DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ANTIVIRAL DRUGS ADVISORY COMMITTEE
Friday, March 11, 2005
Salons A and B
Hilton Washington DC North/Gaithersberg
620 Perry Parkway
P A R T I C I P A N T S
Janet A. Englund, M.D., Chair
Anuja M. Patel, M.P.H., Executive Secretary
John A. Bartlett, M.D.
Victor G. DeGruttola, Sc.D.
Douglas G. Fish, M.D.
John G. Gerber, M.D.
Richard H. Haubrich, M.D.
Victoria A. Johnson, M.D.
Robert J. Munk, Ph.D. (Consumer Representative)
Lynn A. Paxton, M.D., M.P.H.
Kenneth E. Sherman, M.D., Ph.D.
Eugene Sun, M.D. (Industry Representative)
Maribel Rodriguez-Torres, M.D.
Lauren V. Wood, M.D.
Ronald G. Washburn, M.D.
Special Government Employee Consultants (Voting):
Samuel K. So, M.D., B.S.
Kathleen Schwarz, M.D.
Government Employee Consultants (Voting):
Beth P. Bell, M.D., M.P.H.
Ronald Herbert, D.V.M., Ph.D.
Leonard B. Seeff, M.D.
SGE Patient Representative (Voting)
Mark J. Goldberger, M.D., M.P.H., CDER
Debra B. Birnkrant, M.D., CDER
Linda L. Lewis, M.D., CDER
James G. Farrelly, Ph.D., CDER
C O N T E N T S
Call to Order and Opening Remarks,
Janet Englund, M.D., Chair 4
Conflict of Interest Statement, Anuja Patel, M.P.H.
Executive Secretary, FDA 7
Overview of Issues, Debra B. Birnkrant, M.D.,
Director, DAVDP 10
Introduction, Elliott Sigal, M.D., Ph.D. 16
Background, Richard Colonno, Ph.D. 20
Nonclinical Safety, Lois Lehman-McKeeman, Ph.D. 28
Clinical Efficacy and Safety, Evren Atillasoy, M.D. 37
Resistance, Richard Colonno, Ph.D. 58
Pharmacovigilance and Summary, Donna Morgan Murray,
Questions from the Committee 77
Carcinogenicity Issues, James G. Farrelly, Ph.D.. 108
Clinical Issues, Linda L. Lewis, M.D. 119
Advisory Committee Discussion of Questions
Question 1: 185
Question 2: 202
Question 3: 204
Question 4: 221
Question 5: 235
Question 6: 267
1 P R O C E E D I N G S
2 Call to Order and Opening Remarks
3 DR. ENGLUND: Good morning. Welcome,
4 everyone. My name is Janet Englund. I am the
5 acting chairperson today and I would like to
6 welcome you to the Antiviral Drugs Advisory
8 Today we are going to discuss the new drug
9 application 21-797 and 21-798 for entecavir tablets
10 and entecavir oral solution, respectively, by
11 Bristol-Myers Squibb Company. These drugs are
12 proposed for the treatment of patients with chronic
13 hepatitis B infection.
14 With that, I would like to call the
15 meeting to order and introduce the committee
16 members. In fact, I will have you introduce
17 yourselves because that would be better. I would
18 like to just remind everyone on this committee that
19 this is being transcribed and so, before you speak,
20 you are going to need to identify yourself but, for
21 now, if we could just start maybe with Dr. Sun and
22 just introduce yourself and your affiliation.
23 DR. SUN: Eugene Sun, Abbott Laboratories.
24 DR. GERBER: John Gerber, University of
Colorado Health Sciences Center.
1 DR. WASHBURN: Ron Washburn, Shreveport VA
2 and LSU.
3 DR. FISH: Douglas Fish, Albany Medical
4 College, Albany, New York.
5 DR. HERBERT: Ron Herbert, National
6 Institutes of Environmental Health Sciences and the
7 National Toxicology Program.
8 DR. SHERMAN: Ken Sherman, University of
10 DR. JOHNSON: Victoria Johnson, University
11 of Alabama at Birmingham.
12 DR. PAXTON: Lynn Paxton, Centers for
13 Disease Control and Prevention.
14 DR. WOOD: Lauren Wood, National Cancer
16 MR. GRODECK: Brett Grodeck, patient
18 MS. PATEL: Anuja Patel, Executive
secretary for the Antiviral Drugs Advisory
1 Committee, the Food and Drug Administration.
2 DR. ENGLUND: I am Janet Englund, from
3 Children's Hospital and University of Washington,
4 in Seattle.
5 DR. DEGRUTTOLA: Victor DeGruttola,
6 Harvard School of Public Health.
7 DR. BARTLETT: I am John A. Bartlett, from
8 Duke University.
9 DR. HAUBRICH: Richard Haubrich,
10 University of California in San Diego.
11 DR. MUNK: Bob Munk, consumer
13 DR. SEEFF: Leonard Seeff, Liver Disease
14 Branch, NIDDK, National Institutes of Health.
15 DR. BELL: Beth Bell, Centers for Disease
16 Control and Prevention.
17 DR. SCHWARZ: Kathy Schwarz, Johns Hopkins
19 DR. FARRELLY: Jim Farrelly, Division of
20 Antiviral Drugs, FDA.
21 DR. LEWIS: Linda Lewis, Division of
22 Antiviral Drugs, FDA.
23 DR. BIRNKRANT: Debbie Birnkrant, Division
24 Director, Division of Antiviral Drugs, Food and
1 DR. ENGLUND: And Dr. Mark Goldberger,
2 from the FDA, will be joining us momentarily. At
3 this point I would like to have Anuja Patel read
4 for us the conflict of interest statement.
5 Conflict of Interest Statement
6 MS. PATEL: Thank you. The following
7 announcement addresses the issue of conflict of
8 interest and is made part of the record to preclude
9 even the appearance of such at this meeting. Based
10 on the submitted agenda and all financial interests
11 reported by the committee participants, it has been
12 determined that all interests in firms regulated by
13 the Center for Drug Evaluation and Research present
14 no potential for an appearance of a conflict of
15 interest, with the following exceptions:
16 In accordance with 18 USC Section
17 208(b)(3), full waivers have been granted to the
18 following participants, Dr. Johnson for her
employer's contract with a federal agency to
1 provide virology laboratory support for the adult
2 AIDS clinical trials group. The contract is funded
3 for greater than $300,000 per year. Dr. Gerber for
4 consulting on unrelated matters for the sponsor and
5 a competitor. He receives less than $10,001 per
6 year per firm. Dr. Bartlett for serving on
7 speakers bureaus for two competitors. He receives
8 greater than $10,000 from one firm and between
9 $5,001 to $10,000 per year from the other. Dr.
10 Sherman for serving on speakers bureaus for two
11 competitors. He receives from $5,001 to $10,000 a
12 year from each firm. Dr. Munk for consulting on
13 unrelated matters for a competitor. He receives
14 less than $10,001 a year.
15 Dr. Schwarz has been granted waivers under
16 (b)(3) and 21 USC 355(n)(4) for her employer's
17 grant to study competing products. Each grant is
18 funded for less than $100,000 per firm per year.
19 Dr. Haubrich has been granted a (b)(3) waiver for
20 consulting on unrelated matters for a competitor
21 and the sponsor. He receives less than $10,001 per
year per firm. Brett Grodeck has
been granted a
1 355(n)(4) waiver for owning stock in a competitor,
2 valued at less than $5,001. Because the stock in a
3 competitor does not exceed $25,000, 5 CFR
4 2640.202(a)(2) exception applies and a (b)(3)
5 wavier is not required. Dr. DeGruttola has been
6 granted a (b)(3) waiver for consulting on unrelated
7 matters for two competitors. He receives less than
8 $10,001 a year from each firm.
9 A copy of the waiver statements may be
10 obtained by submitting a written request to the
11 agency's Freedom of Information Office, Room 12A-30
12 of the Parklawn Building.
13 In the event that the discussions involve
14 any other products or firms not already on the
15 agenda for which an FDA participant has a financial
16 interest, the participants are aware of the need to
17 exclude themselves from such involvement and their
18 exclusion will be noted for the record.
19 We would also like to note that Dr. Sun
20 has been invited to participate as an industry
21 representative, acting on behalf of the regulated
industry. Dr. Sun is employed by
2 With respect to all other participants, we
3 ask in the interest of fairness that they address
4 any current or previous financial involvement with
5 any farm whose products they may wish to comment
6 upon. Thank you.
7 DR. ENGLUND: Thank you, everyone. With
8 that done, I would like to introduce Dr. Debra
9 Birnkrant who will now proceed to give us an
10 overview of the issues and our plan for today.
11 Overview of Issues
12 DR. BIRNKRANT: Good morning. I would
13 also like to welcome our advisory committee members
14 and consultants to this meeting.
15 Today, as was mentioned, we will be
16 discussing the new drug application for the tablet
17 and solution formulations for entecavir for the
18 treatment of chronic hepatitis B infection.
19 The last time this committee met to
20 discuss a similar topic was back in 2002 when we
21 presented the new drug application for adefovir,
on the second day of that meeting we discussed
1 general drug development for hepatitis B. Today's
2 meeting gives us another opportunity to discuss
3 this serious problem.
4 The next two slides were downloaded from
5 cdc.gov. This slide shows the geographic
6 distribution of chronic hepatitis B infection.
7 What you can see in red are high andemic areas in
8 Africa and Asia with hepatitis B prevalence at a
9 rate more than 8 percent, and this is considered
10 high. In gold we have medium prevalence areas, and
11 in green we have low prevalence areas, such as the
12 United States, excluding Alaska. In the high
13 prevalence areas the lifetime risk of acquiring
14 hepatitis B infection approaches 60 percent and is
15 acquired mainly during childhood, whereas in the
16 low prevalence areas the lifetime risk is much
17 lower and occurs in adolescents, adults and
18 well-defined risk groups.
19 This slide shows hepatitis B incidence by
20 year through the years 1966 through 2000 in the
21 United States. What this is dramatic for is the
decline in hepatitis B occurring soon after
1 licensure of hepatitis B vaccine. You can see that
2 the incidence drops dramatically over the years in
3 the late '80s and beyond after public health
4 programs adopted hepatitis B vaccination.
5 Although we see this dramatic decrease in
6 the United States of acute hepatitis B it still
7 remains a major problem. It has been estimated
8 that chronic hepatitis B infection affects 350-400
9 million subjects worldwide and approximately 1.25
10 million subjects in the United States. It accounts
11 for, it is estimated, approximately one million
12 deaths per year due to complications of the
13 disease, namely cirrhosis and hepatocellular
14 carcinoma. The treatment options are quite
15 limited. As you can see, there are only three at
16 this point, interferon, lamivudine and adefovir
18 I will briefly touch on the pros and cons
19 of these therapies. Interferon is used in a
20 limited patient population, however, it is used for
21 a definite period of time and in the limited
population the effect is durable.
1 side effect profile is somewhat limiting. With
2 interferon we see flu-like syndrome, depression,
3 alopecia and exacerbation of autoimmune disorders.
4 Lamivudine, a nucleoside analog, is much
5 better tolerated, however, subjects taking
6 lamivudine develop resistance at a rate approaching
7 20 percent per year.
8 Adefovir dipivoxil, a prodrug of adefovir,
9 a nucleotide analog, was approved in 2002. It is
10 active against lamivudine-resistant virus, and is
11 tolerated well except for nephrotoxicity that
12 appears in decompensated patients, more so, and
13 other advanced patients such as those undergoing
15 Let's turn now to today's subject, that
16 is, entecavir. Entecavir is also a nucleoside
17 analog. It has activity against HBV polymerase,
18 and in vitro it inhibits lamivudine-resistant virus
19 at concentrations 8-32-fold greater than that
20 required for wild type virus.
21 Its antiviral activity has been
demonstrated in established animal models. In
1 woodchuck, hepatitis virus infected woodchucks with
2 that disease, 67 percent treated with entecavir
3 survived 3 years compared to a 4 percent survival
4 rate in infected historic controls. So, it appears
5 quite active in this established animal model.
6 Now I will describe pertinent nonclinical
7 pharm/tox findings briefly. There was an increased
8 incidence of tumors in rodent carcinogenicity
9 studies. Lung tumors were observed at low
10 multiples of entecavir exposure relative to humans
11 and it is thought that these tumors may be species
12 specific. Other tumors occurred at much higher
13 multiples of entecavir exposure relative to humans.
14 This topic will be discussed extensively by
15 Bristol-Myers Squibb and Dr. Farrelly of the Food
16 and Drug Administration. What we have to keep in
17 mind here is that the animal data needs to be
18 interpreted in the context of the clinical data,
19 the severity of the disease and the available
20 treatment options. Turning to the clinical
21 studies, I would like to commend Bristol-Myers
Squibb for their drug development program for
1 entecavir. They studied a wide population in
2 e-antigen positive, e-antigen negative and
3 lamivudine-resistant subjects. Their trials were
4 multicenter and multinational, using an active
5 control, lamivudine. The endpoints used were
6 similar to other approved therapies.
7 At today's advisory committee meeting we
8 will be asking you to discuss the clinical trial
9 data in the context of these animal carcinogenicity
10 findings and the implications for human use. In
11 addition, we will be asking you to discuss the
12 adequacy of the proposed pharmacovigilance study.
13 We will also pose a question related to pediatric
15 If in the afternoon session when questions
16 are posed you vote that this drug should be
17 approved, we will then proceed to discuss labeling
18 implications and further post-marketing studies.
19 With that, I would like to just briefly
20 review the agenda. Following my comments,
21 Bristol-Myers Squibb will present. This will be
followed by a break. Then FDA
will present and the
1 presentations will be discussed prior to lunch. At
2 one o'clock there is an open public hearing.
3 Following that hearing, we will continue the
4 discussion and then pose our questions to the
5 advisory committee. Thank you very much.
6 DR. ENGLUND: Thank you very much. Now I
7 think we would like to begin with the sponsor
8 presentation by Bristol-Myers Squibb.
9 Sponsor Presentation
11 DR. SIGAL: Thank you, Dr. Englund and
12 members of the committee and FDA. Good morning. I
13 am Elliott Sigal. I am head of research and
14 development and chief scientific officer for
15 Bristol-Myers Squibb. Today it is our pleasure to
16 bring you data on entecavir for the treatment of
17 patients with chronic hepatitis B infection.
18 As you heard from Dr. Birnkrant, this
19 disease affects well over actually a million people
20 in the United States and accounts for approximately
21 5,000 deaths here a year. Outside the United
States another 400 million people are chronically
1 infected with hepatitis B so it represents a
2 worldwide public health issue of great importance.
