSON, M.D., Consultant
MARIA H. JOGREN, M.D., Consultant
SAMUEL SO, M.D., Consultant
BRIAN WONG, M.D., Consultant
LILLIAN THIEMANN, Patient Representative (non-voting)
JAY H. HOOFNAGLE, M.D., HHS Federal Employee (non-voting)
I N D E X
Call to Order 4
Introduction of Committee 4
Conflict of Interest Statement 7
Introduction, Karen D. Weiss, M.D. and
Emanuel F. Petricoin, Ph.D. 10
Sponsor Presentation:
Introduction 17
Overview of Pegasys-Copegus Development
Program 20
Efficacy 32
Safety 51
Conclusions 68
FDA Presentation 72
Questions to the Presenters 108
Open Public Hearing 183
Charge to the Committee/Questions/Discussion 200
Adjourn 306
P R O C E E D I N G S
8:35 A.M.
DR. GULICK: Good morning, everybody. I'm Trip Gulick from Cornell University in New York and I'm pleased to call to order this meeting of the Antiviral Drugs Advisory Committee.
I'd like the members of the Committee to introduce themselves. Please state your name and your affiliation for the record. And we'll start with Dr. Sun.
DR. SUN: Eugene Sun, Abbott Laboratories.
MS. THIEMANN: Lillian Thiemann, Visionary Health Concepts and the Women's HIV Collaborative of New York.
DR. HOOFNAGLE: Jay Hoofnagle with the Division of Digestive Diseases and Nutrition, NIDDK, NIH.
DR. SO: Sam So from Stanford University.
DR. ALTER: Miriam Alter from the Division of Viral Hepatitis, Centers for Disease Control and Prevention.
DR. JOHNSON: Victoria Johnson, Infectious Diseases, UAB.
DR. ENGLUND: Janet Englund, Department of Pediatrics, University of Washington.
DR. GULICK: On the telephone we have Dr. Stanley. Can you hear us Sharilyn?
DR. STANLEY: Yes, good morning, Trip, here I am.
DR. GULICK: Okay, and just state where you're from.
DR. STANLEY: Texas Department of Health.
DR. GULICK: Thanks. Thanks for joining us.
DR. FLETCHER: Courtney Fletcher, Department of Clinical Pharmacy, University of Colorado Health Sciences Center.
DR. TURNER: Tara Turner, Executive Secretary for the Committee.
DR. WOOD: Lauren Wood, HIV and AIDS Malignancy Branch, NCI, NIH.
DR. WONG: Brian Wong, VA Connecticut Health Care System and Yale University.
DR. KUMAR: Princy Kumar, Georgetown University, Washington, D.C.
DR. FLEMING: Thomas Fleming, University of Washington.
DR. PETRICOIN: Emanuel Petricoin, CBER, FDA.
DR. TAUBER: Bill Tauber, FDA, CBER.
DR. MARZELLA: Lou Marzella, Division of Clinical Trials, CBER.
DR. SIEGEL: Jay Siegel, Office of Therapeutics at CBER.
DR. GULICK: Thanks, everyone. To start off, I'd like to call on Dr. Deborah Burncraft of the Agency who would like to say a few words.
DR. BURNCRAFT: Good morning. I'd like to acknowledge Dr. Brian Wong's service on the Antiviral Drugs Advisory Committee. Dr. Wong is Associate Professor of Medicine at Yale University School of Medicine and Chief of Infectious Diseases at the VA Connecticut Health Care System.
Dr. Wong has served on this Committee in an exemplary fashion since 1998, providing input and insight on some very difficult and interesting deliberations that we've had. So today, we'd like to recognize your service with a letter of recognition and a certificate of appreciation and a placque will be coming to you and we look forward to working with you as a consultant.
Thank you very much for all of your help.
DR. WONG: Thank you.
(Applause.)
DR. GULICK: Brian, I can add that we will miss your uncanny ability to cut through things and straight takes on the questions and issues.
Okay, Tara Turner will read the Conflict of Interest Statement.
DR. TURNER: Thank you. The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
All Committee Members and consultants have been screened for conflicts of interest with respect to the products at issue, competing products and their sponsors. The reported financial interests have been evaluated and it has been determined that the interests reported by the participants present no potential for a conflict or the appearance of such at this meeting with the following exceptions.
Dr. Thomas Fleming has been granted a waiver under 18 USC 208(b)(3) for his participation on a data safety monitoring board for a competitor to Pegasys, peginterferon alfa-2a and Copegus ribavirin on an unrelated matter. He receives less than $10,001 a year.
Dr. Princy Kumar has been granted a waiver under 18 USC 208(b)(3) for her participation on a scientific advisory committee for a competitor to Pegasys and Copegus. She receives less than $10,001 per year. Dr. Kumar has also been granted a waiver under 21 USC 355(n)(4), amendment of Section 505 of the Food and Drug Administration Modernization Act for ownership of stock in a competitor to Pegasys and Copegus. The stock value is less than $5,001.
A copy of the waiver statements may be obtained by submitting a written request to the Agency's Freedom of Information Office, Room 12A-30 of the Parklawn building. We would also like to note that Dr. Eugene Sun is participation in today's meeting as the Acting Non-voting Industry Representative.
With respect to FDA's invited non-voting patient representative, Ms. Lillian Thiemann, has reported interests that we believe should be made public to allow the participants to objectively evaluate her comments. In the past, Ms. Thiemann has received grants from Amgen, Roche and Schering for hepatitis C virus educational programs. In the event the discussions involve any other products or firms not already on the agenda for which FDA participants have a financial interest, the participants' 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 firm whose product they may wish to comment upon.
Thank you.
DR. GULICK: Thanks very much. Dr. Karen Weiss from the Agency will make a few introductory remarks for this morning's meeting.
DR. WEISS: Good morning. I just also want to extend my welcome to the Committee and to the public and to thank you all in advance for what I know will be a very interesting discussion later this afternoon.
One of the reasons we're here, there are a number of reasons why, but almost a year ago in December of '01 we updated this Committee on another interferon based therapy for the treatment of chronic hepatitis C infection and we had a very, I think, vigorous and useful discussion and at that time the Committee and members of the public all asked that next time applications come before this Committee that we bring them to the Committee a little bit earlier in the process so that there will be a time for additional input as the FDA goes through its processes. And so we heard that message. We appreciate that there is a large amount of interest in the community for products intended for the treatment of hepatitis C infection. There are a lot of interesting questions and we look very forward to your input and to the discussions.
I think that Hoffman-LaRoche is to be commended for coming to the Committee and bringing to the Agency such a thorough and extensive application and evaluation of their combination of Pegasys, Copegus for the treatment of patients with hepatitis C infection and then lastly, this review was a joint effort between numerous individuals from the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research, brought together experts from a number of different disciplines who came together in this collaborative effort to review this application and those people are all too numerous to tell you all their names, but I want to thank everybody for all their hard work and with that I would like to then just introduce Emanuel Petricoin who will bring to you some introductory comments about this application.
DR. PETRICOIN: Good morning. I'll be talking over the next 5 to 10 minutes or so about the biologic component of this submission, the Pegasys component which is comprised of a pegylated interferon. The interferon alpha-2a biologic is recombinant, human leukacyte interferon produced in E.coli. Molecular weight approximately 19,000 Daltons. The pegylated moiety is approximately 63,000 Daltons. This is a lysine based pegylation, that is the pegylations occur on the lysines of the interferon molecule and therefore the molecule itself is comprised of multiple isoforms.
All of the critical components that produce this compound have been inspected by the FDA within the last several months and all outstanding inspection and CMC issues have been resolved and they were minor to begin with. Inspection of Roche Penzburg facility occurred in July. This is for the Pegasys molecule that's been approved recently. The critical component, the pegylation entity itself manufactured by Shearwater has been extensively reviewed and the compounding that takes place at Nutley in the formulation of the product itself was recently inspected in August on all outstanding and minor issues that were noted at the time have been resolved prior to the approval of the Pegasys molecule itself.
Now there were changes in manufacturing that took place after the critical Phase III trial. These changes were made to the product and manufacturing to address the market supply and the critical market supply issues that would have to then be addressed going forward. These changes require evaluation of analytical comparability in pharmacokinetic profiles. Now at that time, PK comparability was not demonstrated. However, through thorough and rigorous evaluation by Roche who is to be commended for their rigorous evaluation of the molecule and a lot of hard work by the Agency working with Roche, it was determined that product specifications could be tightened and a new PK trial was performed that then compared the Phase III material to the commercial product that was made under tightened specifications.
The result of this trial demonstrated comparability at the PK level for the Phase III material compared to the commercial product.
We reviewed the time line for the BLA/NDA for the Pegasys component. We received this application May 22, 2000. A complete response letter was issued April 10, 2001. The PDUFA goal date for this was April 12, 2001.
For the PK trial, meeting and consultations between CBER and the sponsor for the clinical trial to evaluate PK comparability was initiated and completed between April 2001 and April 2002. So this is when Roche went back, worked with the Agency, redid a PK trial to demonstrate comparability under tightened specifications that was then demonstrated. A complete response to the complete response letter was received April 16, 2002. The PDUFA action goal date was October 16, 2002 and the application was approved on that date.
The peginterferon alpha-2a, the Pegasys component and the co-Pegasys was received June 3, 2002 with the PADUFA action goal date December 3, 2002.
Conclusions are this time for the molecule, the CMC part of this presentation for Pegasys, changes in manufacturing were made after Phase III trials to address market supply, required further demonstration of PK comparability to the commercial product.
The Agency worked with Hoffman-LaRoche as they thoroughly evaluated the PK and analytical data. Based on this, product specifications were tightened to ensure product consistency, robustness of the process and PK equivalency. That was demonstrated. And all CMC issues and pre-approval for Pegasys inspection items were resolved.
For the ribavirin component, there's still some small outstanding issues, a small amount of data for the NDA still needs to be submitted and reviewed and that's on-going and shouldn't cause any problems for the final product.
I'll take any questions at this time.
DR. GULICK: Can you just help the Committee with the abbreviation PDUFA?
DR. PETRICOIN: Certainly. That's the Prescription Drug User Fee Act. These are milestones that are Congressionally set so that we meet some type of deadline that is a reasonable amount of time to review all the data, the product data, the pharmacokinetic data, the clinical data for any product that's submitted to the FDA.
DR. GULICK: Thanks. Are there other questions for Dr. Petricoin?
Dr. Sjogren?
DR. SJOGREN: I have a question. I saw in one of your slides that the pegylated product is 63 kiloDalton. We've grown accustomed to seeing 40 kiloDalton in presentations at major meetings. Is that a significant difference? Why 63 kiloDalton in your slide and why 40 kiloDalton in other presentations?
DR. PETRICOIN: The peg moiety itself is 40 kiloDalton, the final product, the interferon which is about 20 kiloDalton and then the peg component comprise about a 60 kiloDalton final molecule.
DR. SJOGREN: So it's the sum of both. Thank you.
DR. GULICK: We are going to have plenty of time for questions after the morning presentations. Are there any other burning ones for Dr. Petricoin at this time?
Okay. Thank you.
Great, we'll move to the sponsor presentation from Hoffman-LaRoche.
(Pause.)
DR. TEUBER: Hi, good morning. Thank you very much, Dr. Gulick and good morning to FDA, Members of the Committee. My name is Dr. Candace Teuber and I'm the regulatory leader for Pegasys. On behalf of Roche, we're pleased to present to you today our Pegasys, peginterferon alpha-2a and Copegus, Roche's ribavirin in combination therapy development program.
