1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ANTIVIRAL DRUGS ADVISORY COMMITTEE
Friday, March 11, 2005
8:00 a.m.
Salons A and B
Hilton Washington DC
North/Gaithersberg
620 Perry Parkway
Gaithersburg, Maryland
2
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
Committee Members:
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)
Brett Grodeck
FDA Participants:
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
3
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
Sponsor Presentation:
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,
Ph.D.
70
Questions from the Committee 77
FDA Presentation:
Carcinogenicity Issues, James G.
Farrelly, Ph.D.. 108
Clinical Issues, Linda L. Lewis,
M.D. 119
Discussion
151
Advisory Committee Discussion of
Questions
Question 1: 185
Question 2: 202
Question 3: 204
Question 4: 221
Question 5: 235
Question 6: 267
4
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
7
Committee.
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
25
Colorado Health Sciences Center.
5
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
9
Cincinnati.
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
15
Institute.
16
MR. GRODECK: Brett Grodeck,
patient
17
representative.
18
MS. PATEL: Anuja Patel, Executive
19
secretary for the Antiviral Drugs Advisory
6
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
12
representative.
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
18 University.
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
25
Drug Administration.
7
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
19
employer's contract with a federal agency to
8
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
22
year per firm. Brett Grodeck has
been granted a
9
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
22
industry. Dr. Sun is employed by
Abbott
10
1
Laboratories.
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,
22 and
on the second day of that meeting we discussed
11
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
22
decline in hepatitis B occurring soon after
12
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
17
dipivoxil.
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
22
population the effect is durable.
However, the
13
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
14
transplant.
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
22
demonstrated in established animal models. In
14
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
22
Squibb for their drug development program for
15
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
14
usage.
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
22
followed by a break. Then FDA
will present and the
16
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
10 Introduction
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
22
States another 400 million people are chronically
17
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.
22
Entecavir has clinical benefits based on
18
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
18
entecavir.
19
To accomplish this we have submitted to
20 FDA
draft pharmacovigilance plans, approaches and
21
observational studies that we plan to conduct to
22
allow for a continuous benefit-risk assessment once
19
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.
22
Dr. Rich Colonno will now begin the data
20
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?
6 Background
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
25
infection. Only about 10-30
percent of people
21
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
19 this
long course of chronic infection with HBV is
22
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
13
levels.
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.
22
Currently, three drugs are approved to
23
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.
22
With lamivudine treatment by 32 months the rate of
24
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
22
treatment provides benefit, it also suggested that
25
1 a
more effective antiviral with both greater
2
potency and less resistance will be more
3
efficacious in preventing downstream clinical
4
disease.
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
22
polymerase. Its potency reflects
the fact that it
26
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
22
efficacy and safety of drugs subsequently used in
27
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
22
chronic infection was verified. They had 4-year
28
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
22 was
identified as a carcinogenic hazard in rats and
29
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
22 a
relatively high background rate of tumors in
30
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
22 for
entecavir. These results have been
reviewed
31
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
4
safety.
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
22
studies. Entecavir was dosed to
mice across a dose
32
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
22
mg/kg entecavir increased the incidence of lung
33
1
carcinomas.
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
22
tumors as well. The increased
numbers of
34
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,
22
specifically hemangiomas. In both
cases there was
35
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
18
development.
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.
22 The
4 dosage levels are noted here along with the
36
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
18
rats.
19
Carcinogenicity studies in rodents
20
identify whether a compound is a carcinogenic
21
hazard. In the absence of data in
humans it is
22
assumed that carcinogenic effects in rodents
37
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
22
program is comprehensive and assesses the efficacy
38
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
22
studies you will be hearing about today.
Small
39
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
22 mg
and 1 mg daily. Therefore, these doses
were
40
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.
22
Clinical failure was defined as detectable viremia
41
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
22
disease, together with an elevated ALT, or were
42
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
22
were well matched for baseline HBV disease
43
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.
22
In all three studies, paired biopsies were
44
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
6
programs.
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
22
evaluable cohort who had missing or inadequate week
45
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
25 for
superiority. Two independent co-primary
46
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
25 and
lamivudine are comparable. This is not
47
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
13
lamivudine.
14
Non-histologic secondary
endpoints were
15
also assessed at week 48. These
included
16
virologic, biochemical and serologic endpoints.
48
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
22
points. In both populations there
is an early
49
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.
22
Entecavir is superior to lamivudine across
50
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
22
interaction is poorly understood.
In the naive
51
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
22
presentation will differ slightly from that of the
52
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
22
entecavir rollover trial.
Observation periods for
53
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
25
severity and were common, reflecting the long
54
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
19 an
off-treatment flare is substantially longer for
55
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
4
treatment.
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
22
this analysis of events that are infrequent. A new
56
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
22
both treatment groups the greatest number of new
57
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
22
lamivudine. Also, the safety of
entecavir is
58
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.
9 Resistance
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
22 by
entecavir in our clinical studies results in a
59
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
22
entecavir, virologic rebounds noted in two patterns
60
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
22
lamivudine-resistant substitutions alone are
61
1
present.