3 We, at Bristol-Myers Squibb, have
4 concluded, based on the data you will hear today,
5 that entecavir represents an important therapeutic
6 advance. Our application is being considered first
7 here, in the U.S., but we have filed in Europe and
8 in China, and intend to file elsewhere around the
9 world as part of a larger global commitment.
10 All new therapies present a need to assess
11 both benefits and risks. Years ago, knowing this
12 compound to be a nucleoside analog, we
13 intentionally completed and analyzed rodent
14 carcinogenicity studies before initiating a Phase
15 III program. Then we continued to explore the
16 mechanisms of these rodent findings and we
17 collaborated with health authorities around the
18 world on how to characterize clinical benefit. The
19 goal has been to determine benefits seen in the
20 clinic and weigh those against the potential for
21 risk raised by nonclinical studies.
Entecavir has clinical benefits based on
1 its antiviral potency and these are superior
2 suppression of viral replication; a favorable
3 resistance profile; and improvement in both liver
4 histology and in biochemical abnormalities. To
5 establish all of this we conducted an extensive
6 Phase III program, the first in this field with an
7 active comparator. As the sponsor, we concluded
8 that the benefits in the clinic, including the
9 resistance profile, outweigh the potential seen of
10 risk in nonclinical studies and entecavir, to us,
11 represents an important therapeutic option for
12 patients with chronic hepatitis B infection.
13 However, as with any new medicine, an
14 assessment of benefit-risk at the time of approval
15 can only be an estimate. Therefore, our company is
16 committed to further defining therapeutic benefits
17 and to understanding any potential human risk with
19 To accomplish this we have submitted to
20 FDA draft pharmacovigilance plans, approaches and
21 observational studies that we plan to conduct to
allow for a continuous benefit-risk assessment once
1 entecavir is available for patients. For the
2 medical community these studies will advance the
3 overall scientific knowledge about this disease.
4 Bristol-Myers Squibb has a history of antiviral
5 clinical research in the treatment of patients with
6 HIV infection. Now with entecavir we are expanding
7 that commitment to advance the medical science of
8 chronic hepatitis B infection.
9 Furthermore, let me say that our efforts
10 in the marketplace will be directed to ensure the
11 appropriate use of this new medicine. We will
12 create a U.S. field organization solely dedicated
13 to entecavir. It will combine medical
14 professionals and representatives who will be
15 specifically trained in chronic hepatitis B. Their
16 focus will be on a relatively small number of
17 physicians, 3,500, that provide care for nearly all
18 the U.S. patients treated for chronic hepatitis B.
19 This focused approach will ensure high quality
20 interaction with prescribing physicians and
21 appropriate use of entecavir for patients.
Dr. Rich Colonno will now begin the data
1 presentation. Dr. Englund, two of our speakers
2 fell ill over the last 36 hours so you will see a
3 few different names on the program. One of our
4 internal hepatologists, Dr. Atillasoy, will be the
5 one presenting our clinical data. Dr. Colonno?
7 DR. COLONNO: Good morning. Sorry for the
8 confusion. Entecavir is under review for the
9 proposed indication shown here, the treatment of
10 chronic hepatitis B disease in adults with evidence
11 of liver inflammation. The usual dose will be 0.5
12 mg daily and a higher 1.0 mg dose is proposed for
13 patients who are lamivudine-refractory.
14 Our presentation will follow the outline
15 shown on this slide, covering nonclinical safety,
16 clinical efficacy, clinical safety, resistance and
17 pharmacovigilance. We have been assisted in
18 evaluating our data by a number of experts who are
19 listed on the next slide. These consultants,
20 covering hepatology, health policy, toxicology,
21 pathology and biostatistics, are here and available
22 to the committee.
23 Dr. Birnkrant and Dr. Sigal outlined the
24 disease burden and consequences of chronic HBV
infection. Only about 10-30
percent of people
1 currently affected with HBV go on to develop a
2 chronic infection. But the millions who do, it is
3 sometimes decade-long process that for a
4 substantial number of patients ends with cirrhosis,
5 liver failure, hepatocellular carcinoma, transplant
6 or death.
7 This is a viral disease and the clinical
8 course of liver injury is driven by the continuous
9 replication of the virus perpetuating a cycle of
10 inflammation. HBV is not inherently cytopathic but
11 liver cells support a continuous cycle of viral
12 replication that triggers the inflammatory response
13 that over time leads to fibrosis, cirrhosis and
14 liver cancer. HBV has recently been designated a
15 carcinogen, in recognition that HBV-induced
16 hepatocellular carcinoma is the fifth most frequent
17 single type of cancer.
18 It has now been shown that the outcome of
long course of chronic infection with HBV is
1 not just caused by the initial infection but is
2 related to the degree of continued viral
3 replication. This was supported by a prospective
4 Taiwan cohort study in which three key points
5 emerged: The incidence of hepatocellular carcinoma
6 and liver cirrhosis correlated with baseline HBV
7 DNA levels. The higher the baseline, the higher
8 the incidence. Two, persisting elevation of the
9 viral load over time has the greatest impact on
10 hepatocellular carcinoma risk. Viral load
11 predicted risk of future hepatocellular carcinoma
12 independent of e-antigen status and serum ALT
14 The concept that viral replication drives
15 disease process is depicted in the schematic shown
16 on this slide. Viral replication, monitored by
17 serum HBV DNA levels, drives the downstream
18 inflammation, measured by ALT levels and by
19 histology assessments. These were our week 48
20 endpoints, and we will be referring to this
21 simplified schematic later in our presentation.
Currently, three drugs are approved to
1 treat chronic hepatitis B infection, interferon,
2 lamivudine and adefovir. Interferon is an
3 immunomodulator while adefovir and lamivudine are
4 antivirals whose demonstrated antiviral activity
5 led to their approval. In their clinical studies
6 both lamivudine and adefovir were shown to be
7 superior to placebo using the endpoints of liver
8 histology, viral suppression and ALT normalization
9 at week 48. They decreased viral load, the first
10 stage of the schema, and interrupted the process
11 measured by ALT and histology, in the center
12 section. Beyond the week 48 data points,
13 lamivudine has now shown superiority to placebo in
14 affecting some of the long-term outcomes seen in
15 the far right-hand slide of the schema,
16 characterized as disease progression.
17 In the recent landmark paper by Liaw et
18 al., lamivudine treatment was prospectively
19 compared with placebo in patients with compensated
20 cirrhoses who are at greatest risk for disease
21 progression, including HCC and worsening cirrhosis.
With lamivudine treatment by 32 months the rate of
1 disease progression was significantly reduced
2 relative to placebo, 8 percent versus 18 percent.
3 This study confirmed the hypothesis that effective
4 antiviral therapy results in a better long-term
5 clinical outcome than indicated by the week 48
6 histology, virology and ALT endpoints.
7 The study also pointed out that a
8 development of resistance to a particular antiviral
9 therapy limits its benefit. By the end of the
10 study roughly half of the lamivudine-treated
11 patients who had developed lamivudine resistance,
12 or YMDD virus, and these patients had twice the
13 percentage of disease progression when compared to
14 those where the virus remained fully susceptible,
15 11 percent versus 5 percent respectively.
16 So, while lamivudine is effective and
17 lacks the tolerability concerns of interferon and,
18 unlike adefovir, does not require careful
19 monitoring of renal function, resistance impacts
20 the ability of lamivudine to deliver long-term
21 benefits. While the study confirmed that antiviral
treatment provides benefit, it also suggested that
1 a more effective antiviral with both greater
2 potency and less resistance will be more
3 efficacious in preventing downstream clinical
5 This morning you will see that entecavir,
6 by the accepted and proven histologic, virologic
7 and biochemical endpoints of our studies, was
8 superior to lamivudine. We will demonstrate that
9 entecavir is effective, safe and well tolerated;
10 has excellent potency and very low rates of
11 resistance; and maintains future options because it
12 doesn't select for lamivudine or adefovir
13 resistance and is, therefore, an important advance
14 in therapy for chronic HBV disease.
15 The activity of entecavir results from its
16 being a cyclopentyl guanosine analog. It is a
17 selective and potent inhibitor of HBV replication.
18 It has no significant activity against HIV. The
19 selectivity contributes to its safety since it is a
20 poor substrate for sailor DNA polymerases and does
21 not inhibit human mitochondrial or gamma
polymerase. Its potency reflects
the fact that it
1 inhibits all three functional activities of the HBV
2 polymerase, priming, DNA-dependent synthesis and
3 reverse transcription. It is also a function of a
4 highly efficient conversion of entecavir to its
5 active form entecavir triphosphate, seen
6 consistently in a wide variety of cell types.
7 Entecavir undergoes rapid and efficient
8 phosphorylation by sailor enzymes at low
9 concentrations, and can be detected within one
10 hour. Once formed, the intracellular half-life of
11 entecavir triphosphate is approximately 15 hours.
12 With an EC 50 of 4 nM it
is the most potent inhibitor
13 of hepatitis B virus. Entecavir is greater than
14 300 times more potent than either of the available
15 agents, lamivudine or adefovir, or two newer agents
16 under development dibividine[?] and tenofovir.
17 Animal models of HBV have been developed
18 using woodchucks and ducklings and entecavir
19 demonstrated impressive potency in these systems as
20 well. The woodchuck model is of particular
21 importance because it has been predictive of the
efficacy and safety of drugs subsequently used in
1 humans to treat hepatitis B virus. The antiviral
2 susceptibility of the woodchuck hepatitis B virus,
3 or WHBV, is similar to the human virus. In this
4 model greater than 95 percent of chronically
5 infected animals will development HCC and die, and
6 less than 5 percent will survive to age 4.
7 In our study, animals standard established
8 chronic infection were dosed with entecavir at 0.5
9 mg/kg, a dose that results in exposure levels of
10 approximating the exposure in humans with the 1 mg
11 dose. The drug was initially administered daily
12 for 2 months and then weekly for a total of 14-36
13 months. In both groups entecavir treatment
14 resulted in viral DNA levels being reduced by as
15 much as 8 logs to undetectable levels. The
16 reductions were sustained for up to 3 years, with
17 no evidence of virologic rebound or resistance.
18 The study compared the improvement in
19 survival versus historical controls, shown in grey.
20 The 11 woodchucks, represented by the yellow bars,
21 started treatment at 8 months of age as soon as a
chronic infection was verified. They had 4-year
1 HCC-free survival of 50 percent and 80 percent
2 respectively for the 14- and 36-month treatment
3 groups. The non-concurrent historical control had
4 a survival rate of 4 percent. Although the numbers
5 of animals were small, these results were of high
6 statistical significance. Surviving animals were
7 also shown to have no histological evidence of HCC
8 development upon subsequent examination.
9 In summary, the nonclinical data and the
10 expected benefit of antiviral treatment supported
11 going forward with development of entecavir for
12 treatment of chronic HBV infection. As with any
13 drug being developed for long-term chronic dosing
14 in humans, the carcinogenicity potential of
15 entecavir was evaluated in lifelong dosing studies
16 in rats and mice. Dr. Lois Lehman-McKeeman will
17 now present this data.
18 Nonclinical Safety
19 DR. LEHMAN-MCKEEMAN: Today's discussion
20 of the nonclinical safety of entecavir is focused
21 on the rodent carcinogenicity studies. Entecavir
identified as a carcinogenic hazard in rats and
1 mice, and the benefit-risk evaluation for entecavir
2 must consider this risk identified in animals
3 relevant to the human clinical benefit.
4 For background on the rodent data, I will
5 briefly describe the design, conduct and
6 interpretation of these studies. Rodent
7 carcinogenicity studies are lifetime studies,
8 typically 2 years, and group sizes are large with
9 50-60 animals per sex per group. Dose selection is
10 critical, and highest dosage is expected to
11 represent a maximum tolerated dose, or MTD. The
12 simplest definition of an MTD is a dose that causes
13 no more than a 10 percent decrease in body weight
14 gain relative to controls. The lower dosages
15 studied, typically 2 additional levels, are
16 selected to be some fraction of the MTD or some
17 multiple of the relevant human clinical exposure.
18 At the end of the study all tissues are
19 evaluated microscopically for tumors. Several
20 tissues in rats and mice are prone to spontaneous
21 tumor development. For example, in mice there was
relatively high background rate of tumors in
1 liver and lung, while in rats liver, pituitary and
2 mammary gland tumors occurred at high spontaneous
3 rates. So, finding tumors in animals, including
4 controls, is not surprising and we rely on
5 statistical methods and an understanding of
6 historical control tumor rates to identify those
7 that are drug related.
8 Statistical significance in rodent tumors
9 is established by sequentially testing for a linear
10 dose-dependent trend starting with all dose groups.
11 Tumor incidence is adjusted for survival and the
12 time and cause of death and the level of
13 statistical significance varies with whether a
14 tumor is common or rare. The more common the
15 tumor, the more rigorous the statistical analysis.
16 When the results identify a positive trend, data
17 are reanalyzed by dropping the highest dose and
18 repeating the test. This cycle is repeated until
19 no significant trend is observed.
20 With that as an overview on rodent
21 carcinogenicity studies, let's review the results
entecavir. These results have been
1 with the FDA's Executive Carcinogenicity Assessment
2 Committee, or CAC, and the full CAC and a number of
3 tumor sites were concluded to be relevant to human
5 Entecavir-induced tumors followed two
6 distinct patterns. The first pattern was observed
7 in tissues that showed preneoplastic changes, that
8 is, sites were early changes, consistent with the
9 increased likelihood of tumor development, were
10 observed. The only site that showed this pattern
11 was the mouse lung.
12 The second pattern of increased tumors was
13 in tissues that showed no evidence of preneoplastic
14 changes and occurred at high exposure multiples
15 relative to anticipated human exposure. These
16 tumors included liver carcinomas in male mice;
17 vascular tumors in female mice; gliomas in male
18 rats; and gliomas, liver adenomas and skin fibromas
19 in female rats.
20 In addition to listing the tumor sites,
21 let's look at the incidences observed in these
studies. Entecavir was dosed to
mice across a dose
1 range of 0.004 mg/kg to 4 mg/kg. To orient you to
2 this slide, the dosages are shown in the top line
3 and the exposure multiples are noted below the
4 dosages representing the comparison of the plasma
5 area under the curve in mice relative to human
6 exposure at the 0.5 mg or 1 mg dose. The exposures
7 are presented as those in the males, followed by
8 the females. 4 mg/kg was an MTD and this dose
9 represented at least a 40-fold multiple over the
10 human exposure at 1 mg.
11 The mouse lung is a major target organ for
12 tumor development following entecavir treatment.
13 Lung tumors are common in mice. There was a 12
14 percent incidence of tumors in the control males in
15 this study.