The combination therapy development program was submitted to FDA as a BLA for Pegasys and an NDA for ribavirin in June of this year as mentioned by Dr. Petricoin.
We'd also like to mention that we'd like to thank FDA for acknowledging the collaborative efforts and hard work that went into working together for the monotherapy application and also in working together for the combination application in making it today to the Advisory Committee.
The approved indication for Pegasys monotherapy is as follows on the slide. Pegasys peginterferon alfa-2a is indicated for the treatment of adults with chronic hepatitis C who have compensated liver disease and who have not been previously treated with interferon alpha.
Patients for whom efficacy was demonstrated included patients with compensated cirrhosis. Also, the approved dosage and administration for Pegasys and monotherapy is 180 micrograms administered subcutaneously once weekly for 48 weeks.
And we're before the Committee today to seek approval for Pegasys and Copegus in combination to expand this indication as follows:
For Pegasys peginterferon alpha-2a in combination with Copegus ribavirin for the existing monotherapy indication.
In addition, the data we'll be presenting to the Committee also supports an expansion of the dosage and administration section for a modification of the treatment duration of ribavirin dose according to the important prognostic factor of genotype.
In looking at the regulatory history of the application, the USIND was submitted in July of 1998 and subsequent to the IND filing, we had several key interactions with the Agency including an end of Phase II meeting, the granting of fast track designation, a pre-BLA/NDA meeting with both -- jointly with CBER and CDER which resulted in the filing of the NDA and BLA applications in June.
As mentioned previously in the presentation and also by Dr. Petricoin, monotherapy for Pegasys was approved on October 16th this year and we're before the Committee today to seek approval for Pegasys and Copegus in combination for hepatitis C.
Our presentation will begin with an overview of the Pegasys and Copegus development program by Dr. Joe Hoffman. Dr. Hoffman is the Vice President and Group Leader for Virology and Transplantation Clinical Development at Roche.
Our Phase III findings from our two pivotal trials will be presented by Dr. Frank Duff and Dr. Duff is the Clinical Leader for the Pegasys Development Program.
Dr. Jonathan Solsky, our Director of Drug Safety and Risk Management, will be presenting the safety findings in the trials and Dr. Hoffman will conclude with a risk benefit assessment.
We also have two hepatology experts who are available for your questions today, Dr. Don Jensen, Director, Section of Hepatology, Rush Presbyterian St. Luke's Medical Center from Chicago, Illinois; and Dr. Mitch Schiffman, Chief Hepatology Section, Virginia Commonwealth University Health System, Medical College of Virginia in Richmond.
We also have several Roche experts who are available for questions, Dr. Mike Brunda from Clinical Science and Dr. Brunda was responsible for the design and analysis of our Phase III trials; Ms. Celine Eliahou, our toxicologist; Ms. Amy Lin, our statistician; and Drs. Matthew Lamb and Karin Jorga from Clinical Pharmacology. And with this, I'd like to turn the presentation over to my colleague, Dr. Hoffman.
DR. HOFFMAN: Thank you, Candace. Over the next few minutes, I'd like to give you a rationale for the development of Pegasys, briefly review the clinical program and then discuss dose selection in the combination therapy program.
We first began developing Pegasys back in 1997, the only approved therapy for chronic hepatitis C was standard interferon three times per week. What I've shown here are some of the results that could be expected with that therapy. These actually come from our monotherapy program from the control arms. And what you can see here with sustained virological response on the Y axis, overall responses of less than 20 percent; responses in genotype 1 are only about 7 percent; responses in cirrhotics about 5 percent; and in those patients with genotype 1 with either high viral load or cirrhosis, only about 1 to 2 percent.
A probable explanation for this is given on this slide which shows the activity time profile of interferon given three times per week and what you can see is following an initial dose, there's a rapid upstroke in activity, followed by a rapid downstroke such that between doses, there is no detectable drug and it's during these times that the virus can rebound.
Pegasys was developed to overcome this limitation. What you see here is the interferon which is about 20 kiloDaltons, interferon alpha-2a, covalently bound to a branched 40 kiloDalton polyethylene glycol moiety.
This results in the maintenance of a soluble formulation that retains it's intermodulatory and antiproliferative properties and because of improved pharmacokinetics, has a sustained action provided both by a decreased clearance and an extended absorptive phase.
It has a relatively limited volume of distribution that allows for fixed dosing.
This is a concentration time profile for Pegasys and what you can see here is following a weekly dose that there's maintenance of concentration through the end of the dosing period, thereby maintaining antiviral pressure through that time.
Now I previously mentioned that the volume of distribution for Pegasys is relatively small, it's smaller than that of other available interferons and what that results in is a relatively consistent clearance shown here for a broad range of weights, from 45 kiloDaltons up through 95 or 100 kiloDaltons. This consistent clearance results in relatively consistent concentration in the blood across weights and therefore allows for fixed dosing.
As has been mentioned, Pegasys as monotherapy was approved last month and I'm only going to go over results as they pertain to the combination program. Within that program of monotherapy, we did four studies, a dose finding study in Phase II,
non-cirrhotic patients, a powered study in patients with cirrhosis and then two, pivotal Phase III trials, one versus standard interferon and one versus an induction regimen of interferon.
In that program, there were 1600 patients, approximately 1,000 received Pegasys and about 600 received the control.
So what's the appropriate dose of Pegasys? Our first trial was a Phase II study, proof of concept, dose finding trial in patients without cirrhosis. And what we did was to compare interferon alpha-2a, three million units three times per week to four weekly doses of Pegasys; 45, 90, 180 and 270 micrograms. And what you can see here is that all of the doses, all of the dose groups of Pegasys had a higher sustained virological response than the interferon which was only 3 percent and that there was a dose response from 45 up to 180 micrograms. Importantly, at a higher dose of 270 micrograms, there was a plateauing of the effect and there was an increase in the need for dose modification.
So the two highest responses were seen at 90 and 180, 30 and 36 percent. But when you looked closely at this, more closely and look at it by response to genotype 1, what you see is that in 180 microgram group, the response was 31 percent versus only 14 percent in the 90 microgram group. So these results were very encouraging, but also indicated that 180 micrograms was the appropriate dose.
The second trial that we conducted was a power trial in patients with cirrhosis. Again, we used interferon alfa-2a, three million units, three times per week as the control. And this time we looked at two weekly doses of Pegasys, 90 and 180 micrograms. We used the 90 microgram dose group in this trial as well because as everyone here knows, patients with cirrhosis tend to be older, tend to be sicker, can be more medications, so we wanted to have a back up dose in this population.
Once again, in both of the Pegasys dose groups, the responses were higher than in the control. Eight percent in the control; 15 percent in the 90 microgram and 30 percent in the 180 microgram group. Importantly, only the 180 microgram group achieved statistical significance in terms of superiority to the control.
Once again, very encouraging results in a difficult to treat population and again indicating 180 micrograms to be the appropriate dose. Now in one of two phase 3 trials we inserted a 135 microgram arm, the purpose of which was to investigate a step down dose between 90 and 180. Once again the control arm, interferon alpha-2a, three million units, three times per week and what you can see here are the results, both the 135 and the 180 microgram dose groups achieved statistical superiority over the control group. The sustained virologic responses at week 72 were not different. However, if one looked at interim virological points here the week 24 is shown, there was a consistency in higher responses in the 180 microgram group.
In addition, we looked at histology. It was only the 180 microgram group that showed statistically significant improvement over the interferon control.
From a safety standpoint, what you see here for 135 and 180 are major safety findings, severe AEs, serious AEs including treatment related, AEs in laboratory abnormalities resulting in withdrawal and AEs in laboratory abnormalities resulting in dose modification. The numbers are very similar, a slight increase here in the 180 microgram group in terms of dose modifications. However, it's important to point out that these patients were generally dose reduced to 135 micrograms while these patients were generally reduced to 90 micrograms which is clearly a suboptimal dose.
Based on these and other data, the 180 microgram dose was approved in Pegasys monotherapy in the United States and elsewhere.
And just to summarize the results of the monotherapy program, I've already shown you this slide of results with standard interferon and these are the result from our pivotal trials program. Once again, overall with Pegasys, 180 micrograms; 28 to 39 percent versus less than 20 percent; 22 to 28 percent versus about 7 percent in genotype 1; 30 percent versus approximate 5 percent in cirrhotics and in the difficult to treat, geno-1 high viral load and geno-1 patients with cirrhosis, 13 to 14 percent versus about 1 to 2 percent.
So very encouraging results including difficult to treat patients, but clearly a lot of room for improvement, especially down this end.
That's why we proceeded into a combination therapy program which is summarized here. The program consisted of three trials, a pilot safety study and then two registration trials that you'll hear about in more detail today.
Before moving forward, just a few words about ribavirin. When combined with interferon, there is improved efficacy over interferon alone. It is teratogenic in animals and mutagenic and induces hemolysis.
The dose of 1000 or 1200 milligrams per day is safe and efficacious with standard interferon and is an approved regimen, Rebetron.
And the 1000 or 1200 milligram ribavirin dose was combined with Pegasys in the pilot safety study.
Now whereas the pharmacokinetic data did not support weight base dosing for Pegasys, it is reasonable to take weight into consideration in dosing ribavirin.
What you see here is a simulated exposure by body weight. Here you have the AUC according to body weight for a dose of a 1000 micrograms and what you can see is that as weight increases there is a drop with 1000 micrograms which would continue in that fashion at the higher weights. So what's done is that the patients who weigh 75 kilograms or more, the dose is increased to 1200 milligrams which gives this step up and then a continued decline, but when one looks across a broad range of weights, there's a relatively narrow band of concentrations that are seen.
As I mentioned, we did a pilot safety study, represented here as the NV15800 trial in which we combined Pegasys 180 micrograms with 1000 or 1200 milligrams of ribavirin, Copegus. And based on the result, the safety results from that study, we moved into a comparative trial. In that trial, we went with the 180 microgram dose which for the reasons that I've explained in the monotherapy program combined with Copegus 1000 or 1200 milligrams. We chose that dose for three reasons. One, it was the approved dose of ribavirin with standard interferon. Secondly, it was the dose we had already investigated in the pilot study. And thirdly, we wanted to be able to compare the ribavirins across the two arms.
We also included Pegasys monotherapy dose so that we could investigate the effects of ribavirin on both the safety and the efficacy.
And you'll hear the results of that trial shortly, but what I wanted to mention though is that we felt it was important to do a companion study and that is because of these data which are a summary of the Rebetron registration data and what was established with Rebetron was that certain subgroups of patients, genotype 2,3 low viral load might be treated adequately with only 24 weeks of therapy rather than a full 48 weeks.
We wanted to a companion trial along with the comparative study to investigate whether we could reduce exposure without loss of efficacy in patient subgroups.
And these studies are tied together by a common arm which is the Pegasys 180 microgram group with full dose; Copegus, 1000 to 1200 milligrams.
Now designing this study there were three things we could change in looking at decreasing exposure. One was the duration of combination therapy which we thought was a primary way to go based on the Rebetron data, but also because in this way you decrease exposure to both of the components of the regimen.
We also considered looking at a lower Pegasys dose or a lower Copegus dose. Because of the reasons I mentioned, we felt that 180 micrograms was the dose to move forward with, but with Copegus there certainly were data available suggesting that a lower dose might be adequate and safer.
