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 th