16 Entecavir increased the incidence of lung
17 adenomas with a statistical increase in tumors,
18 here noted in yellow, observed at the 0.4 mg/kg
19 dose in males. This dose is 3-5 times higher than
20 human clinical exposure. Lung adenomas were
21 further increased at the 2 higher dosages and at 4
mg/kg entecavir increased the incidence of lung
2 In female mice lung tumors occur at a
3 higher spontaneous rate than in males, with a
4 background incidence of 20 percent in this study.
5 Entecavir increased pulmonary tumors in female mice
6 but the statistical significance was noted only at
7 the highest dose.
8 Other toxicology studies indicated that
9 entecavir elicited unique changes in the mouse
10 lung, and we conducted experiments to define these
11 changes and to determine whether they were linked
12 to the increased susceptibility to tumor
13 development. The results showed preneoplastic
14 changes in the mouse lung that consisted of
15 increased numbers of macrophages and Type II
16 pneumocyte hyperplasia. Cell proliferation is a
17 recognized risk factor for tumor development and
18 entecavir caused a sustained proliferation of Type
19 II pneumocytes. Most mouse lung tumors arise from
20 Type II pneumocytes and these cells were identified
21 as the progenitor cells for entecavir-induced lung
tumors as well. The increased
1 macrophages was required to support the
2 proliferation of the Type II pneumocytes and
3 entecavir increased the number of alveolar
4 macrophages in the lung because it was chemotactic
5 for mouse monocytes.
6 In contrast to the mouse, no similar
7 changes were observed in the lungs of rats, dogs or
8 monkeys treated with entecavir. Finally, although
9 entecavir was chemotactic for mouse monocytes, it
10 was not chemotactic for human monocytes, suggesting
11 that an accumulation of macrophages in the human
12 lung would be unlikely to occur. The results
13 suggest that entecavir causes unique effects in the
14 mouse lung and lung tumors observed in mice may be
15 species specific.
16 The second presentation of entecavir-
17 induced tumors in mice was in organs that, unlike
18 the lung, showed no evidence of preneoplastic
19 change. In males entecavir increased the incidence
20 of liver carcinomas and in females entecavir
21 increased the incidence of vascular tumors,
specifically hemangiomas. In both
cases there was
1 no dose response relationship noted, with tumors
2 observed only at the highest dosage.
3 We have not explored mechanisms underlying
4 the high dose tumor findings on an organ by organ
5 basis, but we have looked at whether a common mode
6 of action may contribute to tumor development.
7 Entecavir is phosphorylated to entecavir
8 triphosphate, the active form that inhibits viral
9 replication, and we determined that, likely by
10 competing for phosphorylation as depicted here,
11 entecavir disrupts deoxynucleotide triphosphate
12 pools, dNTP pools, in male mouse liver. Data in
13 the scientific literature demonstrates that such
14 perturbations disrupt the fidelity of DNA synthesis
15 and repair. We conclude that changes in the dNTP
16 pools may explain tumor findings, particularly when
17 there is a high dose response for tumor
19 Moving on to rats, in Sprague-Dawley rats
20 entecavir was dosed to males at dosages up to 1.4
21 mg/kg or to females at dosages up to 2.6 mg/kg.
4 dosage levels are noted here along with the
1 exposure multiples as were presented on the mouse
2 slides relative to the 0.5 mg or 1 mg clinical
3 dose. Maximum exposures were at least 35 times
4 human exposure in male rats or 24 times human
5 exposure in female rats. In rats all tumors
6 observed were consistent with the second pattern of
7 tumor presentation, that is, no evidence of
8 development of preneoplastic change.
9 In males and females entecavir increased
10 the incidence of gliomas with statistical
11 significance only at the highest dosage. In
12 females entecavir increased the incidence of liver
13 adenomas and skin fibromas. As determined in mice,
14 we have postulated that the dNTP pool perturbations
15 resulting from high doses of entecavir that
16 overwhelm the strict regulation of nucleotide
17 metabolism may explain entecavir-induced tumors in
19 Carcinogenicity studies in rodents
20 identify whether a compound is a carcinogenic
21 hazard. In the absence of data in humans it is
assumed that carcinogenic effects in rodents
1 suggest a possible carcinogenic risk in humans.
2 However, to extrapolate these findings to humans
3 other relevant data, such as genetic toxicity and
4 species differences in biological response, along
5 with dose-response relationships and exposure
6 comparisons, are important considerations that may
7 increase or decrease the likelihood of human cancer
8 risk. For entecavir there is evidence suggesting a
9 unique biological response in the mouse lung and
10 mouse lung tumors may be species specific.
11 Extrapolation of the other tumor findings
12 is more difficult, but the weight of evidence
13 suggests that human risk is minimal because rodent
14 tumors were observed at dosages that greatly exceed
15 human clinical exposure.
16 Dr. Evren Atillasoy will now review the
17 benefit of entecavir as determined from the Phase
18 III clinical trials.
19 Clinical Efficacy and Safety
20 DR. ATILLASOY: Thank you and good
21 morning. The entecavir clinical development
program is comprehensive and assesses the efficacy
1 and safety of entecavir for the treatment of
2 chronic hepatitis B infection. The experience was
3 broad with major disease patterns well represented.
4 Studies addressed hepatitis B e-antigen positive
5 patients and e-negative disease, and assessed
6 entecavir in lamivudine-refractory as well as
7 nucleoside-naive patients.
8 The global program recruited patients from
9 5 continents in over 30 countries. Separate
10 programs are in progress in China and Japan. The
11 studies that contribute to the NDA review provide
12 analyzed data on approximately 1,500
13 entecavir-treated patients. Entecavir is the first
14 nucleoside program to be evaluated for HBV using an
15 active comparator, lamivudine, which was the only
16 approved HBV nucleoside at the time that the
17 program was initiated.
18 The map of the clinical program
19 illustrates the sense of the size, breadth and
20 complexity. The core of the program is represented
21 by the green box and includes the three Phase III
studies you will be hearing about today.
1 studies in special populations include experiences
2 in liver transplant patients, co-infected
3 HIV-positive patients and decompensated patients,
4 the trial which we are still actively enrolling.
5 Two long-term rollover studies provide for
6 prolonged observation and data collection. Study
7 901, at the bottom left, provides an ongoing
8 treatment option for those patients in whom
9 long-term treatment is appropriate. Study 049 is a
10 post-treatment observational study, designed to
11 collect long-term safety and efficacy information.
12 All Phase III patients have the opportunity to
13 enroll in these trials. These data in 049 have not
14 yet been analyzed.
15 Dose selection for entecavir anticipated
16 that lamivudine-refractory patients would require a
17 higher dose than naive patients because of the
18 higher EC 50 of
lamivudine-resistant virus in vitro.
19 An earlier proof of principle study testing doses
20 over a range from 0.5 mg to 1 mg daily hinge on
21 overlapping responses for the highest doses of 0.5
and 1 mg daily. Therefore, these doses
1 used as the highest ones tested in dose selection
2 studies, 0.5 mg in naive patients, in yellow on the
3 left graph, and 1 mg refractory patients, in orange
4 on the right graph. The lamivudine control is
5 represented in blue in both graphs.
6 A dose response was demonstrated in each
7 population, with the greatest responses occurring
8 at the two highest doses with diminishing
9 incremental benefit at the last increase.
10 Entecavir 0.5 mg daily and 1 mg daily were taken
11 forward as the doses to be tested for Phase III for
12 naive and refractory patients respectively.
13 Clinical efficacy--Phase III included
14 trials in three disease settings, nucleoside-naive
15 e-antigen positive patients, nucleoside e-antigen
16 negative patients and lamivudine refractory
17 e-antigen positive patients. The definition of
18 lamivudine refractory was that patients must have
19 clinical failure after at least 6 months of
20 lamivudine, or earlier failure with the
21 confirmation of lamivudine-resistant virus.
Clinical failure was defined as detectable viremia
1 using the bDNA assay. Today's presentation of
2 clinical results will be by treatment population
3 rather than study number.
4 Lets turn to study design across Phase
5 III. Patients were screened and randomized 1:1 to
6 either entecavir or lamivudine in a double-blind
7 fashion and were treated for a minimum of 52 weeks.
8 Lamivudine-refractory patients who were required to
9 have breakthrough viremia while on lamivudine were
10 switched on treatment day 1 directly from
11 lamivudine to blinded study drug without a period
12 either of overlap or washout. Liver biopsies were
13 obtained at baseline and at week 48 for assessment
14 of the primary efficacy endpoint, histologic
15 improvement. Patient management at week 52 was
16 based on lab results using data from the week 48
17 visit, with results of the 24 follow-up period
18 presented in the briefing document that you have.
19 Inclusion criteria, let's talk about these
20 for the three studies. Inclusion criteria required
21 that patients needed to have compensated liver
disease, together with an elevated ALT, or were
1 required to have detectable viremia by bDNA. The
2 different virologic characteristics of the
3 e-antigen positive and e-antigen negative disease
4 patients resulted in different minimal requirements
5 for enrollment by HBV DNA.
6 The baseline demographics of each study
7 population are consistent with the characteristics
8 expected for the patient population. In the
9 presentations that follow results for the naive
10 e-antigen positive patients will appear on the left
11 of the slide. In the middle you will see data for
12 the naive e-antigen negative patients and on the
13 furthest right you will see results for the
14 lamivudine-refractory e-antigen positive
15 population. Within each study the
16 entecavir/lamivudine study groups were well matched
17 for demographic characteristics.
18 Turning to baseline HBV characteristics,
19 these are also expected to differ according to the
20 pattern of disease studied. Again, within each
21 study the entecavir/lamivudine treatment groups
were well matched for baseline HBV disease
1 characteristics. Looking across studies, HBV
2 e-antigen positive patients, whether
3 nucleoside-naive or lamivudine-refractory, had mean
4 HBV DNA values that were approximately 2 logs
5 higher than the mean value for the e-antigen
6 negative population.
7 Finally baseline histology across the
8 studies showed a higher mean necroinflammatory
9 score, using Knodell, than nucleoside-naive
10 subjects. Only a minority had biopsy evidence for
11 cirrhosis as classified by Knodell fibrosis score
12 of 4. This is because participants were selected
13 to have compensated liver disease.
14 Patient disposition--patient disposition
15 for the first 48 weeks across the three studies
16 demonstrates high retention rates, with at least 94
17 percent of entecavir-treated patients completing 48
18 weeks of treatment in each of the three studies.
19 Lamivudine retention rates ranged from 87-95
20 percent, with the lowest rate in the
21 lamivudine-refractory study.
In all three studies, paired biopsies were
1 scored using a single reader, who was Dr. Zachary
2 Goodman. Dr. Zachary Goodman was blinded to drug
3 assignment as well as the temporal sequence of the
4 paired biopsies. Dr. Goodman also read the
5 biopsies for lamivudine and adefovir registrational
7 Overall, paired baseline and week 48
8 biopsies were available for efficacy assessment in
9 88 percent of patients. Histologic improvement at
10 week 48 as compared to baseline is the primary
11 efficacy endpoint in these trials. Histologic
12 improvement was defined as at least a 2-point
13 reduction in the Knodell necroinflammatory score
14 with no concurrent worsening in Knodell fibrosis.
15 In order for a biopsy pair to be
16 evaluable, the baseline sample must have had enough
17 tissue pathologically and it also must have had a
18 necroinflammatory score of at least 2, and 89
19 percent of patients had a baseline biopsy that fit
20 these criteria and constitute the evaluable
21 baseline histology cohort. Patients from the
evaluable cohort who had missing or inadequate week
1 48 specimens were considered to have no
2 improvement. Therefore, the primary analysis for
3 histologic improvement is analogous to a
4 non-completer or equal failure analysis but is
5 applied to the evaluable cohort rather than the
6 all-treated population.
7 The nucleoside-naive studies were designed
8 with two-stage testing. The first test was for
9 non-inferiority and, if that was met, then
10 superiority was tested. Non-inferiority is
11 established if the lower confidence limit is above
12 minus 10 percent. Superiority is met if the lower
13 confidence limit is above zero. In comparing two
14 active treatments it was expected that differences
15 in histologic improvement, a downstream endpoint,
16 might take longer than 48 weeks to emerge.
17 Nevertheless, at week 48 entecavir 0.5 mg daily was
18 superior to lamivudine 100 mg daily for histologic
19 improvement in both nucleoside-naive populations.
20 Entecavir achieved a 72 percent response rate in
21 naive e-antigen positive patients and a 70 percent
22 response rate in the naive e-negative population.
23 Looking to the study in
24 lamivudine-refractory patients, this was designed
superiority. Two independent co-primary
1 endpoints were evaluated because histologic
2 response hadn't been characterized in this
3 population previously. The first co-primary
4 endpoint is histologic improvement, as we have
5 discussed. The second is a composite reflecting
6 both virologic response and hepatic inflammation as
7 measured by serum ALT. Entecavir 1 mg daily was
8 superior to continued lamivudine 100 mg daily for
9 both co-primary endpoints, and 55 percent achieved
10 the endpoint of histologic improvement; likewise,
11 55 percent achieved an HBV DNA below the detection
12 of the bDNA assay, together with an ALT less than
13 1.25 times the upper limit of normal. Changes in
14 fibrosis are expected to follow changes in
15 necroinflammation. While the primary endpoint,
16 histologic improvement, assessed primarily
17 necroinflammation, secondary histologic endpoints
18 included an assessment of changes in fibrosis using
19 the Ishak scoring system.
20 The numbers in the circles along the zero
21 line represent the proportions with no change,
22 while the bars above and below the line represent
23 the proportions with improvement and worsening
24 respectively. In the two naive studies entecavir
lamivudine are comparable. This is not
1 unexpected as week 48 is relatively an early time
2 point for assessing this downstream endpoint,
3 especially when comparing two active treatments.
4 The effect of large differences, however, can be
5 seen in lamivudine-refractory patients. Here
6 entecavir was superior to lamivudine for
7 improvement in fibrosis. The distribution of
8 responses in entecavir-treated patients mirrors
9 that in the naive studies and 34 percent had
10 improvement while only 11 percent worsened while on
11 entecavir. This compares to only 16 percent
12 improvement and 26 percent worsening for continued
14 Non-histologic secondary endpoints were
15 also assessed at week 48. These included
virologic, biochemical and serologic endpoints.
1 These assessments are all used routinely in the
2 clinical management of patients with chronic HBV.
3 Treatment comparisons were made using a
4 non-completer or equal failure analysis, and all
5 treated patients were counted in the denominator.
6 Results for virologic endpoints
7 demonstrate superiority for entecavir in all three
8 populations studied. The proportion of patients
9 achieving an HBV DNA less than 400 copies/mL by PCR
10 is presented here as a function of time on
11 treatment, and 69 percent of naive e-antigen
12 positive patients treated with entecavir achieved
13 an HBV DNA of less than 400 copies/mL as compared
14 to 38 percent for lamivudine, an absolute
15 difference of 31 percentage points.