So as I mentioned in the common arm for bridge, we selected the 1200 milligram dose per day and although there were no power dose finding studies of ribavirin, what was available in the literature and anectdotally suggested that 800 milligrams would be safer and might be adequate. However, 600 milligrams and lower might not be as efficacious and would provide relatively little safety advantage over the 800.
So in this second trial what we did was investigated the duration of combination therapy, 24 versus 48 weeks. We kept the Pegasys dose constant at 180, but varied the Copegus dose down to 800 versus the full dose.
So just to summarize what you're going to hear now in terms of our program, the program was designed to evaluate the efficacy and safety of Pegasys and Copegus across genotypes versus Rebetron and versus Pegasys monotherapy. But importantly, it was also designed to evaluate the impact of shorter treatment duration on response in genotype non-1 and genotype 1 and also the impact of a lower Copegus dose on responses according to genotype.
And with that I will turn over the microphone to Dr. Frank Duff who will talk about the efficacy results from the combination trial.
DR. DUFF: Good morning, ladies and gentlemen of the Committee and the audience, the FDA. I'm pleased to have the opportunity to present the efficacy results from our two pivotal Phase III studies which Dr. Hoffman has introduced.
Beginning with study NV15801, our comparative trial versus Rebetron. The efficacy objectives are outlined on this slide. The primary objective was to compare the efficacy of Pegasys plus Copegus versus Rebetron; secondarily, to compare the efficacy of Pegasys plus Copegus versus monotherapy. And finally, to compare the efficacy across treatment arms by HCV genotype.
This was a randomized study. It was open label for Pegasys and for ribavirin and it was blinded for Copegus versus placebo in the two Pegasys arms. It was stratified by country as well as by HCV genotype.
Patients were randomized to one of three treatment arms. The first, Pegasys 180 microgram given once weekly, plus Copegus in a standard dose of 1000 or 1200 milligrams a day using the 75 kilo weight split that Dr. Hoffman mentioned.
Patients were also randomized to receive Rebetron which is a combination of Intron A, 3 million international units given subcutaneously three times a week with Rebetol, again doses of 1000 or 1200 milligrams with the weight consideration at 75 kilos.
Finally, to Pegasys 180 micrograms, given subcutaneously, once weekly versus placebo. I should mention that this was a 2 to 2 to 1 randomization scheme and I should also mention that patients were treated for 48 weeks with 24 weeks of follow up and our end points were determined at 72 weeks.
This study and the study that I will refer to next were conducted in North and South America, as well as in Europe, Australia and Asia.
The primary endpoint for this study was combined sustained virological response and sustained biochemical response at the end of follow up. Sustained virological response was defined as 2 negative PCR determinations and sustained biochemical response was defined as two normal ALT at end of follow up.
Our secondary endpoints included sustained virological response, sustained biochemical response and end of follow up histological response on a subset of 20 patients randomized to the study. The analysis population was all patients randomized.
Inclusion criteria included serological evidence of HCV infection, detectable HCV RNA with a lower limit threshold of 2000 copies per mil; evidence of elevated serum ALT; a liver biopsy consistent with chronic hepatitis C; evidence compensated liver disease defined as Child-Pugh grade A; having an age greater than or equal to 18 years; and finally, being naive to interferon and to ribavirin.
Patients were excluded if they had evidence of decompensated liver disease defined as Child-Pugh grades B and C. They were also excluded from our pivotal studies if they had evidence of coinfection with HIV or HBV. They were excluded if they had evidence of anemia or an ability to tolerate anemia and finally, if they had any of several significant comorbid medical conditions that were outlined in the protocol.
Patient characteristics were well balanced across the three treatment arms and I've outlined major ones which have been identified with outcome in terms of sustained virological response. Two thirds of patients were genotype 1. HCV RNA titer was approximately 6 times 106. Twelve to 15 percent of patients had evidence of bridging fibrosis of cirrhosis at baseline liver biopsy. The mean age was approximately 42 years.
Patient mean weight evenly distributed approximately 79 kilos and finally, approximately 70 percent of the patients were male. I should also note that 85 percent of the patients randomized to the three treatment arms were Caucasian. Approximately 5 percent of patients were categorized in our trial as black and 5 percent as Oriental, the remaining 5 as other.
This slide reviews our premature withdrawals. Jonathan Solsky will spend considerable detail reviewing our safety. I wanted to just highlight some of our nonsafety reasons for withdrawal. I will point out that there were somewhat higher premature withdrawals on our Pegasys arm at 32 percent, that is Pegasys monotherapy, as well as our Rebetron arm at 32 percent. The premature withdrawal rate in our Pegasys plus Copegus arm was 22 percent and the primary driver for this difference is the category insufficient therapeutic response and I wanted to point this out because in this study patients who had not achieved evidence of a sustained virological response, I should say of a virological response by week 24 were given the opportunity to leave the study, if they wished and were categorized as nonresponders. And this occurred somewhat more frequently in the Pegasys monotherapy arm and the Rebetron than in the Pegasys plus Copegus arm.
Moving on to our protocol defined analyses. To orient the Committee to the left hand side, the comparison will be our primary comparison Pegasys plus Copegus versus Rebetron. On the right hand side, our secondary comparison, Pegasys plus Copegus versus Pegasys monotherapy.
You will note that our combined endpoints sustained virological response and sustained biochemical responses here at the bottom, 45 percent of patients randomized to Pegasys plus Copegus as compared to 39 percent of patients randomized to Rebetron achieved a combined endpoint with a P-value of 0.057 borderline statistical significance.
However, looking at the individual components of this definition we see that for sustained virological response, those randomized to Pegasys plus Copegus were 50 percent SVR as compared to 42 percent SBR for those randomized to Rebetron, a statistically significant difference.
Similarly for our sustained biochemical response, 50 percent of patients randomized to Pegasys plus Copegus as compared to 43 percent of those randomized to Rebetron achieved a sustained biochemical response, a statistically superior difference. If we look at the comparisons of Pegasys plus Copegus to Pegasys monotherapy, statistically significant, higher rates of response were seen in our combination arm, looking at sustained virological response, sustained biochemical response and the combined endpoint of SVR and SBR.
There has been an evolution in thinking and in endpoints since this study was developed which has been acknowledged in the FDA and the sponsor's briefing package. We now have a validated HCV RNA assay and virological response is considered the preferred efficacy endpoint.
Having presented our protocol defined analyses, I will now move on to focus on sustained virological response data and I want to point out the definition that we have as defined in our protocol. I mentioned it previously. Two negative HCV RNA assessments, at least 21 days apart after week 60. It should be noted that there is an additional somewhat less conservative efficacy measure which is a single PCR determination. However, because we had focused on a two PCR definition in the protocol, we will be presenting that more conservative endpoint today.
Additionally, I will be presenting data using an all treated population, defined as patients randomized who have received at least one dose of HCV therapy.
Looking at the comparative trial versus Rebetron, you will note in terms of sustained virological responses that 52 percent of patients randomized to Pegasys plus Copegus as compared to 43 percent of those randomized to Rebetron achieved a sustained virological response which was a significant difference in superiority for Pegasys plus Copegus. Similarly, a higher SVR of 52 percent compared to 28 percent for Pegasys monotherapy, a statistically significant difference.
We were interested in assessing sustained virological response by genotype as has been outlined in our protocol and you will see here the breakdown of sustained virological response for our genotype 1 patients as compared to our genotype non-1 patients. And for genotype 1 patients you will see the same pattern of response in terms of our three treatment arms. The highest sustained virological response achieved for Pegasys plus Copegus followed by a 35 percent virological response for Rebetron and a 19 percent virological response for Pegasys monotherapy. And with our genotype non-1 patients, again a similar pattern. The highest sustained virological response for Pegasys plus Copegus as compared to 57 percent for Rebetron and 44 percent for Pegasys monotherapy. There's been considerable interest in understanding the impact of high and low viral load within the genotype 1 population and we've performed some additional descriptive analyses of sustained virological response looking at our low and high viral load patients. And what I can say is that numerically, a similar pattern of response across the three arms have been observed for both our low viral load patients represented on the left and our high viral load patients represented on the right.
The efficacy findings for this comparative trial versus Rebetron are therefore the Pegasys and Copegus sustained virological responses are superior to Rebetron as well as Pegasys monotherapy. This was seen in our overall population. It was seen in our genotype 1 population with contributions from both our high and low viral load patients and finally, it was observed in our genotype non-1 patients as well.
As Dr. Hoffman has mentioned, having confirmed the superiority of our Pegasys plus Copegus combination as compared to a non-pegylated interferon combination and to Pegasys monotherapy, we were interested in assessing the effect of dose and duration on patient subgroups with a particular emphasis on genotype. And as such, the second study NV15942 was conducted.
The primary efficacy objectives of this study were to compare the efficacy of Pegasys plus Copegus for 24 weeks versus 48 weeks. And secondarily, to compare the efficacy of Copegus 800 milligrams versus 1000 or 1200 milligrams in combination with Pegasys. And the rationale for the doses selected have been outlined by Dr. Hoffman.
This study was also randomized. Treatment duration was blinded until week 24. Copegus dose was blinded throughout the study. This trial was stratified by genotype 1 versus non-1; by viral load, low versus high; as well as by geographic region. And patient selection criterion in terms of inclusions and exclusion criteria were the same as those that I've outlined in NV15801 or comparative trial versus Rebetron and I will not repeat them here.
Patients in this study were randomized to one of four treatment arms and I'll begin by saying that the Pegasys dose was the same throughout, that is, 180 micrograms subcutaneously given once a week. And the arm represented on the top of the slide, we see Pegasys plus Copegus in standard doses of 1000 or 1200 milligrams given for 48 weeks which is what we refer to as the common arm in that it was the same dose and duration as represented in the previous study.
The second arm is Pegasys plus Copegus, but this time in a dose of 800 milligrams, also for 48 weeks.
The third arm is Pegasys plus Copegus in standard doses of 1000 or 1200 milligrams, administered for 24 weeks.
The fourth and final arm is Pegasys plus Copegus, 800 milligrams, also administered for 24 weeks. And in this study, patients were given 24 weeks of follow-up after the completion of treatment, before the determination of their efficacy endpoints.
The primary endpoint for this study was sustained virological response. Secondary endpoints included sustained biochemical response and the end of follow up histological response, again on a subset of 20 percent of patients randomized to the study. And the analysis population was all patients treated.
This slide represents the patient characteristics across the four arms. And I have a couple of points that I'd like to make in terms of genotype and viral load. The Committee will note that the proportion of patients randomized with genotype 1 to our 48 week treatment arms was higher than that randomized to 24 weeks.
Similarly, patients with higher viral load essentially the genotype 1 high viral load patients were also preferentially enrolled to the 48 week arms. And this was the result of a pre-planned, unbalanced analysis which favored genotype 1 high viral load patients randomized to 48 weeks as compared to 24.
Other demographic characteristics that are known to have a potential impact on sustained virological response are listed here and are well balanced. I will point out that we have approximately 25 percent of patients with bridging fibrosis or cirrhosis, randomized to all four treatment arms of this study.
The mean age is approximately 42. The mean weight is approximately 77 kilos and the proportion of males is very similar to our comparative trial versus Rebetron, approximately 66 percent.
Again, briefly reviewing the reasons for premature withdrawal, Dr. Solsky will review our safety reasons. The total numbers of premature withdrawal are listed at the bottom of the slide. As might be expected, patients randomized to receive a 48-week course of treatment as compared to a 24-week treatment course did have a somewhat higher rate of premature withdrawal. The primary drivers of this in terms of nonsafety are first of all, insufficient therapeutic response and again, we have the same rule that if a patient had not responded by week 24, they could be categorized as a nonresponder and leave study if they so choose. And also we had somewhat higher rates of refused treatment and failure to return in the two 48-week treatment arms as compared to the
24-week treatment arms.