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
25
greater than or equal to 1 log increase from nadir
62
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
25
that their presence did not result in a significant
63
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
4
therapy.
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
14
resistance.
15
A close examination of the individual
16
patient profiles showed that all 11 patients
64
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
8
susceptibility.
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
22
effective in lamivudine-refractory patients
65
1
enrolled in study 026 and in the 1 mg arm of study
2
014.
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
18
entecavir.
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
22 on
entecavir therapy. Evidence of entecavir
66
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
5
emergence.
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
22
years. Emerging substitutions at
14 other residues
67
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
4
viruses.
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,
22 but
can also select for a number of secondary
68
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
25
likely accounts for the absence of resistance
69
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
19
will now conclude our presentation with
70
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
11
date.
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
22
assessment committee do not definitively eliminate
71
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
22
studies and we have proposed an additional large,
72
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
22
years. In addition to the ongoing
studies, we
73
1
propose initiating a large safety study post
2
approval.
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
22 and
to recruit patients via their own physicians.
74
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
22
variable latency. Since all
patients will be
75
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,
22
treatment with entecavir resulted in up to a 7-log
76
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
10
necroinflammation.
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,
22
long-term benefits of entecavir might include a
77
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
22
specific points related to the presentation we just
78
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.
22
The dog the studies were not conducted to
79
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.
22
The background rate was approximately 4
80
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
11
risk.
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
22
large size of those, we are adequately powered to
81
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
22 did
that work, there is clear chemotactic activity
82
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
22
been on the speakers bureau for the sponsor and two
83
1
competitors.
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
19
placebo.
20
As you can see, the majority of
21
pregnancies identified resulted in elective
22
termination. There was a small
number of
84
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
22
said, about week 7. The patient
then experienced
85
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
22
since the number of mutations is few at this point,
86
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.
22
Can I have slide 1-315, please?
This is a
87
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
22
resistance. So, we have gone out
to the second
88
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
22
resistance. So, out to 2 years in
the
89
1
nucleoside-naive population with that type of viral
2
suppression we have not observed any resistance to
3
entecavir.
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
16
presentation--
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.
22
Acknowledging that the pharmacovigilance plan is
90
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
22
virus to actually replicate that a large amount of
91
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
22
week 48 but the bottom data are presented on two
92
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
22
entecavir.
23
DR. ENGLUND: Dr. Sherman?
24
DR. SHERMAN: The presentation
indicated
25
that phosphorylation was required for this product.
93
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
19
combination studies to look for the effect of
94
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
13
HIV.
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.
18
Grodeck's.
19
MR. GRODECK: In terms of marketing
20
antivirals, one of the biggest games I have seen
21
pharmaceutical companies play is the sequencing
22
game--my drug should come before your drug. In
95
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
22
DNA. In almost 90 percent of
patients you can
96
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
22
evidence of peripheral blood lymphocytes--the same
97
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.
22 For
perspective, that is when a rodent reaches
98
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
25 to
ethnicity. This is related to the fact
that I
99
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
18
pharmacovigilance.
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.
25
The primary endpoint for your study was
100
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
16
reduction.
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
23
drop.
24
DR. SEEF: That is fine. Thank you.
The
25
second thing is your secondary endpoints,
101
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?
25
DR. SO: There is a common belief
by many
102
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
10
have so-called sustained response and what
103
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
22
management of the patient, which was simply a
104
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
22 the
rollover study they were considered failures to
105
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
20
misleading.
21
DR. BRETT-SMITH: Point taken, 24
weeks is
22
what had been agreed upon with regulatory
106
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?
22
DR. DIENSTAG: Jules Dienstag,
Mass.
107
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
14
presentation.
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
20
presentation.
21 FDA Presentation
22
Carcinogenicity
Issues
23
DR. FARRELLY: Good morning. My name is
24 Jim
Farrelly. I am the pharmacology team
leader in
25 the
Division of Antiviral Drugs.
108
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
19 to
break chromosomes. Indeed, entecavir has
been
109
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
22
than a nucleoside analog, and was found to be
110
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
22
study. The doses in male rats
represent the human
111
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
22
entecavir at the high dose in which these tumors
112
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
21
mg/kg/day.
22
As seen here, entecavir caused a
113
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
22 was
a significant increase in combined hemangiomas
114
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
22
higher than those. So, if
entecavir was examined
115
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
22
depending on which division reviewed them. Two
116
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
22
offices; and each of the supervisors from the
117
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
22
rats, two, the skin fibromas in female rats and,
118
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
25 for
the entecavir review team. I would like
to
119
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
19
options for chronic hepatitis B are somewhat
120
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
22 the
clinical trials, making up only 2 percent of
121
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
20
daily.
21
In order to expand the safety
database for
22
lamivudine-refractory patients we included in our
122
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
7 lamivudine.
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
22
trial in post-liver transplant patients who had
123
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
22
analyses and subgroup analyses were performed and
124
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
22
lamivudine-refractory study, study 026.
In the
125
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
22 to
the fact that more patients in the lamivudine
126
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
5
lamivudine.
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
22
entecavir had a greater mean log decrease in PCR
127
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
11
trials.
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
22
proportion of patients of subjects who achieved a
128
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
12 rep