16 The lower baseline viremia and e-antigen
17 negative patients is associated with higher rates
18 of viral suppression. Here, 91 percent of
19 entecavir-treated patients achieved an HBV DNA less
20 than 400 copies as compared to 73 percent for
21 lamivudine, an absolute difference of 18 percentage
points. In both populations there
is an early
1 separation response, with superiority for entecavir
2 as early as week 24. This was the first time point
3 in which a PCR measurement was taken.
4 In the lamivudine-refractory population
5 entecavir was also superior to continued
6 lamivudine, with early separation during the first
7 24 weeks of treatment, and 21 percent of
8 entecavir-treated patients achieved an HBV DNA less
9 than 400 copies.
10 An additional way of assessing virologic
11 response is looking at the mean log reduction in
12 HBV DNA from baseline. For this analysis results
13 depend upon the characteristics of the population
14 studied and the HBV DNA used. The maximum
15 reduction possible for a particular population
16 depends on the starting baseline values for those
17 individuals. In a responder the endpoint will
18 reflect the lower limit of detection for an assay.
19 Therefore, comparisons of this endpoint across
20 different populations must account for differences
21 in baseline characteristics and HBV DNA assay.
Entecavir is superior to lamivudine across
1 all three populations. Naive e-antigen positive
2 patients who started out with an HBV DNA of 9.7
3 logs in wild type virus demonstrate--so that
4 entecavir demonstrates its full potential with a
5 mean decrease of nearly 7 logs at week 48,
6 differing by 1.5 logs or 30-fold from lamivudine.
7 In the e-negative population the 5-log decrease for
8 entecavir approximates the maximal change possible
9 given the lower starting HBV DNA and the PCR limit
10 of quantitation at 2.5 logs, or 300 copies/mL. In
11 the lamivudine-refractory population entecavir
12 achieves a substantial 5.1-log decrease in HBV DNA.
13 Viral suppression also leads to reduced
14 hepatic inflammation as judged by ALT. Here,
15 entecavir is superior to lamivudine for
16 normalization of ALT in all three populations. As
17 expected, the largest treatment difference is seen
18 in the refractory population.
19 Reduced viral replication may also induce
20 an immunologic response resulting in HBe antigen
21 seroconversion. The precise biology of this
interaction is poorly understood.
In the naive
1 e-antigen population entecavir and lamivudine are
2 comparable for seroconversion with response rates
3 of 21 and 18 percent respectively.
4 In summary, across the three Phase III
5 studies entecavir is consistently superior to
6 lamivudine for histologic improvement, virologic
7 response and ALT normalization. For the four key
8 endpoints across the three studies there were 11
9 efficacy comparisons. Entecavir demonstrates
10 statistical superiority to lamivudine in 9 of these
11 11, with confidence intervals for treatment
12 differences lying to the right of zero. The two
13 seroconversion endpoints favor entecavir
14 numerically and establish non-inferiority with
15 confidence intervals lying above the minus 10
16 boundary. In addition, the mean log reduction is
17 consistently superior for entecavir, ranging from
18 5-7 logs across the three populations.
19 Let's move to safety. The clinical
20 profile of entecavir has been extensively
21 characterized. The format for the safety
presentation will differ slightly from that of the
1 efficacy presentation. These analyses use
2 augmented patient cohorts and integrate data across
3 studies in order to increase the sensitivity to
4 possible safety signals.
5 The nucleoside-naive lamivudine-refractory
6 populations are considered separately, primarily
7 because the exposure to entecavir differs with
8 dose. The safety cohort includes patients from 10
9 analyzed Phase II and Phase III studies. For the
10 Phase III populations mean treatment duration was 5
11 weeks longer for entecavir-treated naive patients
12 and 17 weeks longer for entecavir-treated
13 refractory patients. The follow-up observations
14 were consistently longer for entecavir than for
15 lamivudine across all populations.
16 Follow-up is defined as the period of
17 post-treatment follow-up during which no
18 alternative HBV therapy was given. Its duration
19 was shorter in refractory patients as compared to
20 naive patients due to earlier initiation of
21 alternative therapy or early enrollment into an
entecavir rollover trial.
Observation periods for
1 the safety cohort are expanded to include
2 open-label treatment and post-treatment observation
3 on alternate HBV therapy.
4 The safety presentation is divided into
5 three sections, general safety, hepatic safety and
6 malignant neoplasms. General safety analyses
7 provide standard assessments for rates of clinical
8 adverse events and laboratory abnormalities. All
9 analyses use data from all treated patients in the
10 selected studies. Analyses are cumulative from the
11 first day of dosing through the last contact with
12 each patient. Therefore, year 2 data are included
13 for some patients.
14 Rates for three standard safety
15 assessments--discontinuations due to an adverse
16 event, serious adverse events and deaths, were low
17 for both treatments across both populations. The
18 types of serious events reported for entecavir and
19 lamivudine were comparable, and no individual
20 serious adverse event occurred in more than one
21 percent of patients. None of the events leading to
22 death was considered related to study drug.
23 In terms of adverse events, on treatment
24 adverse events were generally mild to moderate in
severity and were common, reflecting the long
1 duration of study observation. The frequencies of
2 individual events and the types and distribution of
3 these events were comparable for both treatment
4 groups across both populations.
5 Hepatic safety--hepatic safety focuses on
6 hepatic flares because these can represent an
7 important clinical risk in the treatment of
8 hepatitis B regardless of the specific therapy
9 which is used. ALT flares were defined as
10 increases in ALT greater than 10 times the upper
11 limit of normal and 2 times the patient's own
12 reference value. The reference value was the
13 baseline value for on-treatment flares. For
14 off-treatment flares the reference was the lower of
15 the baseline or the end of treatment value.
16 Rates for on- and off-treatment flares are
17 consistently less than 10 percent for entecavir.
18 Of note, the median time from stopping therapy to
off-treatment flare is substantially longer for
1 entecavir. The delayed time course for
2 off-treatment flares for entecavir may be related
3 to the extent of virologic suppression achieved on
5 ALT flares are frequently asymptomatic. A
6 deterioration in hepatic function can, however,
7 occur without ALT changes that meet this flair
8 definition. Therefore, we performed analyses to
9 identify individuals meeting flair criteria who had
10 associated relevant laboratory abnormalities or
11 relevant hepatic clinical events, or those who had
12 a serious hepatic adverse event without meeting
13 flair criteria. These events were infrequent among
14 both naive and refractory patients, with the number
15 of individual cases summarized here.
16 Safety surveillance of the entecavir
17 development program involved the assessment of
18 comparative incidences for new or recurrent
19 malignancy diagnoses in entecavir- and
20 lamivudine-treated subjects. Use of the larger
21 safety cohort database increases sensitivity in
this analysis of events that are infrequent. A new
1 diagnosis or a new recurrence of malignancy was
2 counted from the time of first study dose to the
3 time of the last patient contact regardless of
4 whether the event was diagnosed on or post
5 treatment. In the safety cohort the
6 entecavir/lamivudine treatment groups differed in
7 size and the duration of observation.
8 Event rates are presented as incidences of
9 patients diagnosed per 1,000 patient-years of
10 observation. Hepatocellular carcinoma is the
11 single most frequent type of cancer identified, not
12 unexpectedly, due to the underlying HBV disease.
13 Incidences across the treatment groups are
14 comparable whether assessed for any malignancy, any
15 malignancy excluding non-melanoma skin tumors or
16 the category of great interest, non-hepatocellular
17 carcinoma, non-skin malignancies.
18 Further analyses in the entecavir program
19 demonstrate that the distribution of new or
20 recurrent non-skin malignancy diagnoses over time
21 is comparable for entecavir and lamivudine. In
both treatment groups the greatest number of new
1 diagnoses occurred between weeks 24 and 48. This
2 temporal clustering may reflect tumors that were
3 latent at the time of study enrollment. There is
4 an apparent leveling off for new diagnoses after
5 week 48.
6 In order to establish a comparative
7 context for the observed tumor rates in the
8 development program, Bristol-Myers Squibb provided
9 grants to two independent research groups. These
10 groups identified cohorts of chronic HBS antigen
11 positive patients within their established
12 databases. The results are provided in the two
13 right-hand columns. The Taiwan cohort had been
14 prospectively identified as part of an established
15 cancer incidence study which started in 1991 and is
16 sponsored by the Taiwan Ministry of Health. The
17 rates of malignancy in the entecavir-lamivudine
18 arms are comparable to the Taiwan and the Kaiser
19 observational cohorts.
20 In summary, the safety profile of
21 entecavir is consistently comparable to that of
lamivudine. Also, the safety of
1 comparable across the nucleoside-naive and
2 lamivudine-refractory populations, and across the
3 two doses of 0.5 mg and 1 mg daily. Importantly,
4 the malignancy incidences among approximately 1,500
5 entecavir-treated patients are comparable among
6 those observed in the lamivudine-treated control
7 group. Dr. Richard Colonno will now present the
8 resistance profile for entecavir.
10 DR. COLONNO: Thank you. For all
11 antivirals there is a direct relationship between
12 potent viral suppression and absence of viral
13 resistance emergence because viruses require a
14 minimal threshold level of replication to select
15 for resistant variants. Sustained suppression of
16 viral DNA undetectable levels in the woodchuck
17 model, described earlier, resulted in the absence
18 of virologic rebound and no evidence of resistance
19 over the 14- and 36-month treatment periods.
20 To ascertain whether the potent and
21 sustained suppression of viral replication achieved
entecavir in our clinical studies results in a
1 favorable resistance profile, a comprehensive
2 resistance evaluation was conducted that included
3 both in vitro and in vivo studies, along with
4 characterization of over 1,500 clinical samples
5 from entecavir-treated patients.
6 In vitro studies showed entecavir
7 susceptibility was reduced when viruses contained
8 the two primary lamivudine-resistant substitutions,
9 a leucine thymodin[?] change at residue 180 and a
10 methionine to valine or isoleucine change at
11 residue 204. Despite this reduction, entecavir
12 remains greater than 50-fold more potent than
13 adefovir against lamivudine-resistant viruses.
14 There was no cross-resistance between entecavir and
15 adefovir since adefovir-resistant viruses
16 containing resistant substitutions at residues 181
17 or 236 remain fully susceptible to entecavir.
18 During Phase II studies two extensively
19 pretreated patients, designated as patient A and
20 patient B, exhibited virologic rebounds on
21 entecavir therapy. Following at least 76 weeks of
entecavir, virologic rebounds noted in two patterns
1 of genotypic resistance emergence were identified.
2 Entecavir resistance emergence in patient A
3 required two additional substitutions, an
4 isoleucine change at residue 169 and a valine
5 substitution at residue 250. Patient B needed
6 glycine and isoleucine substitutions at residues
7 184 and 202 respectively, along with a subsequent
8 change at residue 169. In both cases these changes
9 occurred in the background of preexisting
10 lamivudine-resistant substitutions. Both isolates
11 were growth impaired and remained fully susceptible
12 to adefovir.
13 The impact of substitutions at each of
14 these four residues of entecavir's susceptibility
15 are shown on this slide. Recombinant viruses
16 containing the indicated substitutions at residues
17 169, 184 and 202 alone had no significant impact on
18 entecavir's susceptibility relative to wild type
19 virus, while a change at residue 250 reduced
20 entecavir's susceptibility levels by less than
21 10-fold, about the same as when
lamivudine-resistant substitutions alone are
2 The 169 substitution appears to act as a
3 secondary mutation and did not further reduce
4 entecavir's susceptibility in the
5 lamivudine-resistant viruses. However, when
6 lamivudine-resistant substitutions are combined
7 with the entecavir-resistant substitutions at
8 residues 184, 202 and 250 significantly higher
9 levels of entecavir resistance are observed.
10 Presence of multiple entecavir-resistant
11 substitutions further decreased entecavir's
12 susceptibility levels.
13 An extensive resistance monitoring program
14 was undertaken. In the nucleoside-naive trials all
15 available entecavir-treated e-antigen positive and
16 two-thirds of randomly selected e-antigen negative
17 patients were genotyped at study entry and at week
18 48, a total of 550 pairs of patient samples. For
19 the lamivudine-refractory population all available
20 patient samples were genotyped. All emerging
21 changes identified were tested for their potential
22 impact on entecavir susceptibility.
23 In addition, samples from all patients
24 experiencing a virologic rebound, defined as any
greater than or equal to 1 log increase from nadir
1 identified by PCR, were genotyped and subjected to
2 population phenotyping to determine if they
3 harbored circulating viruses resistant to study
4 drug. In nucleoside-naive patients treated with
5 entecavir there was no evidence of genotypic or
6 phenotypic resistance by week 48.
7 The figure plots the distribution of
8 patients with the HBV DNA levels indicated at study
9 entry and at week 48 for both entecavir and
10 lamivudine. The size of each circle corresponds to
11 the percentage of patients and each column of
12 circles adds up to 100 percent. And, 81 percent of
13 entecavir-treated patients achieved viral DNA
14 levels of less than 300 copies/mL, represented by
15 the bottom circle, compared to only 57 percent for
16 lamivudine-treated patients. Overall, 88 percent
17 of patients, represented by the bottom two circles
18 in each case, achieved viral DNA reductions below
19 1,000 copies/mL on entecavir by week 48.
20 Genotyping identified 76 emerging changes
21 but no distinctive patterns were observed, and no
22 change was present in more than three isolates,
23 representing 0.6 percent of those treated.
24 Phenotypic analysis of these emerging changes show
that their presence did not result in a significant
1 decrease in entecavir susceptibility. There were
2 11 virologic rebounds on the entecavir arms of
3 these studies compared to 88 rebounds on lamivudine
5 This slide shows the origin and frequency
6 of rebounds by study. When genotyped, nearly all
7 of the observed virologic rebounds on lamivudine
8 therapy coincided with the emergence of resistance
9 substitutions at residues 180 and 204, yielding a
10 confirmed resistance frequency of 8-18 percent by
11 week 48. In contrast, none of the entecavir
12 virologic rebounds observed in nucleoside-naive
13 patients could be attributed to emergence of
15 A close examination of the individual
patient profiles showed that all 11 patients
1 exhibiting a rebound on entecavir had at least a
2 3-log reduction in viral DNA levels and 7 of the 11
3 had greater than a 5-log reduction. Most
4 importantly, all patients had viral populations
5 that were full susceptible to entecavir at the time
6 of rebound, and there was no evidence of emerging
7 genotypic changes that reduced entecavir
9 From this comprehensive analysis we
10 conclude that there was no evidence of emerging
11 genotypic or phenotypic resistance to entecavir in
12 any of the nucleoside-naive patients by week 48, a
13 result that is most likely due to the high degree
14 of sustained viral suppression observed. We
15 continue to monitor these patients for resistance
16 in subsequent treatment years.