As you will recall, our primary comparison for this study was treatment duration. An analysis of the data revealed that 48 weeks of treatment was superior to 24 weeks of treatment. In terms of our secondary comparison which was the Copegus dose, our analysis showed that 1000 or 1200 milligrams was statistically superior to 800 milligrams and this was an overall pooled analysis.
Looking further at impacts in terms of the patterns by genotype, we do note that for the genotype 1 patient population, 48 weeks was noted to be superior to 24 weeks and 1000 or 1200 milligrams appeared superior to 800 milligrams and we interpret this that the genotype 1 responses appear to be driving largely the overall pooled results that I have just shared with you.
Interestingly and importantly, however, in terms of our genotype non-1 patients, we were unable to detect a difference between 24 and 48 weeks of treatment and between 800 and 1000 or 1200 milligrams of Copegus.
And in order to further understand this we've proceeded in a predefined manner to explore descriptively the specific responses by genotype across the four treatment arms and I will review that data now.
Beginning with our genotype 1 patients, sustained virological response across the four treatment arms of the study, the Committee will note that the highest sustained virological responses were seen in the genotype 1 patients randomized to 48 weeks of treatment and 1000 or 1200 milligrams of Copegus. There are lower point estimates, 39 percent, 41 percent and the lowest point estimate of 29 percent as we reduce Copegus dose or we reduce the exposure to treatment with the lowest genotype 1 response seen for patients randomized to receive only 24 weeks of treatment and 800 milligrams of Copegus.
A similar pattern of response was observed in both our high and low viral load patients. You will note a step-down from 48 weeks of treatment through 24 weeks of treatment for our genotype 1 high viral load patients, very similar to the overall genotype 1 group and again for our low viral load patients with a step down from 60 to 41 percent as we reduce dose and exposure.
A different pattern emerged with our genotype non-1 patients as may have been suggested by the pooled statistics that I shared with you. What we noted here was that high sustained virological responses were achieved when patients were randomized, non-1 patients to 24 weeks of treatment and 800 milligrams of Copegus and there was no increase apparent in terms of sustained virological response with either an increase in Copegus dose or a doubling of treatment exposure.
Our efficacy findings therefore are that superiority of longer treatment duration and higher Copegus dose has been shown in our overall population and that for genotype 1 which we believe is essentially driving this effect, there is a consistent response with the overall. That is that the highest sustained virological responses are seen with 48 weeks of treatment and with Copegus 1000 or 1200 milligrams.
However, for genotype non-1 as has been suggested from some of the literature that Dr. Hoffman referred to, available with non-pegylated products, we see that high and maximal responses can be achieved with 24 weeks of treatment and lower doses of Copegus presenting a real opportunity to reduce exposure to both treatments without risking efficacy.
Moving on to predictability analyses, the objective of these exploratory analyses were to confirm predictability findings that we have seen from our monotherapy program and these findings were that if a patient had not achieved an early virological response, response by week 12 which was defined as achieving at least a 2 log drop in HCV RNA or undetectability, there was a very low likelihood that this patient would proceed to sustained virological response with a negative predictive value in the range of 98 percent and this is actually represented in our labeling for monotherapy.
We were interested in validating these findings and seeing if similar predictability conclusions could be drawn with our combination data and for that reason we have performed this analysis on the Phase 3 patients who receive 48 weeks of treatment and 1000 or 1200 milligrams of Copegus from the two studies that I've just reviewed.
I've defined the early virological response, but I will recap it briefly. That is, that HCV RNA had to be reduced by greater than or equal to 2 logs or undetectability by week 12.
I'm going to focus this presentation on our genotype 1 findings although I will say that in this analysis our overall results are essentially the same. The reason for focusing on genotype 1 is that we believe that this is the patient population where the ability to determine early virological response will be particularly helpful because these are patients who will require a full year of therapy for maximal efficacy.
Looking at the 569 patients who were genotype 1 included in this analysis, you will note that 82 percent did achieve an early virological response, but for this analysis the emphasis is on those who did not. The 18 percent or 102 patients who did not achieve an early virological response are represented on the low part of this figure. Of these patients only 4 or 4 percent went on to achieve a sustained virological response and 96 percent did not. So a negative predictive value can be calculated at 96 percent which is very similar to the numbers that we were seeing with monotherapy.
So we believe that this analysis certainly confirms what we had seen with monotherapy and it has been supported by our combination data and as I've mentioned this does allow for early decision making by patients and prescribers for those with a low likelihood of achieving a sustained virological response.
In conclusion, the pivotal Phase 3 studies have demonstrated that Pegasys plus Copegus has achieved sustained virological responses that are superior to Rebetron as well as to Pegasys monotherapy; that for genotype 1, the highest sustained virological responses were achieved when Pegasys and Copegus were administered for 48 weeks and when the Copegus dose was retained as a standard dose of 1000 or 1200 milligrams according to a 75 kilo weight split.
However, for genotype non-1, maximal sustained virological responses were achieved -- can be achieved with Pegasys and with Copegus 800 milligrams used for 24 weeks without an apparent increase in benefit by moving to a full 48 weeks of therapy.
And with that I will close and ask Dr. Jonathan Solsky to join me at the podium to review the safety results from the two Phase 3 studies that I have just presented.
DR. SOLSKY: Good morning. The safety profile of the Pegasys-Copegus combination has been well characterized based on the two large, multicenter clinical trials that Dr. Duff has just presented which in total enrolled 1,735 HCV patients who received the Pegasys-Copegus combination and of which 377 at baseline had compensated cirrhosis or bridging fibrosis. Nodal scores F3, F4.
My safety presentation today will consist of two main parts: a safety comparison of the Pegasys combination versus Pegasys monotherapy and Rebetron based on our comparative trial NV15801 and then I will turn to a safety comparison of the Pegasys-Copegus combination by duration of treatment and Copegus dose based on duration and dosing by genotype study, NV15942.
This slide provides an overview of the safety profile of the Pegasys-Copegus combination in comparison to Pegasys monotherapy and Rebetron. In comparing the Pegasys-Copegus combination to Pegasys monotherapy one notes in both treatment groups, almost all patients reported one or more adverse events. Serious adverse events including those assessed to be unrelated to therapy by the investigators were reported at the same rate of 12 percent in both groups.
There were two deaths reported on Pegasys monotherapy and none on the Pegasys-Copegus combination.
Dose modifications of Pegasys were reported at a rate of 27 percent on Pegasys monotherapy and 32 percent on the Pegasys-Copegus combination and this was attributable more due to adverse events and neutropenia. Furthermore, dose modifications of ribavirin were noted at a rate of 40 percent on the Pegasys-Copegus combination and this was attributable to both adverse events and anemia.
In terms of premature withdrawals, 7 percent were reported on the Pegasys monotherapy and 10 percent were reported on the Pegasys-Copegus combination.
Turning to a comparison of the
Pegasys-Copegus combination in relation to Rebetron, one notes once again that in both treatment groups almost all patients reported one or more adverse events.
In terms of serious adverse events, including those that were considered to be unrelated to therapy as assessed by the investigators, on the Pegasys-Copegus combination, it was noted at a rate of 12 percent in comparison to 9 percent on Rebetron. Looking at these serious adverse events that were considered to be treatment related to therapy, there was a similar rate of 4 percent in both groups.
There was one death that was reported on Rebetron and in terms of dose modification of note is that dose modification of Pegasys occurred on 32 percent on the combination in comparison to 18 percent on Rebetron. This was mainly attributable due to neutropenia and thrombocytopenia.
In terms of dose modifications of ribavirin this was noted to be at a similar rate of 40 percent on the Pegasys-Copegus combination versus 37 percent on Rebetron.
Finally, in terms of premature withdrawals in both treatment groups, they were reported at the same rates. This last finding suggests that dose modification for laboratory abnormalities in most cases are effectively managed by dose modification and rarely were these laboratory abnormalities treatment limiting.
The follow slides I will now go through will go in further detail regarding each of these particular safety parameters I have just touched upon in my overview.
First, turning to the most common adverse events reported in this trial, overall, in all three treatment groups, the overall incidence was reported at a comparable rate. Of note, in comparing the Pegasys-Copegus combination to Pegasys monotherapy, there were differences in point estimates between the two groups. With the addition of ribavirin to Pegasys one notes that there was a difference in terms of fatigue, insomnia, appetite decreased and dermatitis.
In comparing the Pegasys-Copegus combination to Rebetron, again one noted point estimate differences in terms of flu-like symptoms such as pyrexia, myalgia, rigors as well as depression.
Turning to serious adverse events in all three treatment groups, serious adverse events were reported infrequently. In addition, on looking at unusual or unexpected adverse events, none were reported on the Pegasys-Copegus combination that have not been previously reported with interferon therapy in general. Furthermore, when we group these particular adverse events under their respective body systems, we noted that the most common adverse events included infections, gastrointestinal disorders and neuropsychiatric disorders. Since infections and depression are two areas of major concern with interferon therapy, we looked at both of these areas in greater detail and I would like to present this information to you.
First, in terms of patients with infections, you'll note that there was a report of all infections reported at a rate of 40 percent on Pegasys monotherapy; 46 percent on Pegasys-Copegus combination; and 35 percent on Rebetron. In terms of the most common causes for these particular infections they included sinusitis, upper respiratory tract infections, tooth abscess, herpes simplex, bronchitis and influenza. We then did a very thorough and comprehensive review of all serious adverse events that were reported in our data base to see if they had an infectious etiology. We looked to see whether a pathogen was isolated or that patients were treated with antibiotics and in so doing identified 7 cases on Pegasys monotherapy, 16 cases on the Pegasys-Copegus combination and 18 cases on Rebetron.
On further review of the 16 cases on the Pegasys-Copegus combination, we noted no predominance of any particular type of infection or involved organ system or particular type of pathogen. In those cases where a pathogen was isolated, the most common pathogens included staph aureus, strep pneumonia and e.coli.
We looked at the time to onset of these infections from the initiation of therapy and as you can see here these infections occurred throughout the course of the study itself. We noted that there was no correlation of infection with a preceding rate for neutropenia. It's important to note that in many of these cases, the patients were hospitalized for these serious infections and therefore the emitting hospital labs were not entered into our data base. And so in order to do another analysis of this information, we looked at a time window around the infection and their lowest ANC and in so doing we have summarized these findings here. The majority of these cases of infection had absolute neutrophil counts of greater than 1500 and there was only one case where the patient had an ANC of less than 500 around the time period of infection. In this particular case, it was a situation of an Oxacillin resistant staph aureus epiglottitis that occurred. At the time of the symptomatology first presenting, the person had an PMN of 1600 and during the next two weeks both the patient's PMN and platelet counts continue to drop prior to them being hospitalized and antibiotic therapy being initiated.
There were 3 of the 16 patients who were withdrawn from therapy and the remaining 13 were able to be effectively treated with antibiotics, the events resolved and the patients continued on therapy. I should also note that none of these 16 cases required GCSF.
Turning to depression, depression was reported at a rate of 20 percent on Pegasys monotherapy; 22 percent on the Pegasys-Copegus combination; and 30 percent on Rebetron. In terms of serious depression necessitating hospitalization, there were no cases on Pegasys monotherapy, two cases on the Pegasys-Copegus combination and seven cases on Rebetron.