17 Let us now turn to the
18 lamivudine-refractory patient population where
19 previous studies indicated that entecavir
20 resistance emergence can occur. Similar to
21 nucleoside-naive patients, entecavir was highly
effective in lamivudine-refractory patients
1 enrolled in study 026 and in the 1 mg arm of study
3 The figure again plots the distribution of
4 lamivudine-refractory patients having the HBV DNA
5 levels indicated at study entry, week 24 and week
6 48. While reductions were somewhat less than those
7 observed in nucleoside-naive patients, 22 percent
8 of entecavir-treated patients achieved viral DNA
9 reductions below 300 copies/mL by week 48. There
10 was a clear trend of sustained and increasing
11 reductions from week 24 to week 48, and superiority
12 to continued lamivudine therapy.
13 As part of our comprehensive resistance
14 evaluation, all patients, regardless of treatment
15 arm, were genotyped at study entry and week 48.
16 There were 5 virologic rebounds among the
17 lamivudine-refractory patients treated with
19 The figure plots the HBV DNA levels for
20 the first two patients, labeled 1 and 2. Both
21 exhibited only modest reductions in HBV DNA levels
entecavir therapy. Evidence of entecavir
1 resistance substitutions at residue 184 were noted
2 in both patients and population phenotypes
3 indicated a 15-19-fold decrease in entecavir
4 susceptibility, consistent with resistance
6 In contrast, the three other patients,
7 labeled 3, 4 and 5, all experienced at least a
8 4-log reduction in viral DNA levels and further
9 reductions following rebound either on continued
10 therapy or off treatment, with no evidence of
11 genotypic or phenotypic changes beyond those
12 expected for lamivudine-resistant viruses.
13 Based on this evaluation, only two
14 patients or one percent of lamivudine-refractory
15 patients treated with entecavir experienced
16 virologic rebound due to resistance by week 48.
17 Entecavir-resistant substitutions were, however,
18 noted in 12 entecavir-treated patients by week 48,
19 all with a background of lamivudine-resistant
20 substitutions. These patients continue to be
21 monitored for virologic rebounds in subsequent
years. Emerging substitutions at
14 other residues
1 were also identified, but none were present in more
2 than 3 patients or reduced entecavir susceptibility
3 beyond those expected for lamivudine-resistant
5 An unexpected finding was that lamivudine
6 can preselect for entecavir-resistant
7 substitutions. This was further supported by the
8 observation that lamivudine-treated patients showed
9 evidence of emerging changes at residues 169 and
10 184 in study 026. Among the greater than 360
11 lamivudine-refractory patients genotyped, at least
12 22 had detectable changes at entecavir-resistant
13 substitutions at study entry. Nine were randomized
14 to an entecavir treatment arm, where two progressed
15 to have resistance-induced virologic rebounds
16 described earlier. Only 2/9 patients were able to
17 reduce viral DNA levels below 300 copies/mL. This
18 observation, along with the other results described
19 in this presentation, indicate that extended use of
20 lamivudine will not only select for the primary
21 lamivudine-resistant substitutions at 180 and 204,
can also select for a number of secondary
1 substitutions that can significantly reduce
2 entecavir susceptibility and clinical efficacy.
3 This slide summarizes our current
4 understanding of the entecavir resistance profile
5 at week 48. There was no evidence of genotypic or
6 phenotypic resistance in any studied
7 nucleoside-naive patients treated with entecavir.
8 Entecavir did not select for lamivudine-resistant,
9 or entecavir-resistant substitutions, or other
10 novel substitutions that result in decreased
11 entecavir susceptibility and there were no
12 virologic rebounds due to resistance.
13 Among the patients having primary
14 lamivudine-resistant substitutions at residues 180
15 and 204, 7 percent exhibited emerging
16 entecavir-resistant substitutions while on
17 entecavir therapy, and only 1 percent of
18 lamivudine-refractory patients exhibited a
19 virologic rebound due to resistance by week 48.
20 The preexistence of entecavir-resistant
21 substitutions appears to be a marker for decreased
22 efficacy and potential virologic rebound.
23 In summary, the potent and sustained
24 suppression of viral replication by entecavir
likely accounts for the absence of resistance
1 emergence in nucleoside-naive patients. An
2 extensive analysis of nucleoside-naive patients
3 showed no evidence or resistance. Entecavir was
4 also effective in lamivudine-refractory patients
5 where only 1 percent of patients experienced a
6 virologic rebound due to resistance by week 48.
7 Substitutions correlated with entecavir resistance
8 were identified at primary residues 184, 202 and
9 250 and the secondary residue 169.
10 Lamivudine-resistant substations are a prerequisite
11 for achieving high level entecavir resistance and
12 lamivudine treatment can preselect for some
13 entecavir-resistant substitutions.
14 We conclude that this virologic profile
15 provides critical information to physicians
16 regarding the placement of entecavir in the
17 armamentarium of drugs available to treat chronic
18 hepatitis B infection. Dr. Donna Morgan Murray
will now conclude our presentation with
1 pharmacovigilance and final summary.
2 Pharmacovigilance and Summary
3 DR. MORGAN MURRAY: As you have heard this
4 morning, the entecavir clinical development program
5 was extensive. It was the largest HBV program
6 conducted to date and the only antiviral HBV
7 program to use an active comparator in Phase III
8 trials. That comparator was lamivudine, the only
9 agent available at the time of initiation of the
10 trials and the most common HBV therapy used to
12 Entecavir demonstrated substantial
13 clinical benefit in Phase III and was superior to
14 lamivudine in the prespecified primary endpoint of
15 improved histology. Entecavir was also superior to
16 lamivudine in most of the secondary endpoints.
17 Based on the rodent tumor findings,
18 entecavir is a rodent carcinogen. The lung tumors
19 appear to be species specific, and the other tumors
20 occur at high exposure multiples. The
21 investigative data submitted to the carcinogenicity
assessment committee do not definitively eliminate
1 a risk for humans. With more than 2,300 patients
2 treated with entecavir, there is no safety signal
3 related to malignancy in the clinical development
4 program. While this is reassuring, we recognize
5 that the observation period is short.
6 As Dr. Sigal mentioned, we are committed
7 to continuously assessing the benefit versus risk
8 profile of entecavir, and have proposed a
9 post-marketing pharmacovigilance plan with three
10 main components. In addition to routine
11 post-marketing surveillance, the pharmacovigilance
12 plan also includes real-time monitoring of special
13 events, specifically malignancies and hepatic
14 events. We have designed special questionnaires to
15 aid in collecting follow-up information for reports
16 of both malignancies and hepatic events. We will
17 periodically review post-marketing and clinical
18 trial adverse event data, using quarterly aggregate
19 frequency reports, and we will review these events
20 of special interest.
21 There are three ongoing long-term safety
studies and we have proposed an additional large,
1 prospective, randomized safety study to be
2 conducted post-marketing. First let's review the
3 ongoing studies.
4 The clinical development program included
5 one- to two-year treatment studies and long-term
6 safety studies with careful observation for the
7 development of malignancies. Responders from the
8 Phase II/III trials were encouraged to enroll in an
9 observational study that was aimed to gather safety
10 data off treatment. Malignancy was the primary
11 focus of this observational study. Some patients
12 from the Phase II treatment studies were eligible
13 to enroll in open-label treatment studies, and
14 these patients were also encouraged to enroll in
15 the observational study.
16 To date, more than 80 percent of patients
17 from Phase III have enrolled in at least one of the
18 long-term safety studies, and the observational
19 study has more than 400 patients enrolled, with the
20 expectation that we will enroll up to 1,500
21 patients and all patients will be followed for 5
years. In addition to the ongoing
1 propose initiating a large safety study post
3 Given the limitations of pre-approval
4 clinical studies, we recognize that we cannot rule
5 out a cancer risk in patients treated with
6 entecavir. Pre-approval studies do not provide
7 sufficient numbers of patients to rule out such
8 uncommon events. We considered several options for
9 further assessment and concluded that a randomized,
10 prospective study would permit rigorous analysis of
11 these events of special interest--mortality,
12 neoplasms and progression of liver disease.
13 The draft protocol for this study calls
14 for patients to be randomized 1:1 to entecavir
15 versus another standard of care nucleoside or
16 nucleotide; to be stratified as naive or previously
17 treated; and to be followed for at least 5 years.
18 It is our intent to engage an external, independent
19 data safety monitoring board to conduct periodic
20 reviews of the data from this study.
21 We propose to conduct the study globally
to recruit patients via their own physicians.
1 Patients who are starting a new HBV therapy or are
2 changing their therapy will be eligible to enroll.
3 We expect to enroll a total of 12,500 patients. We
4 will report annually on rates of all-cause
5 mortality, malignancy and progression of liver
6 disease. While other common nucleosides also have
7 rodent tumor findings, and the benefit-risk
8 assessment was favorably concluded based on the
9 serious nature of the disease, such as AZT for HIV,
10 few have been the subject of the rigorous
11 assessment that we propose here.
12 However, the proposed study does have
13 several challenges. First, the planned primary
14 analysis is intent-to-treat and, as patients will
15 inevitably switch therapies over the course of the
16 study, the primary analysis may be confounded.
17 However, we will not limit our review of the data
18 to this analysis and we will look at the data in
19 several different ways.
20 Second, there may be limited ability to
21 detect treatment group differences for events of
variable latency. Since all
patients will be
1 studied for at least 5 years, and many may well be
2 studied for up to 8 years, we should detect a
3 signal if there is an increased risk.
4 Third, the study is designed to detect
5 differences in overall malignancy rates and in
6 rates of HCC, but is not designed to detect
7 treatment group differences for individual
8 malignancy types.
9 Finally, attrition will occur but this
10 does not mean that patients will be lost to
11 follow-up. We will implement tactics to enhance
12 follow-up, and we have developed strategies to
13 address these challenges listed on this slide, and
14 conclude that the proposed study will provide
15 important data on both the benefits of entecavir
16 and on further risk assessment.
17 Adequate data exist to demonstrate the
18 substantial benefit of entecavir over existing
19 therapies. Entecavir provides superior viral
20 suppression in both nucleoside-naive and
21 lamivudine-refractory patients. Specifically,
treatment with entecavir resulted in up to a 7-log
1 decrease in HBV DNA.
2 Entecavir results in superior
3 normalization of ALT in both nucleoside-naive and
4 lamivudine-refractory patients. Up to 78 percent
5 of patients achieve normal ALT.
6 Entecavir also provides superior
7 improvement in histology in both nucleoside-naive
8 and lamivudine-refractory patients. Treatment with
9 entecavir resulted in up to 72 percent reduction in
11 Entecavir has a favorable resistance
12 profile compared to lamivudine. As you heard from
13 Dr. Colonno, no resistance substitutions emerged in
14 nucleoside-naive patients and resistance
15 substitutions were uncommon in
16 lamivudine-refractory patients.
17 Given the demonstrated superiority of
18 entecavir in viral suppression, ALT normalization
19 and improved histology, and the favorable
20 resistance profile both in nucleoside-naive and
21 lamivudine-refractory patient populations,
long-term benefits of entecavir might include a
1 reduction in disease progression, such as lower
2 rates of liver failure, liver cancer, liver
3 transplant and liver-related deaths.
4 We conclude that the demonstrated benefits
5 of entecavir represent an important treatment
6 advance for HBV infection. The demonstrated
7 benefits of entecavir against HBV, a known
8 carcinogen, are indeed substantial and outweigh the
9 theoretical risk posed by the rodent tumor data.
10 Thank you for you attention this morning.
11 Questions from the Committee
12 DR. ENGLUND: Thank you very much, Dr.
13 Murray. I would like to thank the Bristol-Myers
14 Squibb people for a very clear, concise and timely
15 presentation. It was very nice. Thank you.
16 This is the time that we are going to open
17 up for questions to the panel, but I would like to
18 caution people that the questions are supposed to
19 be directly related to the information presented
20 today. We will have discussion time later on but
21 if there are clarifications or questions about
specific points related to the presentation we just
1 heard, now is the time to begin so I will open it
2 to the panel for questions. Dr. DeGruttola?
3 DR. DEGRUTTOLA: Yes, I have two
4 questions. The presentations mentioned that the
5 studies in dogs and rats did not find an increased
6 risk of lung cancer associated with entecavir. I
7 was wondering how long those studies had gone on;
8 were they powered to be able to detect such an
9 effect? Then, regarding the post-marketing study
10 to try to determine an effect on cancer in humans,
11 I was wondering what the power will be in that
12 study; what magnitudes of effects is the study
13 powered to detect?
14 DR. MORGAN MURRAY: First I will ask Dr.
15 Lois Lehman-McKeeman to address your first question
16 about the duration of studies in dogs and rats.
17 DR. LEHMAN-MCKEEMAN: I will speak to the
18 rats first because they were, in fact, one of the
19 species used in the lifetime carcinogenicity study.
20 So, in two years, for the lifetime of the rat,
21 there were no tumors in the lung that developed.
The dog the studies were not conducted to
1 be carcinogenicity studies; they were chronic
2 toxicology studies and they were three months in
3 duration. However, what we understand about the
4 lung lesion in the mouse is that it develops very
5 quickly and the early preneoplastic change that I
6 described occurs within the first two weeks of
7 dosing. In the course of a three-month study in
8 dogs we saw no early preneoplastic change.
9 DR. DEGRUTTOLA: Thank you.
10 DR. MORGAN MURRAY: And for your second
11 question about the power of our post-marketing
12 study to detect differences, Dr. Phil Pierce will
13 address that.
14 DR. PIERCE: The primary goal of the large
15 safety trial is to investigate the potential
16 treatment effect on the development of non-HCC
17 malignancies. First we had to establish what the
18 background rate in this population is, and we
19 utilized the data from the Taiwan cohort that was
20 presented, as well as the background rates that we
21 saw in the BMS studies.
The background rate was approximately 4
1 non-HCC cancers over 1,000 patient-years of
2 follow-up. We estimated from that that there would
3 be 16 non-HCC malignant events per 1,000
4 patient-years per arm over 5 years. Also, the
5 total accrual of time will be 65,000 patient-years.
6 Our study was designed to show a 30 percent
7 increased risk of malignancy. That translates into
8 5 additional cancers per 1,000 patient-years over
9 the 16 that I mentioned earlier. I believe BMS
10 concludes this is a reasonable assessment of that
12 Slide 1-520, please. I gave you a lot of
13 numbers with that and I want to show the expected
14 events in the untreated population over the 5
15 years. The rate that I mentioned for the non-skin,
16 non-HCC cancers is 16 as the expected rate and we
17 would have a power to detect, with this sized
18 population, an increase of 5 over that 16. The
19 additional benefit of this study is that we will
20 also be able to analyze the impact on the other
21 events of interest which, obviously because of the
large size of those, we are adequately powered to
1 show whether we have an impact on the rates of HCC
2 and on the progression to cirrhosis.