In terms of treatment for the depression, 11 percent were reported on Pegasys monotherapy; 14 on the Pegasys-Copegus combination; and 21 percent on Rebetron.
In terms of dose modification, this was, as you can see, rarely done in these treatment groups. And were similar.
Suicidal ideation and suicide attempt were reported relatively infrequently within these groups and at a somewhat similar rate and premature withdrawals were no different in terms of Pegasys, Copegus and Rebetron and was reported at a lower rate on Pegasys monotherapy.
Turning to the deaths that were reported in this trial, there was in total three deaths that occurred; two on Pegasys monotherapy; one on Rebetron and as I indicated there were none on the
Pegasys-Copegus combination. All three of these deaths were considered to be unrelated to therapy and all of them were reported after the discontinuation of therapy.
Turning to dose modification, as I had mentioned in terms of the overview, one notes a higher rate of dose modification of 32 percent on the Pegasys-Copegus combination in comparison to 18 percent on Rebetron. As you can see, this difference is not attributable due to a dose modification for adverse events since these were reported at the same rate in both treatment arms, but rather due to laboratory abnormalities, specifically neutropenia and to a lesser extent thrombocytopenia.
Turning to dose modifications for the ribavirin component of these two combinations, one notes a similar reported rate of 40 percent on Pegasys-Copegus versus 37 percent on Rebetron. The slight difference that is noted is attributable due to anemia.
Turning to laboratory abnormalities, since we had noted this increased rate of modification on the Pegasys-Copegus combination, we wanted to better understand how these laboratory abnormalities were managed.
This slide summarizes patients who had the lowest neutrophil count, grade 4, defined as a neutrophil count of less than 500 cells per ml during the course of study. Grade 4 neutropenia was reported in 8 cases on Pegasys monotherapy, 21 cases on the Pegasys-Copegus combination; and 5 cases on Rebetron.
Looking at specifically how these events were managed, in terms of dose modification whether it be permanent, temporary or not even done one notes of the 21 cases that occurred on the Pegasys-Copegus combination, 18 of these were managed by dose modification and only 3 of them necessitated treatment withdrawal. This finding is also seen on Pegasys monotherapy, where of the 8 cases of Grade 4 neutropenia all 8 were able to be managed by dose modification and none required treatment withdrawal.
Turning to thrombocytopenia, there were no cases of Grade 4 thrombocytopenia defined as a platelet count of less than 20,000. In terms of Grade 3 thrombocytopenia, defined as a platelet count between 20,000 to 50,000, one notes that there were 14 cases reported on Pegasys monotherapy; 22 cases on the Pegasys-Copegus combination; and 1 case on Rebetron. Similar to what we saw with neutropenia, the majority of the cases, 18 out of the 22 were able to be managed by dose modification and only 4 necessitated treatment withdrawal. This was also seen in Pegasys monotherapy, where 13 of the 14 cases were able to be managed by dose modification and only 1 required treatment withdrawal.
Turning to patients with a hemoglobin of less than 10 grams were deciliter that was reported during the conduct of the study, one notes that there were 8 cases on Pegasys monotherapy and a similar number on both the Pegasys-Copegus combination and Rebetron, with a reported rate of 11 percent in both treatment groups. Again, similar to what we have shown previously, the majority of these cases of anemia could be managed by dose modification and a few patients necessitated withdrawal of treatment for this lab abnormality.
Turning to premature withdrawals, as I had indicated previously, there was no difference between the two treatment groups of Pegasys-Copegus and Rebetron in terms of withdrawal. In terms of the most common cause for treatment withdrawal, this was psychiatric events which were reported at 3 percent on the Pegasys-Copegus combination versus 4 percent on Rebetron.
In terms of blood disorders, specifically the neutropenia, thrombocytopenia, anemia, there were 7 cases reported on the Pegasys-Copegus combination in comparison to 3 on Rebetron.
In terms of other reasons for premature withdrawal defined by body system, as you can see all of these were reported at less than 1 percent for the Pegasys-Copegus combination.
I'd like now to turn to our duration and dosing by genotype study, NV15942, and provide a safety comparison of the Pegasys-Copegus combination by duration of treatment and Copegus dose.
This slide provides an overview of the safety profile of the four treatment groups. In terms of the common arm that was studied in both the previous study as well as this, the safety profile that one sees here is similar and consistent to that which we had reported in our 801 comparative trial.
In terms of further benefits of reducing both the duration and dose of Copegus, one notes that there was a reduction in the rate of serious adverse events, dose modifications for both Pegasys as well as more so for Copegus, as well as also in terms of premature withdrawals.
Looking at serious adverse events, although based on body system there was a relatively small number of cases in any particular body system of a serious adverse event, nonetheless, one sees a consistent trend of a reduction of these serious adverse events as one reduces both the duration and dose of treatments.
This is also seen in terms of patients with a hemoglobin of less than 10 grams per deciliter and as one reduces both the dose of Copegus as well as the duration of treatment, one notes this reduction in rates. Furthermore, and as has been seen in the data I've just presented from our comparative trial, one sees that the majority of the cases were able to be managed by dose modification and few patients necessitated treatment withdrawal.
In terms of deaths that were reported in this trial, there were a total of four. Two of these were considered to be unrelated to therapy and two were considered to be related to therapy. The first three cases, the heroin overdose, case of septicemia and suicide, all were reported while the patients were receiving drug and the fourth case of polysubstance overdose was reported approximately four and a half months after the completion of therapy.
Ribavirin is a known teratogen and as such is a major concern both during the conduct of the study itself and for six months after the completion of the study, given the pharmacokinetics of ribavirin. In our two pivotal trials that we've just discussed, we had 10 cases of pregnancy reported in these trials. Three of these occurred in female patients and seven in female partners of male patients, the latter is of concern as ribavirin is distributed into the sperm. In terms of pregnancy outcome, one notes that there were three elective abortions; five normal births; one premature birth that occurred in a female partner at 25 weeks gestation. This was a child that had a normal appearance, unfortunately four days after the birth, the child died of a pulmonary hemorrhage. Both the obstetrician and the treating physician had indicated that they did not feel that this was related to the ribavirin. And there was one case that the patient was lost to follow-up.
While these overall pregnancy outcomes are not remarkable in comparison to the general population, nonetheless, this is an area of major concern to Roche and as such, we intend to implement a Copegus pregnancy risk management program. The elements of this program are summarized on the following slide.
We will be obviously having detailed information regarding pregnancy risk and teratogenicity that will be labeled within the package insert and this will also be reflected in the patient medication guide.
Furthermore, we intend to provide educational brochures to both patients as well as female partners to better understand the risk of pregnancy when taking this therapy and also to have understanding regarding effective contraceptive use.
We will also be providing similar information to health care providers and physicians regarding this type of information.
In addition, should a pregnancy develop in patients, we are implemented a pregnancy registry where we will systematically collect information on these pregnancies and follow up the patients in terms of evaluating their outcomes.
I'd like to now conclude by summarizing the safety findings from these two trials. The clinical safety profile of the Pegasys-Copegus combination is comparable to Rebetron. While there was a higher incidence of laboratory abnormalities, specifically neutropenia and to a lesser extent thrombocytopenia with the Pegasys-Copegus combination in comparison to Rebetron, these events were clinically manageable by dose modification in most cases. And the incidence of discontinuation for safety reasons was the same between the Pegasys-Copegus combination and Rebetron.
Furthermore, in the appropriate HCV population, a shorter duration of the Pegasys-Copegus combination and a lower dose will provide fewer serious adverse events, fewer cases of anemia, fewer dose modifications and fewer premature withdrawals.
I'd like to now turn the mic over to my colleague, Dr. Hoffman, who will give some concluding remarks regarding benefit risk.
Thank you for your attention.
DR. HOFFMAN: Just very briefly before wrapping up our presentation, I wanted to point out that we have a number of on-going studies. I've told you something about the monotherapy program and you've heard now about the combination therapy program. We have a third registration program of two Phase 3 trials which will be concluding in the next year or so, a trial in HCV/HIV coinfection and also a trial in patients with normal ALT. Patients with normal ALT make up perhaps as many as one third of the patients with chronic hepatitis C.
Other on-going efforts that we have outside of registration program include African American patients, cirrhotic patients, the HALTC trial that you may be familiar with, pediatric patients, patients with previous liver transplants, methadone users, nonresponders to previous interferon-based therapies. We're also looking at Pegasys in combination with new therapies as well as other indications, hepatitis B and oncology.
First, what is the impact of adding ribavirin to Pegasys? As demonstrated in the 801 comparative trial, the superior efficacy demonstrated from the combination of Pegasys and Copegus as opposed to Pegasys monotherapy in the overall population as well as in patients with genotype 1 and genotype
non-1.
The safety profile is similar between the combination of monotherapy with the exception of anemia due to the addition of the ribavirin component.
What about looking the combination of Pegasys and Copegus versus Rebetron. Again, superior efficacy demonstrated in the overall population and also by genotype. In genotype 1, the statistical improvement was contributed to both by the low viral load and high viral load patients and in also in genotype non-1.
Overall, a similar safety profile, although as Dr. Solsky mentioned, there was an increase in neutropenia, thrombocytopenia and infections in the Pegasys-Copegus arm. These rarely resulted in premature withdrawal and are treatable with dose modification and there was a lower incidence of depression and certain flu-like symptoms in the Pegasys combination arm.
The second study added some additional information and that is in genotype 1, the highest efficacy was demonstrated with the full dose of Copegus 1000 or 1200 milligrams given for the full duration of 48 weeks. However, for genotype 2,3 not only could the duration be decreased to 24 weeks without apparent loss of efficacy, but also the Copegus dose from 1000 to 1200 down to 800. And this was associated with a significant safety savings.
Now in both this trial and the first trial, we demonstrated that using a combination of quantitative and qualitative measures, HCV RNA, nonresponders could be identified for the most part at week 12.
So in conclusion, the combination of Pegasys and Copegus represents an improvement in the treatment of chronic hepatitis C, both over Pegasys monotherapy and over Rebetron. Importantly, treatment can be tailored according to genotype to optimize benefit risk relationships. Genotype 1 patients do best with full dose of Copegus for a full duration. However, the use of the week 12 predictability can be used to increase benefit risk due to the fact that patients may be adequately treated with 24 weeks of therapy with a lower dose of 800 milligrams of daily Copegus.
This concludes the sponsors presentation. Thank you.
DR. GULICK: Thanks very much, Drs. Teuber, Duff, Solsky and Hoffman.
We're going to hold questions from the Committee until after the Agency presentation.
We're due for a break right now and we will reconvene at 10:15.
(Off the record.)
DR. GULICK: We'll reconvene. Dr. Stanley, can you hear me?
I'm not sure whether that was a yes or not.
Can you hear me, Sharilyn?
DR. STANLEY: I'm here.
DR. GULICK: Okay. We can hear you.
(Laughter.)
DR. STANLEY: Oh good.
DR. GULICK: We turned you down, so you're fine.
DR. STANLEY: Thank you.
DR. GULICK: Okay, we'll turn now to the Agency's presentation by Dr. William Tauber.
DR. TAUBER: Members of the Advisory Committee, ladies and gentlemen, good morning.
I may need some technical assistance here.
(Pause.)
You'll have to forgive my technical inexperience here. In the next hour, we will consider the FDA perspective on the efficacy and safety of Pegasys Copegus. The FDA presentation has two objectives. The first objective is to confirm the sponsor's analyses and interpretation of key clinical data. The second objective is to identify and explain differences between the Agency and the sponsor in the interpretation of some of the safety and efficacy data.
In general, these differences are in areas where clinical data are too few or inconclusive to provide definitive answers. We will be asking the Committee to discuss and provide advice on these issues.
Next slide. This is the first -- actually, the second slide and its intention is to basically draw to focus the purpose of our meeting. The indications and usage of Pegasys and Copegus in combination are indicated for the treatment of previously untreated patients with chronic hepatitis C infection. This is to highlight the fact that this Roche's pegylated interferon product and Roche's ribavirin product.
Moving on to a very brief review of some of the data already discussed by Dr. Hoffman, on the treatment of hepatitis C, interferon alpha-2a monotherapy enjoys a success rate of around 15 percent. Pegylated interferon alpha-2a monotherapy in the recently approved product demonstrated a sustained virological response of 30 percent. Interferon
alpha-2a with ribavirin has a sustained virological response of 45 percent and pegylated interferon
alpha-2b when used in combination with ribavirin in an approved product that's currently available has a sustained virological response in the 50 percent range.
There are worthwhile factors that again I would like to repeat. I know they've been brought up earlier and that is there are factors that we know influence a patient's response to alpha interferon treatment. These factors include HCV genotype and viral load, cirrhosis, advanced or older age and as you see race is listed as an adverse risk and by this we mean that it has been demonstrated that in African American populations the response rate to alpha interferons has not had the same level as was found in the non-minority population.
The next slide, the study drugs and this may seem repetitious, but its point is to make certain that with all the As and Bs that we keep them all straight.
Hoffman-LaRoche and Schering Plough produced products that are part of the study conduct in this application. This is not meant to be an exhaustive cataloging of all the alpha interferons that are available, but simply those that are found in this particular application.
Hoffman-LaRoche makes interferon alpha-2a or Roferon A. It also makes a pegylated interferon alfa-2a and that is Pegasys and for the purposes of this application, they have produced a ribavirin called Copegus in a table form as opposed to the capsule form produced by Schering Plough.
Schering Plough has -- their contribution to this study includes interferon alpha-2b, ribavirin that is called Rebetol and interferon alpha-2b and ribavirin combination or Rebetron.
Dr. Hoffman did an excellent job of reviewing the clinical development so I won't spend much time on this, but I would like to briefly review that the Phase I studies were in monotherapy and they looked at the pharmacokinetics of Pegasys and they looked for the comparability issues between Copegus and Rebetol. The Phase 2 study which Dr. Hoffman did allude to represented a rather small study of 20 patients. Its goal was to examine safety of the combination as well as to gather pharmacokinetic data in particular the effect of food on ribavirin absorption.
Next. The Phase 3 clinical development, as was mentioned earlier, there were two pivotal studies; 15801 which was randomized partially blinded study, comparing Pegasys Copegus to Rebetron. It enrolled 1121 patients as will be discussed.
Study 15942 was also randomized, double blinded and in this case treatment duration was examined to see whether a 12 or 6-month course of therapy would be superior and it was also designed to examine whether a reduced dose of ribavirin would be equivalent or roughly equivalent to the higher dose.
Some time was spent by Dr. Hoffman regarding the rationale for selection of the peg-interferon and ribavirin dosages and I'd like to just review those briefly. There were three monotherapy studies which I'm not going to spend much time on. I would like to -- I have neglected to mention the Phase 2 study that we talked about, the 15800. There was no dose ranging that was performed for the combination within the context of that study.
The rationale for the selection for the ribavirin dose, again the similarity of PK data of Roche's and Schering's ribavirin and whoops -- we're getting ahead of ourselves. The 1000 to 1200 milligrams is the recommended dosage for the approved product Rebetol and formed a reasonable basis for a study in using this Roche ribavirin product. And 800 milligrams, it should be pointed out, is the recommended dosage for Schering's ribavirin and
peg-interferon alpha-2b combination. So it again made a logical step to use that -- select that dosage.
I'd like now to move to the analysis of Phase 3 clinical trials. I'm not going to dwell on the inclusion and exclusion criteria. Dr. Hoffman demonstrated those very well. I would like to point out that this was very much an international study. There were involvement of North and South America, Europe, Asia, New Zealand and Oceania. U.S. patients made up 37 percent of the total patient enrollment for the study, for both studies, excuse me.
The assessment of response in both studies and now what I'd like to do is talk about what these two shared in common. They both started with a primary endpoint at 24 week post-therapy of a combined sustained virological response and sustained biochemical response. In Study 2, this was amended during the conduct of the study to sustained virological response alone. Both studies had futility withdrawal at 24 weeks. And this was very well described and I always seem to get it backwards whether it's positive or negative, but those individuals who did not meet the criteria for early virologic response were to be discharged at 24 weeks time unless they had evidence of a sustain biochemical response, that being that they had a normalization of their ALT. So yes, it is true that there were individuals who were retained with a sustained virological response not achieved, who were continued on therapy because they had met the sustained biochemical response.
Let's go ahead and look at the particulars of the study, 15801, Study 1. The study design, as was very well discussed, enrolled 1121 patients. They were randomized as was cited, 1 to 2 to 2. I'm taking the monotherapy first. The dosing was Pegasys 180 micrograms, subcu, 2 week; Intron A was given at 3 million international units, 3 times a week; and ribavirin was given 1000 to 1200 milligrams in the formula previously mentioned of the 75 kilogram breakpoint. The respective ribavirins were given to the respective interferons.
The primary efficacy analysis for this study was the intention of treating population which was defined as all randomized. The
Cochran-Mantel-Haenszel test with stratification variables of country and genotype were employed. The primary comparator arms here were the Pegasys Copegus and the Rebetron.
I'd like to discuss the demographics of this population. As was shown earlier, they were very well matched, balanced across the study arms. The population was predominantly white male with a median age of 42 to 43 and the median weight was 79 kilograms.
As you look at this slide, you notice that I have broken down the demographics a little bit and I have the U.S. versus the non-U.S. population listed here and there's a purpose for that. The first of these being that although the gender and race attributes are the same between the two divisions, U.S. versus non-U.S., when you look at those patients over the age of 44 and I guess it's difficult to call that elderly, but those over 44, I chose the median point of U.S. population versus non-U.S. and you'll see that half of the American patients or U.S. patients were over 44 years old as opposed to 35 percent of the non-U.S. and I know only too well weight was a bigger factor in U.S. patients than it was in non-U.S. patients.
What about the baseline disease characteristics? As was mentioned earlier, we know that high viral load, genotype 1 and cirrhosis are all adverse factors. Well, how did that work in terms of the U.S. versus the non-U.S.? Well, the U.S. had a little bit more of everything: 68 percent of the high viral load, 70 percent of the U.S. patients had genotype 1 and cirrhosis was found 16 percent versus 11 percent.
Well, that's who was enrolled. What happened to them? This is the primary advocacy outcome, you've already seen and this is the combined response that we spoke of, that was spoken of earlier. And there's a 6 percent difference between these two values and the P-value is 0.057.
If the primary efficacy analysis is examined as the sustained virological response, the numbers are a bit different with 50 percent versus 42 and at this point the P-value is now 0.01.
What about subgroups? Obviously, at this point we're looking at more descriptive analyses since we've already moved beyond the primary statistical analysis.
This is the all treated population and you see that again the delta between the Pegasys Copegus and the Rebetron is now 9 percent. The striking thing about this -- there are a couple of things that I'd like to bring to your attention about this particular slide. First of all, the delta was positive in all the categories with the one exception being in black patients versus white patients. And the reason for this is that the numbers are so -- perhaps are so small that we cannot determine the meaning of this data. There's 40 individuals involved in the two arms.
Another thing that I'd like to point out and the standard things that we would have expected occurred. Patients with cirrhosis did less well than patients without cirrhosis. Patients that were younger did better than patients who were older. And the other thing I wanted to point out is perhaps a little bit unexpectedly, but maybe not, the U.S. patients, although the same difference with the superiority of Pegasys Copegus existed, you'll notice that the difference between within the arm, between U.S. and non-U.S. patients is considerable in both arms. This was not just Pegasys Copegus, but Rebetron also demonstrated this very same phenomenon.
What about histologic responders? This has obviously been a very important issue that has been addressed in the past and I wanted to touch on it today.
The first point I wanted to make is that only a small fraction of the total population had a liver biopsy. We're talking about there were 198 patients that actually underwent impaired liver biopsy. There were approximately 285 that had been originally planned.
When you look at the results, the results are somewhat similar across all three study arms. You see that from a low of 72 percent up to a high of 80 percent. There still is, regardless of treatment, a large number of responders in both groups. You might ask what is the type of response that you see and it's predominantly inflammatory. For those that are responders, the majority were individuals that showed improvement in inflammatory scores. The HAI scores, you all recall, is a compilation of four factors with a numerical score assigned and the fourth factor being fibrosis and the other three being inflammatory.
If you look at fibrosis alone, of these responders, the only -- about 31 individuals out of 198 actually showed improvement in their fibrosis scores.
Well, what about sustained virological response by genotype and region? We've talked about the region. We've seen some things, what does it look like when we compare it graphically?
Genotype 1, you'll notice -- to orient you, the first -- the red, I'm sorry, the red and the orange are somewhat similar, but the red is the Pegasys Copegus SVR in the U.S. The green is the Rebetron in the U.S. The blue is the Pegasys in the non-U.S. and the orange is the Rebetron in the non-U.S.
And what you see -- what we were talking about earlier is that in each case this bar is taller than this bar except perhaps this one here, but the blue bars are, as you see, invariably taller than the red bars which again is graphic evidence that there is a difference between the two populations in terms of sustained virological response.
If we take away the region, then this all becomes a lot simpler and the red bar which is the Pegasys is uniformly superior in all categories, genotype 1, genotype non-1, high viral titer and low rival titer.
Well, here's my favorite. Body weight. Does it make a difference? Well, actually it does. If you choose 85 kilograms, that's the 50 percent mark for the U.S. population, you find that the red bars which are those individuals that are under 85 kilograms appeared to have a better efficacy than those individuals who were greater than 85 kilograms.
I'd like to move to adverse events. I would like to point out that as was pointed out by Dr. Solsky, that the severe adverse events were fairly well matched across all three study arms. The serious adverse events were as you see them 12 percent in the two Pegasys containing arms versus 9 percent in the Rebetron arm. I have the deaths percentages, but they're the same numbers that Dr. Solsky presented.
Withdrawals between the two comparator arms are very similar, at 10 percent, 11 percent. I'd like to stress, however, the difference between the dose modification and point out that Pegasys had a 32 percent increase and Rebetron, an 18 percent. The two ribavirin containing arms had very similar adverse events.
How about serious adverse events? Serious adverse events were numerically higher in the study arms containing Pegasys, either as monotherapy or in combination with Copegus than they were in the Rebetron arm. If we combined neuro-psychiatric because it's sometimes difficult to tease these apart, patients with insomnia and with difficulty concentrating it may be we we're talking about depression or maybe it's a neurologic, but what is seen that there's pretty much a constant value across. There's not a large difference between the three study arms.
Infection, I guess it depends on how you round it. The sponsor has 4 percent for infection. I have 3 percent. It's really 3.4. I guess we'll just have to go with that.
Gastrointestinal adverse events, serious adverse events were more common in those individuals that were receiving ribavirin.
How about number of serious infections? Well, the incidence of serious infections was numerically twice as high in the Pegasys arm. Actually, in both Pegasys arms than it was in the Rebetron arm, although the difference is more marked in the Pegasys Copegus than it is in the Pegasys monotherapy. Most of the infections, although there wasn't a predominant organism, there was a predominant type. These were bacteria and not only were they bacteria, they were bacteria that were members of a patient's normal flora.