3 DR. DEGRUTTOLA: Thank you.
4 DR. ENGLUND: Thank you. Dr. Washburn?
5 DR. WASHBURN: It is very interesting that
6 the study drug is chemotactic for mouse monocytes
7 but not human monocytes. I wonder if there is any
8 work that can be shared that would discuss some
9 mechanism of that difference. Does it relate to
10 complement activation, or a macrophage chemotactic
11 peptide, or other? The question is of potential
12 relevance in the carcinogenicity of disease.
13 DR. MORGAN MURRAY: Dr. Lehman-McKeeman
14 will address that.
15 DR. LEHMAN-MCKEEMAN: At this point in
16 time we don't know the molecular basis of that
17 difference. What we know is that based on the fact
18 that macrophages were accumulating in the lung and
19 were not proliferating to accumulate, we looked
20 specifically for a chemotactic event and we tested
21 that in some standard in vitro systems. When we
that work, there is clear chemotactic activity
1 to the mouse with no effect in the human at all.
2 Now, to go further, we have looked, in
3 doing some investigative work, at whether or not
4 altering macrophage recruitment alters the
5 progression of this lesion. To do that, we have
6 looked at a CCR2 knockout, so chemokine receptor to
7 a knockout animal, and we found that that mouse
8 does, indeed, have a very different response to the
9 drug. It is no unequivocal proof that this is
10 mediated through CCR2, but it suggests that it
11 plays a role.
12 I want to add one other factor though, and
13 that is that the lesion that we see involves
14 accumulation of macrophages but, based on our
15 assessment, those macrophages don't appear to be
16 activated. They are simply accumulating.
17 DR. WASHBURN: Thank you.
18 DR. ENGLUND: Dr. Fish?
19 DR. FISH: I didn't hear my name earlier
20 in the disclosure statement and I just need to add
21 that though I signed the disclosure waiver, I have
been on the speakers bureau for the sponsor and two
2 The question that I have is on the study
3 were there pregnancies and, if so, the outcomes of
4 those pregnancies in entecavir-treated patients?
5 DR. MORGAN MURRAY: I am going to try out
6 Dr. Brett-Smith's voice here. So, Helena?
7 DR. BRETT-SMITH: The studies were
8 designed that if pregnancy was determined to occur
9 during the course of the study the patient was to
10 immediately stop study drug. Indeed, pregnancies
11 do occur. The majority of these actually resulted
12 in elective termination of pregnancies.
13 If we could show slide 5-79, this includes
14 the various treatment combinations that have been
15 used across our entire program to date with
16 entecavir alone, lamivudine alone, entecavir in
17 combination with lamivudine, for the initial period
18 of the 901 long-term rollover study and also in
20 As you can see, the majority of
21 pregnancies identified resulted in elective
termination. There was a small
1 spontaneous abortions. There have been 6 live
2 births. The 4 outcomes that are listed as
3 "unknown" are progressions that are currently under
4 way and for which we are actively pursuing
5 follow-up on those deliveries.
6 With respect to the live births, across
7 those live births there were no reported defects in
8 5 out of the 6 cases. There was, indeed, 1 live
9 birth where the mother had received entecavir 0.5
10 mg for a total of 44 weeks but the diagnosis of the
11 pregnancy was made at approximately week 7 of
12 gestation. That had a fairly complicated history.
13 The child was born with what has been reported to
14 us as a severe cerebral cortex defect.
15 Unfortunately, despite repeated contact with the
16 site, the family has not wished to provide us with
17 further data.
18 The details of the early pregnancy are a
19 little complex so let me walk you through those.
20 The patient had discontinued entecavir immediately
21 at the time that pregnancy was diagnosed, as I
said, about week 7. The patient
1 what was clinically diagnosed as a spontaneous
2 abortion and was told by the gynecologist that no
3 fetus had been present. A subsequent ultrasound
4 actually did reveal a live fetus, but in the
5 interim entecavir had been briefly restarted by the
6 clinician for 2 weeks and the moment the ultrasound
7 became available it was discontinued. So, that
8 represents the sum of our experience to date in the
9 program with pregnancy.
10 DR. ENGLUND: Dr. Haubrich?
11 DR. HAUBRICH: It is clear that emergence
12 of viral resistance to therapy is dependent on the
13 degree of viral suppression and, clearly, drugs
14 that have greater suppression will have less
15 emergence of resistance. It is also clear from
16 extensive experience in AZT that after 15-20 years
17 of nucleoside therapy we are still identifying new
18 mutations. So, perhaps I didn't follow it well,
19 but if you could clarify the emergence of mutations
20 that may have occurred with entecavir. Although
21 they may not lead to phenotypic susceptibility
since the number of mutations is few at this point,
1 you know, they may in the future be defined when
2 greater numbers of samples are available.
3 So, just a comment that it is clear that
4 the resistance profile is better with greater
5 suppression, but it seems a little premature to be
6 saying that there is no resistance that develops on
7 therapy when the number of specimens is low and it
8 may be a bit early. So, if you could comment on
9 that I would appreciate it.
10 DR. MORGAN MURRAY: I will ask Dr. Colonno
11 to comment but first I would like to note that the
12 original NDA and the safety update--at that time we
13 only had 48-week data available and that is the
14 only data that have been submitted for review. But
15 very recently we did complete the analysis on
16 patients who have been treated for two years and
17 Dr. Colonno can perhaps share those data as well.
18 DR. COLONNO: Let me just deal with the
19 first part first in terms of the number of
20 mutations, just to give you a sense of what
21 mutations were found.
Can I have slide 1-315, please?
This is a
1 list of all the mutations that have been found or
2 identified in all patients examined that have taken
3 entecavir--as you can see, a very wide range. The
4 vast, vast majority of these, again, have occurred
5 at polymorphic sites. We call them new emerging
6 substitutions because they have not been described
7 previously at those particular sites.
8 Again, I will point out that these
9 mutations do not occur in any more than three
10 patients. Most of these occur in a single patient,
11 again, representing less than one percent. We have
12 tested all of these different mutations and
13 substitutions not only by themselves but also in
14 the context of their preexisting clinical
15 background and, as you can see by the EC
50s that are
16 present, they really do not alter the normal wild
17 type susceptibility.
18 Now if I can just move to your statement,
19 which I think is a correct one and, again, as a
20 virologist having worked in resistance for many,
21 many years, there is no such thing as no
resistance. So, we have gone out
to the second
1 year, and this is real-time data and the data
2 continues to come in, and I would like to just
3 share with you some very encouraging data for the
4 second year.
5 This is the second year data as it
6 currently stands. On the left-hand side, again,
7 are the bubble charts and the first thing I want to
8 point out is this is study 022 where we have the
9 most data. You can see that the continued
10 progression in decreasing DNA from week 48 to 96,
11 where we have 65 undetectable now, we continue to
12 drive viral load down with 81 percent of patients
13 now with undetectable virus.
14 That correlates with the table on the
15 right where, again, despite the fact that we have
16 treated now for 2 years, we have a very similar
17 profile to what we saw in year 1. In year 2 we
18 have a total of 7 rebounds, virologic rebounds
19 using the definition I described earlier but,
20 again, looking at their genotypes and phenotypes we
21 see no evidence of any genotypic or phenotypic
resistance. So, out to 2 years in
1 nucleoside-naive population with that type of viral
2 suppression we have not observed any resistance to
4 DR. ENGLUND: Dr. Johnson, do you have a
5 specific question about that?
6 DR. JOHNSON: Victoria Johnson, University
7 of Alabama at Birmingham. As a virologist and
8 viral resistance person, I share concerns that
9 despite the elegant data presented, given this
10 compound's potency, as you realize, two years may
11 not be enough, and I want to just ask is this part
12 of the pharmacovigilance monitoring plan? That is
13 one question.
14 The second question is, if you can go to
15 your second to last slide of your previous
17 DR. MORGAN MURRAY: Let me answer your
18 first question first around the pharmacovigilance
19 plan. Several of our studies are ongoing, as I had
20 mentioned, and in all of the ongoing clinical
21 studies we do continue to monitor for resistance.
Acknowledging that the pharmacovigilance plan is
1 very large, we will have many centers and it will
2 be usual practice, we feel it will be impossible
3 for us to get resistance data on all of the 12,500
4 patients. But what we do propose is to have a
5 sub-study, a subset of patients, a center in the
6 U.S., a center, you know, here and there that we
7 will get much more data including resistance data.
8 I will let Dr. Colonno address your second point.
9 DR. COLONNO: We will continue to look for
10 resistance until we find it. Again, there is
11 always going to be resistance at some point. But
12 the key point of this slide, which we don't have
13 with HIV, unfortunately, even with combination
14 therapy, is the ability to drive viral load down by
15 6 or 7 logs, 8 logs in some cases and to maintain
16 that for a very long period of time. Those viruses
17 require a minimal amount of replication to give
18 rise to resistance. So, we are encouraged. Again,
19 that is not to say there will never be resistance
20 but we are highly encouraged with that kind of
21 suppression and with the limited ability of the
virus to actually replicate that a large amount of
1 resistance will all of a sudden come up. We will
2 continue to monitor these patients for the
3 foreseeable future.
4 Another interesting point is that these
5 particular patients do not give rise to any
6 evidence of resistance substitutions being
7 selected. We know lamivudine resistance is a
8 stepping stone to becoming clinically relevant
9 resistance to entecavir. But the fact that we,
10 again in that population, see none of those changes
11 really coming up again is encouraging but, again,
12 it is only two-year data for a large number of
13 patients, but not a tremendous amount, so we will
14 continue to monitor in subsequent years.
15 DR. JOHNSON: My second question is on
16 your second to last slide, just for clarification.
17 DR. COLONNO: My second to last slide?
18 DR. JOHNSON: Yes, from your earlier
19 presentation. It was called summary of viral
20 resistance data at week 48. So, just to clarify,
21 and I think part of this got answered, the title is
week 48 but the bottom data are presented on two
1 patients who had greater than 76 weeks.
2 DR. COLONNO: Those two patients were from
3 the Phase II study. They are not included here;
4 they were Phase II.
5 DR. JOHNSON: So, they are different than
6 the two on this slide that are on the bottom?
7 DR. COLONNO: These two are from the Phase
8 III evaluation.
9 DR. JOHNSON: At week 48?
10 DR. COLONNO: At week 48.
11 DR. JOHNSON: And that is different than
12 the other two patients you described with virologic
13 rebound resistance?
14 DR. COLONNO: That is correct. One was in
15 the 015 study which was a transplant study, and the
16 other one was in 014.
17 DR. JOHNSON: But they appear to select
18 the same signature mutations?
19 DR. COLONNO: They select the same
20 signature mutations. Those three mutations appear
21 to be the key primary resistance markers for
23 DR. ENGLUND: Dr. Sherman?
24 DR. SHERMAN: The presentation indicated
that phosphorylation was required for this product.
1 Could you comment on any data you have regarding
2 interactions with anti-retrovirals that also
3 require phosphorylation in vitro? I know you have
4 limited in vivo HIV-positive patients, but is there
5 any pharmacokinetic analysis and any issues of
6 changes in resistance to HIV or susceptibility
7 because of the interaction?
8 DR. MORGAN MURRAY: I will let Dr. Colonno
9 follow up on that.
10 DR. COLONNO: We have done an extensive
11 analysis of the interactions because it is a
12 nucleoside analog and there are many nucleoside
13 analogs that are used in HIV, interactions based on
14 the phosphorylation patterns of these various
15 combinations. What I can tell you is that because
16 the concentration of entecavir is so low relative
17 to other nucleoside analogs and the efficiency is
18 so high, when one does in vitro cell culture
combination studies to look for the effect of
1 entecavir on the antiviral potency of the HIV
2 nucleoside analogs, or in the opposite direction in
3 the presence of the HIV and RTIs and does it have
4 an impact on entecavir activity, we find, using
5 concentrations of both sets of compounds up to five
6 times their C max,
clinical Cmax, we see no
7 interactions whatsoever; no antagonism; and no
8 decrease in the activity. Again, that is a big
9 plus for entecavir because entecavir is very
10 selective for hepatitis B and so it literally also
11 can be used in a co-infected patient but not having
12 to worry about any kind of selective pressure on
14 DR. ENGLUND: I am going by the order that
15 I saw the hands come up, which may be wrong, and we
16 are only going to have time for about four or five
17 more questions. But the first question was Mr.
19 MR. GRODECK: In terms of marketing
20 antivirals, one of the biggest games I have seen
21 pharmaceutical companies play is the sequencing
game--my drug should come before your drug. In
1 your description of the resistance profile of
2 entecavir, it seems to me that you are setting up
3 the drug to be positioned as a first-line
4 treatment. Is that your position? How does it fit
5 in terms of the range of other treatments available
6 to chronic hepatitis B patients today?
7 DR. MORGAN MURRAY: I will ask Dr.
8 Dienstag to comment on how entecavir might fit into
9 current treatment guidelines and the physicians'
10 armamentarium. I will just remind you, from our
11 data, that we have demonstrated that entecavir is
12 superior to lamivudine. We have substantial
13 benefits in both nucleoside-naive and
14 lamivudine-refractory patients.
15 DR. DIENSTAG: Jules Dienstag,
16 Massachusetts General Hospital. I think if we
17 consider hepatitis B a viral disease, then the drug
18 that suppresses HBV most profoundly is likely to
19 have the most benefit. That has been shown in this
20 study for histology, biochemical markers and
21 especially for the profundity of suppression of HBV
DNA. In almost 90 percent of
patients you can
1 achieve an undetectable level of HBV DNA, which no
2 other antiviral comes close to at this point.
3 So, it is not unreasonable to suggest that
4 this would be a first-line therapy. When you add
5 the resistance profile and when you consider the
6 potential that, for example, a drug like lamivudine
7 sets you up for lamivudine resistance in the future
8 and also sets you up for resistance to any other
9 nucleoside, it makes sense to start with this drug.
10 It is a very reasonable suggestion.
11 DR. ENGLUND: Dr. Paxton, did you get your
12 question answered?
13 DR. PAXTON: Yes, it was. Thank you.
14 DR. ENGLUND: Dr. Wood, or were you first,
15 Dr. Seeff or Dr. Schwarz?
16 DR. SCHWARZ: I have two questions
17 relative to future applications of entecavir. You
18 said that in the animal carcinogenicity models in
19 the organ involved with the tumor there were
20 ETV-induced dNTP pool perturbations. In either the
21 animal studies or in the human studies, was there
evidence of peripheral blood lymphocytes--the same
1 phenomenon occurring in peripheral blood
2 lymphocytes that might be a useful non-invasive
3 surrogate marker for malignant potential?