There was severe neutropenia and leukocytopenia, occasionally documented in proximity to the infections and it's unknown exactly what the contribution of the neutropenia and leukocytopenia might have been, if any.
Next slide. Neutropenia was very common. As was stated earlier, Grade 4 occurred 5 percent of the time, but there is a great deal of neutropenia. Very few patients did not develop neutropenia while on study.
I'd like to point out there are two curves here. There's a blue curve and there's a green curve and the green curve being the Pegasys Copegus is shifted to the Grade 3 neutropenia. The blue curve seems to peak at the Grade 2 or 500 points higher. And you could argue well, okay, so, but obviously this would be a less desirable outcome for the clinician.
What about lymphocytopenia. Lymphocytopenia was also very common, but unlike neutropenia it appeared to be fairly balanced across all three study arms with the exception that it appears the monotherapy and there's a -- the way this is presented, gives you the feeling as if there was a lot more problems with the monotherapy, and that's just because there were very few monotherapy that continued to go on.
What I'd like to point out here is that lymphopenia was more common, appeared to be more common, more severe in the ribavirin containing arms. Again, the role for ribavirin in terms of lymphopenia is not known.
What about patient withdrawal numbers? As was pointed out earlier by Dr. Solsky, the numbers are very similar, 11 percent in the Rebetron and 10 percent in the Pegasys arm. Adverse events were again fairly well matched and there was a tendency or trend toward increased psychiatric discharges in the Rebetron -- withdrawals compared to the Pegasys arm.
Laboratory abnormalities were patients were seldom withdrawn for laboratory abnormalities and they were fairly well matched between the two comparator arms.
What about dose modifications? Well, dose modifications were mostly done for laboratory abnormalities. In this slide, just to orient you again, this goes with this and this goes with that, but I put them side by side so you can see a head to head competition or comparison, better word, between the two interferons and the two ribavirins. The things to point out here is that most common reason for dose modification in the interferon components was neutropenia and thrombocytopenia. That being said, Pegasys appeared to have a higher incidence. These are percentages now, a higher incidence of neutropenia than did the Intron A. Thrombocytopenia, likewise, was more common in the Pegasys than in the Intron A.
I wanted to talk about serum triglyceride briefly. It has been reported in the literature that serum triglycerides do -- are elevated during interferon treatment and that was found in this study. And it looks as if most of the three study arms are fairly well matched. The difficulty with interpreting this data, however, is that these are random triglyceride levels and it is uncertain what the values would be if they were consistently drawn on a fasting -- in a fasting state.
What about laboratory abnormalities by weight? We evaluated the potential influence of body weight on safety profile of interferon alpha-2a ribavirin. The incidence of anemia and that's a hemoglobin less than 10 and to orient you, I selected 65 kilograms and what you'll see that in the monotherapy, there seems to be a slight increase between the under 65 and over or greater than or equal to 65, but in the ribavirin arms that difference is accentuated.
When you look at neutropenia, there is in the nonribavirin containing arms, very little difference between the 65 kilogram and above 65. However, in the Pegasys Copegus group, there is not only is there overall a higher degree of neutropenia, but there is a little bit more of a difference between them, again potentially asking a question about ribavirin.
Well, maybe it isn't just weight. Maybe it has to do with obesity or not obesity. That sounds like a question. If you look at BMI of 25 as being the breakpoint between when a patient is determined to be obese or not and you ask the same question we did with the 65 kilograms, what you find is and that again this seems to hold some merit in that the bar, the under 25, this appears to be taller, ever so slightly than the -- than its companion bar, so maybe obesity has some protective value here. And in neutropenia, again separating them out, the difference is small, but it certainly is consistent.
Summary. The first point I want to make is that Pegasys, 180 micrograms subcu Q week, combined with Copegus 1000 to 1200 milligrams per day in divided doses has a higher sustained virological response than does Intron A with Rebetol, Intron A at 3 million International Units three times a week and the Rebetol being 1000, 1200 similarly dosed.
The treatment difference again using the sustained virological response is 8 percent. Prognostic factors associated with lower response include hepatitis C virus, genotype 1; high viral titer, that being defined as those greater than 2 million copies per milliliter; cirrhosis, older age, higher body weight, which we've added to the list; and response rates are lower in the U.S. compared to the non-U.S.
What about safety? Pegasys Copegus had higher observed incidence of certain adverse events compared to Rebetron. Serious adverse events were numerically higher, 12 percent versus 9 percent. Serious infections were 3.4 percent versus 1.7 percent. Grade 4 neutropenia was 5 percent versus 1 percent. Grade 3 thrombocytopenia was also 5 percent versus 0.2 percent. Dose modifications were required or used in 32 percent versus 18 percent. Both products had similar premature withdrawals and there was greater toxicity perhaps with lower body weight.
Moving on to the second study, 15942. The clinical protocol which has already been gone over, there was 1311 patients who were randomized by genotype, viral load to four arms receiving the same dose of Pegasys, 180 micrograms, subcu per week. The two treatment arms were 24 weeks versus 48 weeks. The two ribavirin dose arms were 800 milligrams of fixed dose and 1200 milligrams, again weight adjusted, crudely at the 75 kilogram level.
The primary efficacy analysis was a sustained virological response and the intention to treat population which in this instance was defined as all randomized patients who had received at least 1 dose of study medication.
The Cochran-Mantel-Haenszel test with stratification variables of region; HCV genotype and titer and ribavirin dose were utilized.
I place this slide because as was mentioned earlier, this was an unequal allocation study. It was reasoned that the individuals with the genotype 1 high viral load were the most difficult to treat and they were categorized as such and it was basically felt that the other three, including genotype 1 low viral load might behave more in common with genotype non-1 than it did with genotype 1 high viral load. Therefore, the allocation and this is the actual numbers. There were some modification during the conduct of the trial and these are the actual proportions that resulted at the end.
There were 1 to 1 to 4 to 4 of the genotype 1 high viral load and all the other three arms, the three strata, excuse me, were allocated alike, it was originally 1 to 2, so when it was changed from 1 to 1 to 1, we got a value in between of 1.5 in the higher ribavirin dosages than in the lower ribavirin dosages.
The primary objective as was stated earlier of this trial was to prove the superiority of 48 week treatment versus 24 week and also to examine whether 800 milligrams of ribavirin was equivalent to 1000/1200 in terms of efficacy.
Here are the population characteristics of this population. Again, I'll point out the same things that are different and that is that Americans are older in this and they're heavier.
What about baseline disease characteristics? The high titer were relatively equally matched between the two populations. As was stated earlier, the genotype 1 because of the nature of the study which was to look at the non-1 population, the overall percentages are 58 percent versus the 65 percent in the first study. So there are more genotype 1 in this study.
Cirrhosis was more prevalent in this study at 25 percent. U.S. population had 29 percent. The non-U.S., 23 percent. And genotype 1 was 61 percent versus as you can see 56.
The way to present this data, because it is important to stress that all four arms of the study are not comparable in the same way because they have different patient populations because of the unequal allocation. Therefore, you can't take a sustained virological response from arm 1 and directly compare it arm 3 and have a meaningful analysis.
Therefore, we're looking at the pooled analysis, comparing 48 weeks with 24 and 1000/1200 with 800. The odds ratio favoring the 48 week was 1.32 and this is the interval. P-value was 0.039. How about the ribavirin dose? Again, the odds ratio was 1.5 favoring the higher dose for the total population and the P-value was 0.018.
At this point we leave the statistically significant area of the analysis and look at the descriptive. What about the percent sustained virological response by strata? I'm afraid the strata have gone through the ceiling. Treatment duration and ribavirin dose.
What you see here again using the same pooled format is that the 48 week for the genotype 1 high viral load appears to be higher than the 24 week and the 1000 -- there's a 1200 milligram there also. Also, appears to be higher than its companion fixed 800 milligram.
If you look at the 3 strata, there were felt to be low, lower difficulty in treating, you find that in genotype 1 again, the same number trends are there, 57 versus 47 and 56 versus 47. And when you get to the non-1s, it seems as though there's very little difference between the 48 week versus the 24 and 1000/1200 versus 800.
What about how would this look if it was presented graphically and what you see here, again, and what's shown earlier in a different slide by the sponsor is that the genotype 1, there seems to be a fairly steady step-wise increase as you start from the 24 week Pegasys with 800 milligram to 24 week all the way up to the Pegasys 1000/1200 milligrams at 48 weeks. And you see graphically the differences are much less in the non-1 and almost the same slide, a different technique, the genotype 1 low with again, the 48 week being preferable with the high dose being with the genotype 1 even in the low titer appeared to be more successful.
Now this is a bit contrary to the hypothesis of the study which was the genotype 1 low viral load would behave in a different way.
What about sustained virological response by body weight. Again, the people that were under 85 kilograms appeared to have a higher level of sustained virological response than those above 85 kilograms.
What about cirrhotics? This is a somewhat difficult area because the number of patients is relatively small. As was stated earlier, the genotype 1 cirrhotics are perhaps the group that is most difficult to treat and using the same formulation with the 48 week versus 24 and the 1000/1200 versus 800, it would appear that in general, the trends appear to favor the high dose of ribavirin in the 48 week, but it is a little bit difficult to make these conclusions because the numbers are small and it's even more of an issue in the non-1 population.
Genotype 4 needs to be mentioned here. And just to remind you, I am well aware of your expertise, but there are five different genotypes within the non-1 group. These genotypes are not -- there are more than five. These genotypes are not entirely uniform in their response to Pegasys Copegus. Genotype 4 is known from the literature to have intermediate sensitivity to alfa interferons and the data collected in the study was consistent with that.
There were 36 individuals, however, so we have to be very cautious in making too great an interpretation. It would seem that in looking at genotype 4 that 48 weeks appears to be superior to 24 and the higher dose ribavirin, the 1000/1200 milligrams appears to be superior to the 800 milligrams. However, when you're dealing with an n of 13 individuals, you probably are on shaky ground for making any large conclusions.
What about histology? Patients with paired biopsies. Two-hundred sixty patients underwent paired biopsy in this study and again, this is the same HAI score with less than two -- with a 2 point or greater decrease in the HAI score being interpreted as being a responder. In this case, it looks like in the portion of patients who had paired biopsies as though the number of responders is somewhat the same across all four study arms. There is some difference, but it's not very large and again, looking for the participation of what does the histology mean, this was -- whoops, we're getting ahead of ourselves.
The histology again was mostly inflammatory. The number of individuals that had a decrease in their fibrotic score was 19 of the 260 individuals and only 17 of those individuals actually sustained definition of being a responder.
DR. FLEMING: Could I ask one point of information before you leave. Dr. Tauber, you've been very careful and appropriate to recognize the confounding in this randomization design when you were looking at sustained viral load.
Now you're getting into histology and the same confounding exists, but you're not accounting for it on this slide.
DR. TAUBER: Point well taken.
DR. GULICK: Can I ask that we hold further comments and then we'll come back in the question and answer period? Thanks.
DR. TAUBER: Moving on to adverse events. There were fewer severe and serious adverse events in the 24 week arms than in the 48 week. Dose reductions for Pegasys occurred in all four arms, but appeared to be highest in the 48 week 1000/1200 milligram ribavirin dose.
Dose reductions for ribavirin appeared to be lower in the 24 week 800 milligram ribavirin arm as was echoing what was stated by the sponsor.
What about serious adverse events? Serious adverse events incidence was higher in the 48 week arms than in the 24 week. The serious adverse events incidence was lower in the 24 week, 800 milligram ribavirin arm than in the 48 week, 1000/1200 milligram arm.
Serious infections had higher incidence in the 48 week, 1000/1200 milligram arm as you can see.
Next. To speak a little bit more about the serious infections, as you can see there was apparent increase as I just stated in the Pegasys Copegus higher 1000/1200 milligram arm for 48 weeks. These were again mostly bacterial. The recovered organisms were bacteria that you would common associated with normal human flora.
Again, the issue of neutropenia and lymphopenia is raised and I wanted to go forward at this point and talk and present two brief case reports from the two studies.
The first of these is a 68-year-old man who developed difficulty swallowing and fever on study day 33. On study day 47, severe neutropenia with an absolute neutrophil of 400 was detected and he was appropriately discontinued from his dosage of Pegasys and 1200 milligrams per day of Copegus. On day 59, hospital admission occurred with severe throat pain, anemia, neutropenia and thrombocytopenia and this case was brought up earlier. Staph aureus epiglottitis was diagnosed by laryngoscopy and he was also noted to have staph aureus recovered from his urine. He was placed on high dose antibiotics, given red cell transfusions and made a very miraculous recovery.
On the -- what is not on here is that on day 65 his ANC had risen to a value of 1000. So he had had a response, but he still fulfilled the criteria of being neutropenic.
The second study is the septicemic death from the second study. This is a 45-year-old man who sustained a splinter injury to his hand on day 55. His treatment regimen was Pegasys Copegus 800 milligrams per day in divided dosage. On day 58 the splinter was removed. His wound was cleansed and he was noted to have an ANC of 800. On day 60 he returned for a wound check and at that time he was offered and refused antibiotics. On day 62 through 63, he developed a fever to 39 degree Celsius, agitation oliguria. By day 64 he was in frank septic shock, was admitted to the hospital in transfer from his clinic. His admission ANC was 2600, but it was then recorded as being 0 within 12 hours of admission. His blood cultures great grand positive cocci, consistent with staph aureus and on day 65 he expired.
Neutropenia during treatment and follow-up, again looking at neutropenia, there was a lot of neutropenia in this study as well. There was the peak because was found mostly in the grade 3 area and about 5 percent as was seen in the first study, developed grade 4 neutropenia during the conduct of the trial.
Lymphopenia was also demonstrated in this study as it was in the first with a peak in the grade 2 area.
What about numbers of patients withdrawn? The incidence of withdrawal was lower in the 24 week arms than in the 48 week. Adverse events would more commonly cause withdrawal than laboratory abnormalities. Neuropsychiatric adverse events were the most frequent cause of patient withdrawal overall.
What about dose modifications? And I've done the same thing here just for reference. This peg-interferon goes with that 800 and this
peg-interferon goes with the 1000/1200 milligrams, but placing them side by side allows you to compare the performance.
Pegasys was most often modified for laboratory abnormalities which were predominantly neutropenia, thrombocytopenia and were pretty well the same in both of these two 24 week study arms.
Copegus in the 24 week arms were more often dose modified for adverse events than they were for laboratory abnormalities and the laboratory abnormalities, when they did occur were -- would be anticipated in the area of anemia.
What about the 48-week arms? Similar trends are seen in the 48 and the 24 week groups regarding dose modifications. Pegasys was modified more commonly for laboratory abnormalities than for adverse events. The most common laboratory abnormalities were neutropenia and thrombocytopenia. The neutropenia and the thrombocytopenia were higher in the 1000 to 1200 milligram ribavirin arms than in the 800 milligram arms.
Ribavirin was -- Copegus was modified more often for adverse events than for laboratory abnormalities. Laboratory abnormalities were predominantly anemia and may have had a contribution to make in terms of the -- I'm sorry, were lower in incidence in the 800 milligram ribavirin arm than in the 1000/1200 milligram arm.
Lab abnormalities by weight. The same principles as we used in the analysis. This is descriptive. Looking at those individuals under 65 kilograms versus those that are over 65 kilograms. Consistently, the under 65 kilogram, there are four arms to the study, but in each of the four, the companion arm is lower in terms of hemoglobins less than 10. When you look at neutropenia grade 3 or higher, that same trend is found with the lower than 65 kilogram arm being somewhat higher in incidence than the companion arm of those greater than 65 kilograms.
What about BMI? Again, looking at the potential influence of obesity with being under 25, being considered to be fit and those over 25 or equal to possibly being obese. The hemoglobins again reflect a very similar trend as found in the 65 kilogram cut point. As you see, the first arm, the under 25 in each of these couplets is taller, even though it's very, very much less discernible in these, the lower ribavirin doses than it is in the higher ribavirin doses. Neutropenia, again appears to be somewhat higher in the 25, in the under 25 BMI versus the over 25.
Conclusions. Sustained virological response in patients infected with genotype 1 had the highest sustained virological response when 180 micrograms of Pegasys and 1000 to 1200 milligrams of ribavirin were administered for 48 weeks.
How about the patients with genotype non-1? The sustained virological response was similar in all four treatment regimens.
What about genotype 4? Well, it seems highest with the combination of 1000/1200 milligrams of ribavirin for 48 weeks, but there really are too few patients to make a conclusion.
Response rates in the U.S. sites were lower compared to the non-U.S. and perhaps further assessment is needed.
What about safety? Twenty-four weeks with Pegasys and the lower or 800 milligram dose of ribavirin compared to the 800 or the 1000/1200 milligram ribavirin compared to the 48 week therapy demonstrated lower incidence of severe or serious adverse events, fewer withdrawals and fewer dose modification of either the Pegasys or the Copegus. The 48 week 1000/1200 milligram ribavirin was associated with higher serious infections, withdrawals for neutropenia. The 800 milligram ribavirin compared to the 1000/1200 milligram ribavirin dose demonstrated lower incidence of ribavirin dose modification and serious adverse events. And there's insufficient data to assess neutropenia in serious infections and it was noted that it was a fatal infection study in which severe neutropenia was recorded.
What about the risk benefit that was derived from these studies? Well, therapy with 800 milligrams of ribavirin for 24 weeks compared to 800 or 1000/1200 milligrams of ribavirin for 48 weeks demonstrated less serious toxicity and similar sustained viral response.
Are there unresolved questions? Well, yes. There are many factors that obviously affect treatment response and toxicity. The dose, the Pegasys and ribavirin and the duration of treatment, the HCV genotype and titers perhaps need further exploration, geographic and other baseline characteristics including weight might be explored.
Needs for additional studies, optimization of peginterferon and ribavirin dose and exposure. Weight base versus fixed dosing. Confirm the hypotheses raised by study 2 in patients with HCV genotype 1 and low viral titer and HCV genotype 4.
Is that it?
I believe that concludes my remarks. Thank you very much for your attention.
DR. GULICK: Thank you. At this point, we're going to open it up to the Committee for questions. I'd like people to really stick to points of information and questions of clarification, try to refrain from jumping into the issues that we will discuss this afternoon.
And these can be either of the sponsor or the Agency.
Dr. So, do you want to start us off?
DR. SO: Could you -- since we are being asked to approve this drug for the treatment of chronic hep C and patients with elevated ALT, could the -- could we define elevated ALT? Is it for inclusion in the trial, was that beyond a certain how many times above normal?
DR. HOFFMAN: Hoffman from the sponsor. Patients who had any elevation in ALT were permitted into the trial on two occasions prior to -- during the screening period.
DR. SO: So if the optimal limit of normal is 40, so if the patient is 42, he's eligible for enrollment?
DR. HOFFMAN: If he had two values which were above the upper limit of normal, the patient would be eligible.
DR. GULICK: Dr. Hoofnagle?
DR. HOOFNAGLE: Ask a question about what you mean by high viral load. I think you misspoke the level of virus as an average in the groups. It was 6 and 5.8. That wasn't 6 million that was 26, wasn't it? And 105.8 in the various groups.
So how did you -- what was the set point for high versus low and how does that compare to the studies that were done with the other peginterferon alpha-2a? Because I believe you used a different methodology for measuring high versus low viral load.
DR. HOFFMAN: No, actually when we designed these studies it was still fairly early on. It was back in 1998 and 1999, so it's still two million. We since that time moved on to the international units where we defined as 800,000, greater than 800,000 or less than 800,000.
DR. HOOFNAGLE: But is that two million similar to the two million obtained in the previous trials reported by Schering? I believe they used the NGI assay?
DR. HOFFMAN: That's difficult to say because of the difference in the techniques.
DR. HOOFNAGLE: And did you look at any other cut points for high versus low? This is important for your second trial where you had the stratification and so forth which showed that it looked like even with a low viral load, genotype 1 patients had a higher response with longer therapy?
DR. HOFFMAN: No, we did not. We looked at 2 million. However, your point is well taken.
DR. HOOFNAGLE: Then I'd like to point out that this is a little bit higher viral load than reported with the previous product. It's more likely a bit higher.
DR. HOFFMAN: Two million versus two million?
DR. HOOFNAGLE: Yes.
DR. GULICK: Dr. Kumar?
DR. KUMAR: Dr. Hoffman, could I ask you what is the difference between your ribavirin product and the Rebetol that's currently available other than one being capsule and one being tablet. Is there any inherent differences between the two products?
DR. HOFFMAN: No. The ribavirin is the same chemical.
DR. KUMAR: And can I follow up with a question? As a clinician, will I be able to rite for your product separately or will it be bundled and will I be able to use it only with pegylated interferon?
DR. HOFFMAN: No, application contains both products as separate components.
DR. KUMAR: Thank you. Could I ask you how you determined depression in your patients? At each site did they actively ask the patients about depression or did patients complain about depression and then was it recorded in the case support form?
DR. HOFFMAN: Yes, this is an area of some methodological problems because there's really no good depression scale that's appropriate for interferon therapy. We don't believe the Becks is the right scale for it as well. And if you ask patients directly about any adverse event you tend to get a higher incidence than if you just wait for them to volunteer it.
So in our studies, what we did is we measured depression according to what patients volunteered.
DR. KUMAR: Thank you.
DR. GULICK: Dr. Sun and then Dr. Wood.
DR. SUN: In the Phase 3 studies for patients that weighed more than 75 kilograms, they could receive either 1000 or 1200 milligrams of ribavirin. How was it determined which dose they received?
DR. HOFFMAN: Here's the clarification. If they weighed less than 75 kilograms, they were assigned to 1000 in that group. If they weighed 75 kilograms or more, they received 1200.
DR. GULICK: Dr. Wood and then Dr. Fletcher.
DR. WOOD: I have several questions regarding African American patients in your studies. I'm very concerned in terms of the response rates because in the first study there was really no difference among the African American subpopulation.
My first question is in reviewing the pharmacokinetic data, you report in your report breakouts according to weight.
Do you have any data specifically that looks at pharmacokinetics in African Americans?
DR. HOFFMAN: Yes, we do and Karin Jorga of clinical pharmacology will respond.
DR. JORGA: We did a population of pharmacokinetic analysis in our Phase 3 pivotal trials and we looked at the effect of covariates and pharmacokinetics of ribavirin and could I have the slide up, please? This is what you are seeing here. This is the influence of race on the clearance of ribavirin. There is a difference. The African Americans have a higher clearance which leads to low exposure in this population. The difference, however, is relatively small if you look at the scale. It's around 20 percent difference between these two races.
DR. WOOD: My next question and follow-up