4 Then the second question is I assume in
5 these lifetime exposure studies that the drug was
6 not started in the immediate newborn period. So,
7 at what age of the animal was it started, and can
8 you make an educated guess about the human
9 equivalent age?
10 DR. MORGAN MURRAY: I will ask Dr.
11 Lehman-McKeeman to address the data that we have in
12 animals around dNTP pool perturbations and also
13 about the rodent studies. I will just comment that
14 we do not have any human data around dNTP pool
15 perturbations. As Dr. Lehman-McKeeman will
16 describe, these perturbations in animals occur at
17 much higher doses than we administer in humans.
18 DR. LEHMAN-MCKEEMAN: I will actually
19 address the second question first for you. The
20 studies that are conducted in rodents basically
21 start when they are approximately 5-6 weeks of age.
perspective, that is when a rodent reaches
1 sexual maturity. So, in a 2-year life span, if I
2 had to extrapolate, I will just say at sexual
3 maturity so it would be roughly teenage.
4 To your first question about the dNTP
5 pools, in the work that we did we specifically
6 looked at target organ effects related to
7 carcinogenicity. So, we specifically looked at the
8 liver and we don't have any data on another system.
9 Those analyses are actually quite, I will say,
10 difficult to do, as it were, simply because the
11 pools themselves are really quite fleeting. So, it
12 really is prohibitive for us to collect more then
13 one sample and we targeted the liver. However,
14 what we know, based on the work we have done, is
15 that that is a high dose phenomenon. So, at
16 dosages where we saw carcinogenic activity we saw
17 perturbations in pools, and at a dose below a
18 carcinogenic effect we did not seriously disrupt
19 pools. So, I think it is a function, again, of the
20 maximum tolerated dosage that we are administering
21 in the carcinogenicity studies.
22 DR. ENGLUND: Dr. Wood?
23 DR. WOOD: My question has to do with
24 analysis of rates of malignant neoplasms according
ethnicity. This is related to the fact
1 believe I read that Asians have a higher
2 pharmacokinetic exposure to entecavir and I was
3 wondering whether or not an analysis had been done
4 on that basis.
5 DR. MORGAN MURRAY: I will ask Dr.
6 Brett-Smith to come up again. I will try and spare
7 her voice a bit and comment that while we have not
8 seen PK differences on the basis of race in
9 particular, the differences that we do detect are
10 related to weight more than to race. Dr.
11 Brett-Smith, on the malignancies?
12 DR. BRETT-SMITH: At this point we have
13 chosen not to look at any subpopulations in terms
14 of the overall rates in malignancies because the
15 total numbers remain low, and we believe that the
16 rates would be sort of unreliably variable. That
17 may become an option later in terms of the
19 DR. ENGLUND: Dr. Seeff?
20 DR. SEEFF: I thought that the efficacy
21 data that were presented were fairly impressive but
22 there are a couple of questions that I just need
23 some clarification on. Perhaps you presented them
24 and I missed them.
The primary endpoint for your study was
1 histologic using the Knodell score. I gather that
2 this is not unusual; this is fairly routine. Is
3 this the 18-point HAI score?
4 DR. MORGAN MURRAY: Yes.
5 DR. SEEFF: In other words, the drop for
6 example from 10 points to 8 points would represent
7 an endpoint having been achieved.
8 DR. MORGAN MURRAY: Correct.
9 DR. SEEFF: What was the average drop? Do
10 you know what the average decline in points was,
11 just to get a sense of how much improvement there
12 was in histology? Do you have those data by any
13 chance? I mean, you have the percentage of people
14 who achieved a 2-point reduction, but what I am
15 interested in knowing is by how much of a
17 DR. MORGAN MURRAY: Dr. Brett-Smith?
18 DR. BRETT-SMITH: Yes, we do have data and
19 I can present it for you if we can show slide 2-66.
20 Overall, in the naive patients it was approximately
21 a 4-point drop in the mean score, and in the
22 refractory patients it was approximately a 3-point
24 DR. SEEF: That is fine. Thank you. The
second thing is your secondary endpoints,
1 essentially a reduction in HBV viral load and
2 normalization of ALT, do you have a composite score
3 taking into account the virologic, histologic,
4 biochemical reduction? Do we have a score of using
5 those three parameters?
6 DR. MORGAN MURRAY: Dr. Brett-Smith?
7 DR. SEEFF: And is it the same between
8 entecavir and lamivudine for example?
9 DR. BRETT-SMITH: If I can just repeat the
10 factors that you are interested in, you are
11 interested in combining histology with virology--
12 DR. SEEFF: And with biochemical response.
13 DR. BRETT-SMITH: With ALT.
14 DR. SEEF: ALT.
15 DR. BRETT-SMITH: Those three. We have
16 looked at a number of ways of combining virology
17 with ALT. I will ask my colleagues to confirm
18 whether we have yet completed the analysis
19 combining with histology. I do not have that at
20 this time.
21 DR. MORGAN MURRAY: So, we will confer
22 during the break and see if we can quickly pull
23 something together to answer that.
24 DR. ENGLUND: Last question, Dr. So?
DR. SO: There is a common belief
1 clinicians that, you know, if you have e-antigen
2 seroconversion you pretty much, you know, have a
3 good response and you might be cured. So, I notice
4 that earlier in this handout to us, the committee
5 members, you did describe some follow-up on the
6 patients in your study 22 where they have so-called
7 complete response. Some of the patients were taken
8 off drugs. Do you have two-year follow-up
9 information regarding how many of those patients
have so-called sustained response and what
1 sustained response means?
2 DR. MORGAN MURRAY: I will ask Dr.
3 Brett-Smith to comment, and I need to make the
4 statement that in the NDA and the NDA update we
5 only had the 48-week data so, again, these data
6 have not been submitted for review.
7 DR. BRETT-SMITH: I heard a two-part
8 question there. Let me just clarify. I heard
9 first for patients who, at the end of year one,
10 went off dosing--you were interested in the
11 sustained response off treatment.
12 DR. SO: Right.
13 DR. BRETT-SMITH: Also, did I hear an
14 interest in what happens to the portion of partial
15 responders who have a virologic response--
16 DR. SO: No, I am just interested in your
17 so-called complete responders.
18 DR. BRETT-SMITH: Let me first summarize
19 for you the design of the studies at the week 52
20 endpoint. A clinical decision was made based on
21 laboratory results from week 48 as to the
management of the patient, which was simply a
1 management algorithm that was modeled on guidance
2 at the time and it differs for each population. In
3 the e-antigen positive population we required, in
4 order to go off therapy, that patients have lost
5 e-antigen and have an HBV DNA less than the bDNA
6 assay level of detection, so less than 0.7. In the
7 e-negative population patients had to meet the
8 virologic requirement of bDNA less than LOQ, and
9 they had to have an ALT less than 1.25 times the
10 upper limit of normal. In the refractory antigen
11 positive patients we again required that the
12 patients achieve the virologic endpoint in
13 association with e-loss. In that last group there
14 were very small numbers of patients going off
15 treatment, therefore, we will not discuss that
16 further; the numbers were substantially small.
17 With respect to the two naive patient
18 populations, if we could show slide 2-380, the
19 studies were designed to follow people out to 24
20 weeks of off-treatment follow-up. If during that
21 time patients went on alternative therapy or into
rollover study they were considered failures to
1 maintain that endpoint. These represent the
2 respective percentages in the naive e-antigen
3 positives on the left, 82 percent for entecavir and
4 73 percent for lamivudine, who maintained their
5 study-defined response rate at week 24 off
6 treatment. Likewise, in the naive e-antigen
7 negative population we had 48 percent for entecavir
8 and 35 percent for lamivudine.
9 DR. SO: But I don't think you answered my
10 question. How many of those patients who were off
11 treatment actually were followed up, like actually
12 48 weeks off treatment, are still off treatment?
13 You know, it could be very misleading for a lot of
14 clinicians when you say sustained response, not
15 knowing, you know, for how many of those patients
16 actually their histologic improvement was
17 sustained? Was the virologic improvement sustained
18 at 48 weeks? So, I feel that the 24-week off
19 treatment, so-called sustained response, could be
21 DR. BRETT-SMITH: Point taken, 24 weeks is
what had been agreed upon with regulatory
1 authorities in the design of the original study.
2 All patients are encouraged to enroll on completion
3 of the original study in the 049 long-term rollover
4 study which remains currently enrolling at this
5 time and has not undergone its initial analysis.
6 DR. SO: Just one last question, how does
7 your company plan to talk to those clinicians who
8 say, you know, if my patient seroconverted--these
9 are naive patients before treatment, if they
10 seroconverted I am planning to stop the treatment?
11 How do you plan to advise those clinicians?
12 DR. MORGAN MURRAY: Our current proposed
13 labeling reflects how the studies were conducted,
14 and in that regard, for those patients who were
15 determined to be responders therapy was stopped at
16 48 weeks and they were monitored. Patients who
17 were partial responders continued on therapy. Our
18 current trials cannot define the definitive
19 duration of dosing for entecavir, which is in
20 general in flux for HBV therapy. Dr. Dienstag, do
21 you have any further comments?
DR. DIENSTAG: Jules Dienstag,
1 General Hospital. No one really knows what the
2 sustained responsiveness or the durability of an
3 e-antigen response is, but in the experience we
4 have for interferon, lamivudine and adefovir if a
5 person maintains that serologic response for 6
6 months after stopping therapy the durability is 80
7 percent. That is the experience in Asia and in the
8 West. I assume that that will be repeated in this
9 experience but that remains to be seen.
10 DR. ENGLUND: Thank you, everyone, for
11 asking questions, answering questions. We will now
12 take a 15-minute break. We will be back at 10:25
13 to resume the FDA portion of this morning's
15 [Brief recess]
16 DR. ENGLUND: Thank you. Welcome back
17 from coffee. We are now going to have an FDA
18 presentation led by Dr. James Farrelly, the
19 pharmacology team leader, and he will begin his
21 FDA Presentation
22 Carcinogenicity Issues
23 DR. FARRELLY: Good morning. My name is
24 Jim Farrelly. I am the pharmacology team leader in
Division of Antiviral Drugs.
1 Today our purpose is to present some of
2 the data relating to the genetic toxicity and the
3 animal carcinogenicity of entecavir. Entecavir is
4 a nucleoside analog and, as such, is a member of a
5 class of molecules which are in general expected to
6 be genetically toxic. Its 5-prime hydroxyl can be
7 phosphorylated to the nucleotide triphosphate and
8 as a guanosine triphosphate analog can be
9 incorporated into the growing DNA chain. It has
10 the three-prime hydroxyl group and is, therefore,
11 not an obligate chain terminator as are many other
12 nucleoside analogs.
13 However, after incorporation of entecavir
14 into the growing DNA chain, it halts DNA synthesis
15 after the addition of a small number of subsequent
16 bases. Its mechanism of action is essentially as a
17 chain terminator, which is consistent with its
18 being a clastogenic compound or having the ability
break chromosomes. Indeed, entecavir has
1 shown to be clastogenic in an in vitro assay in
2 human lymphocytes.
3 It is negative in a number of genetic
4 toxicity tests both in vitro and in vivo. These
5 include an Ames test, an in vitro assay in Chinese
6 hamster ovary cells, in the Syrian hamster embryo
7 cell transformation assay, and in an in vivo rat
8 micronucleus assay, and in an unscheduled DNA
9 synthesis assay. In general, most of the battery
10 of genotoxicity tests can be used only for hazard
11 identification. They are not used for risk
12 assessment but have indicated that entecavir can be
13 a possible genetic toxicity hazard.
14 In an effort to place the results of the
15 genetic toxicity studies into perspective, one can
16 compare the outcome of the studies used to evaluate
17 entecavir with the outcome of the studies used to
18 evaluate the genetic toxicity of the three entities
19 approved for the treatment of hepatitis B. The
20 three are adefovir, lamivudine and interferon.
21 Adefovir is a nucleotide analog rather
than a nucleoside analog, and was found to be
1 mutagenic and to induce chromosomal aberrations in
2 two in vitro genetic toxicology studies.
3 Lamivudine, or 3GC, is a nucleoside analog and was
4 found to be mutagenic in two in vitro assays as
5 well. Interferon was not an active genetic toxin.
6 Since it is a protein one would not expect
7 interferon to be positive in the screening battery
8 used to test for genetic toxicity. However, most
9 of the nucleoside analogs approved as antiviral
10 antigens are positive in genetic toxicology
11 batteries of tests.
12 Now, as is usual for a drug that is going
13 to be administered chronically to humans, entecavir
14 was evaluated in two-year carcinogenicity studies
15 in rats and mice. The design and outcome of the
16 study in rats can be seen in the next slide where
17 the data for male rats are shown.
18 Entecavir was administered by gavage to
19 rats at four doses, 0.003, 0.02, 0.2 and 1.4
20 mg/kg/day. They were administered for 96 weeks.
21 There were two identical vehicle controls in the
study. The doses in male rats
represent the human
1 equivalent exposure of much less than 1, 0.3, 5 and
2 35 times the clinical dose at the 1 mg proposed
3 clinical dose, which you see under MHD.
4 In male rats at an exposure 35-fold that
5 in the clinic entecavir caused the appearance of a
6 low level but significant incidence of brain
7 gliomas. A no-level of tumors was seen, or very
8 low level, at 5-fold the exposure, and below no
9 significant number of tumors was seen in the study.
10 The next slide shows the results in female
11 rats. As can be seen from this slide, entecavir
12 was administered at doses of 0.01, 0.06, 0.4 or 2.6
13 mg/kg/day for two years. Dosing was again by
14 gavage and drug groups as well as two identical
15 vehicle control groups were treated for 104 weeks.
16 As can be seen in the slide, entecavir again
17 induced the appearance of brain gliomas at the high
18 dose. It also induced the appearance of skin
19 fibromas at the high dose, and increased the
20 incidence of liver tumors at the high dose from 1-8
21 adenomas and from 0-3 carcinomas. The exposure to
entecavir at the high dose in which these tumors
1 were seen was approximately 24-fold higher for
2 females than that measured in the clinic at the 1
3 mg dose.
4 Mention should be made regarding the
5 exposure multiples at which tumors were seen in the
6 study. Although a multiple of 24 in exposure is a
7 high multiple of the human exposure, it should be
8 remembered that there were no significant induction
9 or increase in tumors at the 4-fold for females and
10 5-fold level for males. The real cutoff,
11 therefore, is somewhere between the high dose and
12 the next lower dose, and the no-observed effect for
13 tumors was at the 4- and 5-fold human dose.
14 The results of the mouse carcinogenicity
15 study were more complicated. In the next slide it
16 is shown that male mice were treated in a similar
17 manner as were the rats. The doses of entecavir
18 used actually in both the males and the females
19 were the same on a milligram per kilogram per day
20 basis. The doses were 0.004, 0.04, 0.4 and 4
As seen here, entecavir caused a
1 dose-related increase in common bronchoalveolar
2 adenomas in the males, significant at the three
3 higher doses. The lowest of the three doses
4 produced an exposure only 3-fold higher than the
5 clinical exposure. Also increased in the males was
6 the incidence of hepatocellular carcinoma at the
7 high dose, going from 1 in one of the controls to 8
8 at the high dose. The exposure in the latter case
9 was 42-fold higher than the clinical exposure. For
10 the hepatocellular carcinomas no increase was seen
11 at an exposure 40-fold the clinical dose, very low;
12 not significant.
13 The next slide shows the female mice in
14 which entecavir induced a significant increase in
15 the lung tumors only at the high dose, giving an
16 exposure in the animal study 40-fold the exposure
17 in the clinic. There was no significant increase
18 at 11-fold the exposure. Also in female mice there
19 was an increase in ovarian and uterine vascular
20 tumors, again at the high dose. If one combined
21 all the vascular tumors, as is commonly done, there
a significant increase in combined hemangiomas
1 and hemangiosarcomas at the high dose.
2 We have heard the sponsor make a good case
3 for the proposition that the pulmonary tumors seen
4 in the mouse are mouse specific. No cellular
5 proliferation was seen in the lungs of rats and no
6 lung tumors in rats, as well as no cellular
7 proliferation in the dog and monkey studies. If,
8 indeed, the tumors were mouse specific the outcome
9 would be that the only tumors seen in the two
10 studies were at the high dose only.
11 Again, putting the results of the
12 carcinogenicity studies into perspective with the
13 other approved regimens for hepatitis B, no
14 carcinogenicity studies were carried out with
15 interferon. Studies were carried out with adefovir
16 and lamivudine; they were not carcinogenic.
17 However, because of kidney toxicity in the
18 carcinogenicity studies, the exposures of the
19 animals in the adefovir studies relative to the
20 clinical exposures were 10-fold for mice and 4-fold
21 for rats. The maximum tolerated dose cannot go any
higher than those. So, if
entecavir was examined
1 only at those exposures, it would have been
2 positive only for the lung tumors in mice and for
3 no other tumor types.
4 The exposures in lamivudine studies were
5 high relative to the exposures in the clinic, up to
6 34-fold in the mice and 200-fold in the rats. At
7 those exposures the entecavir results would have
8 been at least identical to those which we have seen
9 in these studies. However, many nucleoside analogs
10 approved as antivirals have been positive in
11 carcinogenicity studies.
12 The results of the two carcinogenicity
13 studies were presented to the CDER Executive
14 Carcinogenicity Assessment Committee, which we call
15 the executive CAC, as well as to the full CAC for
16 evaluation. The CDER CAC committees were formed in
17 the late 1980s to examine the protocols of
18 carcinogenicity studies, as well as to examine the
19 outcomes of the same studies. The committees were
20 founded so that the interpretation of the
21 carcinogenicity data would not be inconsistent
depending on which division reviewed them. Two
1 committees exist, the executive CAC, as I said, and
2 the full CAC.
3 The executive CAC consists of four
4 members, the associate director for
5 pharmacology/toxicology in the center; one
6 permanent expert in the evaluation of
7 carcinogenicity studies; the supervisor whose
8 division is presenting the data; and another
9 supervisor from another division chosen on a
10 rotating roster. The executive CAC meets every
11 Tuesday and evaluates a great number of protocols
12 and studies in a year, usually somewhere between
13 150 and 200 either protocols or carcinogenicity
14 studies in a year.
15 The next slide shows the makeup of the
16 full CAC which is empowered to review the studies
17 when members of the executive CAC cannot
18 unanimously agree on the interpretation of the
19 data, or when requested by the sponsor of the drug.
20 The full CAC consists of the associate director for
21 the center; three associate directors for the
offices; and each of the supervisors from the
1 individual divisions in the center. The full CAC
2 is a fairly large committee and meets only rarely.
3 In fact, the meeting for this drug was the first
4 one in over a year for the full CAC.
5 Both the executive CAC and the full CAC
6 agreed that the tumors seen in the studies were
7 probably relevant to a safety evaluation for
8 humans. The full CAC in general voted that the
9 tumors seen in the carcinogenicity studies were
10 relevant to human safety evaluation.
11 The questions asked of the committee were
12 does the CAC agree that the lung tumors in mice
13 were relevant to human safety evaluation? The
14 committee voted yes, 16; no/probably not, 2; and 2
15 answered they don't know.
16 Does the CAC agree that, one, the liver
17 tumors in male mice and, two, the vascular tumors
18 in female mice are relevant to human safety
19 evaluation? The vote was 17 yes; 3 no.
20 Does the CAC agree that, one,
21 hepatocellular adenomas and carcinomas in female
rats, two, the skin fibromas in female rats and,
1 three, the brain gliomas in male and female rats
2 are relevant to human safety evaluation? The
3 answer was yes, 17; 3 no.
4 Now, in our division many carcinogenic
5 nucleoside and nucleotide analogs have been
6 approved for the treatment of viral diseases.
7 Among these are ganciclovir which gives rodent
8 tumors at very low doses relative to the human
9 exposure; zidovudine; abacavir and cidofovir.
10 Cidofovir causes palpable mammary adenocarcinomas
11 in rats after as few as six weekly doses and is
12 closely related in chemical structure to adefovir.
13 Some of the reverse transcriptase inhibitors as
14 well as the HIV protease inhibitors are positive
15 for animal carcinogenicity. Other drugs, such as
16 8-methoxy psoralen, which has been approved for the
17 treatment of psoriasis, are carcinogens. In fact,
18 this compound has been identified as a human
19 carcinogen in epidemiology studies. Dr. Linda
20 Lewis will continue the division presentation.
21 Thank you.
22 Clinical Issues
23 DR. LEWIS: Good morning. My name is
24 Linda Lewis, and I was the lead clinical reviewer
the entecavir review team. I would like
1 give you the perspectives of the entire team on our
2 review of entecavir for the treatment of chronic
3 hepatitis B.
4 My presentation is outlined in this slide.
5 First I will go over a little bit of the
6 development program for entecavir, which you have
7 heard presented earlier by Bristol-Myers Squibb.
8 Then I would like to go over the results of our
9 reviews of the efficacy, safety and
10 virology/resistance data that were contained in the
11 NDA submission. At that point I will turn my
12 discussion to an assessment of the risk-benefit of
13 entecavir and the applicant's proposed
14 pharmacovigilance plan. I will end the
15 presentation with a preview of the questions that
16 we would like the advisory committee to consider
17 later this afternoon.
18 As you heard this morning, the treatment
options for chronic hepatitis B are somewhat
1 limited. Interferon was approved for treatment of
2 hepatitis B in 1992. Its requirement for
3 parenteral administration and its significant side
4 effect profile have somewhat limited its use.
5 Lamivudine was the first effective oral therapy,
6 and it was approved in 1998. Its usefulness has
7 been limited by the predictable emergence of
8 resistance in relatively short periods of time. A
9 most recent addition, adefovir, was approved in
10 2002. It has known renal toxicity that may limit
11 its use in some populations.
12 The entecavir development program included
13 a diverse patient population. The clinical studies
14 were drawn from multinational sites in North and
15 South America, Europe and Asia. Among these
16 studies, patients from the United States made up
17 about 10 percent of the pivotal trials. The
18 entecavir studies were made up of about 20 percent
19 women. There was a good mix of Asian and non-Asian
20 patients in the populations. However, Black or
21 African American patients were under-represented in
clinical trials, making up only 2 percent of
1 the pivotal studies. The development program
2 enrolled patients at different stages of disease
3 and treatment. Although there is a study in
4 progress, the data were insufficient to review the
5 use of entecavir in patients with decompensated
6 liver disease during this review cycle.
7 BMS submitted study reports and electronic
8 data sets for the four key studies that they have
9 mentioned in their presentation earlier. To go
10 over these again, study 022 was the Phase III study
11 enrolling nucleoside-naive, e-antigen positive
12 adults. Study 027 enrolled nucleoside-naive
13 e-antigen negative adults. Both of these studies
14 used a dose of 0.5 mg of entecavir given once
15 daily. Study 026 enrolled patients with persistent
16 HBV viremia despite lamivudine treatment. These
17 are termed lamivudine-refractory subjects.
18 Patients in this study were e-antigen positive and
19 received a dose of 1 mg of entecavir given once
21 In order to expand the safety database for
lamivudine-refractory patients we included in our
1 review patients from study 014, the dose-finding
2 study in that patient population, and used the
3 cohorts that received either 1 mg of entecavir or
4 the standard dose of lamivudine. As has been
5 pointed out, all of the pivotal trials were
6 compared to the standard dose of currently approved
8 For all of the Phase III studies, studies
9 022, 027 and 026, the primary endpoint was the
10 overall histologic improvement in liver biopsy
11 after 48 weeks of treatment. This histologic
12 improvement was defined as greater than or equal to
13 a 2-point decrease in the Knodell necroinflammatory
14 score, with no worsening in the Knodell fibrosis
15 score compared to the baseline biopsy. A series of
16 secondary endpoints were also evaluated and
17 included a number of virologic, serologic,
18 biochemical and composite endpoints.
19 The applicant also submitted data from
20 several important studies in special populations.
21 These included study 015. This was a small pilot
trial in post-liver transplant patients who had
1 recurrent hepatitis B. Study 038 enrolled a cohort
2 of HIV/HBV co-infected patients. Study 048
3 compares the use of entecavir to adefovir in
4 patients we decompensated liver disease. This
5 study is still enrolling and the data were not
6 sufficient for us to conduct any meaningful interim
7 analysis during this review cycle. In these
8 studies histologic endpoints were not used. They
9 relied on a series of virologic, serologic and
10 biochemical endpoints.
11 Now I would like to turn to the efficacy
12 review of entecavir. You will probably notice in
13 these slides that many of our slides look very
14 similar to those presented by the applicant earlier
15 this morning.
16 The FDA statistical review, conducted by
17 Dr. Tom Hammerstron, confirmed the applicant's
18 primary efficacy analysis. A review of secondary
19 efficacy analyses, using the virologic, serologic
20 and biochemical endpoints, was also in agreement
21 with BMS's conclusions. Multiple sensitivity
analyses and subgroup analyses were performed and
1 all supported the primary analysis.
2 This table displays the results of the
3 primary efficacy analysis and some of the other
4 histologic endpoints for each of the Phase III
5 studies, study 022, 027 and 026. The top line of
6 the study shows the primary analysis, the overall
7 histologic improvement after 48 weeks. As you can
8 see, in each of the three studies entecavir
9 performed better than lamivudine in each study, as
10 highlighted--these are supposed to be pink I don't
11 know exactly how it projects.
12 The next two lines display the two
13 individual components that make up the overall
14 histologic improvement score. Again, you can see
15 that patients receiving entecavir achieved that
16 endpoint significantly more often than those who
17 received lamivudine. The last line of the study
18 shows the secondary histologic endpoint of the
19 Ishak fibrosis score. This is another method of
20 evaluating liver histology. In this analysis
21 entecavir was superior to lamivudine only in the
lamivudine-refractory study, study 026.
1 treatment-naive studies the proportion of patients
2 achieving an improvement in their Ishak fibrosis
3 score was similar across the treatment arms.
4 This table displays some of the
5 sensitivity analyses that were done by our
6 statistical reviewers. The top line is a carryover
7 from the previous slide and shows the primary
8 analysis. In the primary analysis the only
9 subjects who had evaluable baseline biopsies were
10 included in the analysis. Subjects with missing or
11 inadequate week 48 biopsies were counted as
12 treatment failures. The sensitivity analyses, done
13 by Dr. Hammerstron, included a series of different
14 methods to impute the missing data for each of the
15 Phase III studies. I am going to show you just two
16 of the many analyses that he did.
17 In FDA sensitivity analysis C, missing or
18 inadequate baseline or week 48 biopsies were
19 excluded from the analysis. In this analysis, in
20 study 022, the results were similar between
21 entecavir and lamivudine and this is due primarily
the fact that more patients in the lamivudine
1 arm were excluded because they did not have week 48
2 biopsies. In the other two studies, again,
3 entecavir achieved the primary endpoint
4 significantly more often than patients who received
6 In sensitivity analysis D, this analysis
7 includes all patients who were treated, not just
8 those who had evaluable biopsies, but missing or
9 inadequate week 48 biopsies were still counted as
10 failures. Although the numbers are lower for all
11 of these analyses, the difference between entecavir
12 and lamivudine remains evident in each of the three
13 pivotal trials.
14 This slide displays some of the analyses
15 of secondary virologic, serologic and biochemical
16 endpoints for the three pivotal trials. Again, the
17 significant values are highlighted in the pink
18 cells. In the Phase III studies a greater
19 proportion of patients receiving entecavir than
20 lamivudine achieved an HBV DNA PCR less than 400
21 copies/mL. Similarly, patients who received
entecavir had a greater mean log decrease in PCR
1 from baseline to week 48 than did patients who
2 received lamivudine. In the two studies that
3 included e-antigen positive patients, studies 022
4 and 026, the proportions of patients who had a
5 seroconversion were roughly the same. You will
6 notice that in study 026 a relatively small number
7 of patients actually met this criteria. Finally,
8 in terms of the proportion of patients who reached
9 a normalized ALT, again, entecavir was shown to be
10 superior to lamivudine in each of the three pivotal
12 We also conducted a number of subgroup
13 analyses for baseline covariates of demographic or
14 disease characteristics. The treatment effect of
15 the primary endpoint was comparable for the
16 covariates gender, race, age, geographic region,
17 HBV subtype, baseline ALT, baseline bDNA or PCR, or
18 by prior treatment with lamivudine or interferon.
19 Similarly, more limited subgroup analyses
20 were performed to assess some of the key secondary
21 endpoints. The treatment effect measured by the
proportion of patients of subjects who achieved a
1 normalization of HBV DNA or those who achieved a
2 viral load less than 400 copies/mL at weeks 24 and
3 48 were similar according to gender, race and age.
4 This slide displays a composite of the
5 subgroup analysis for the Phase III studies. I
6 really show you this for pattern recognition more
7 than to display any kind of specific results. This
8 slide plots the mean difference in treatment effect
9 for the primary endpoint between entecavir and
10 lamivudine, with 95 percent confidence intervals,
11 for the three pivotal trials. This cluster