FOOD AND DRUG ADMINISTRATION

NINETY-SEVENTH MEETING OF THE

CARDIOVASCULAR AND RENAL DRUG ADVISORY COMMITTEE

8:01 a.m.

Friday, July 19, 2002

Versailles Ballroom

Holiday Inn - Bethesda

8120 Wisconsin Avenue

Bethesda, Maryland

ATTENDEES

COMMITTEE MEMBERS:

JEFFREY BORER, M.D., Chairman

Director, Division of Pathophysiology

Weill Medical College

Cornell University

525 East 68th Street, Room F467

New York, New York 10021

JAYNE E. PETERSON, R.PH., J.D., Acting Executive Secretary

Advisors and Consultants Staff

Center for Drug Evaluation and Research

Food and Drug Administration

5630 Fishers Lane, Room 1093

Rockville, Maryland 20857

PAUL ARMSTRONG, M.D.

Professor, Department of Medicine

University of Alberta

251 Medical Science Building

Edmonton, Alberta, Canada T6C37

MICHAEL F. ARTMAN, M.D.

Professor of Pediatrics

Pediatric Cardiology

New York University Medical Center

530 First Avenue, FPO Suite 9-V

New York, New York 10016

BLASE A. CARABELLO, M.D.

Professor of Medicine

Houston Veterans Affairs Medical Center

Medical Service (111)

2002 Holcombe Boulevard

Houston, Texas 77030

SUSANNA L. CUNNINGHAM, PH.D.

Consumer Representative

Professor, Department of Biobehavioral Nursing

School of Nursing, Box 357266

Seattle, Washington 98195-7266

ATTENDEES (Continued)

COMMITTEE MEMBERS: (Continued)

THOMAS FLEMING, PH.D.

Professor and Chair

Department of Biostatistics

University of Washington

Box 357232

Seattle, Washington 98195-7232

STEVEN NISSEN, M.D., F.A.C.C.

Vice Chairman, Department of Cardiology

Professor of Medicine

Ohio State University

The Cleveland Clinic Foundation

9500 Euclid Avenue, F15

Cleveland, Ohio 44195

MEETING GUEST (NONVOTING):

THOMAS G. PICKERING, M.D., D.PHIL.

Professor of Medicine

Director, Integrative and Behavioral

Cardiovascular Health Program and

Hypertension Section

Michael and Zena A. Wiener Cardiovascular Institute

Mount Sinai School of Medicine

One Gustave L. Levy Place

New York, New York, 10029-6574

FOOD AND DRUG ADMINISTRATION STAFF:

ROBERT TEMPLE, M.D.

DOUGLAS THROCKMORTON, M.D.

ANNE TRONTELLE

BRISTOL-MYERS SQUIBB REPRESENTATIVES:

HENRY BLACK, M.D.

CHARLES H. HENNEKENS, M.D., PH.D.

ALLEN KAPLAN, M.D.

ELLIOTT LEVY, M.D.

MILTON PACKER, M.D.

MICHAEL WEBER, M.D.

ANTHONY WACLAWSKI, PH.D.

C O N T E N T S

NDA 21-188, Vanlev (omapatrilat)

Bristol-Myers Squibb Company,

Proposed for the Treatment of Hypertension

\* \* \*

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

By Ms. Jayne Peterson 6

BRISTOL-MYERS SQUIBB PRESENTATION:

Introduction

By Dr. Anthony Waclawski 9

Clinical Efficacy Data

By Dr. Elliott Levy 15

Angioedema: Clinical Overview

By Dr. Allen Kaplan 71

Clinical Safety Data (Continued)

By Dr. Elliott Levy 85

OPEN PUBLIC HEARING 103

BRISTOL-MYERS SQUIBB PRESENTATION: (Continued)

OVERTURE Trial Review

By Dr. Milton Packer 141

Clinician\'s Perspective

By Dr. Henry Black 161

Conclusion

By Dr. Anthony Waclawski 170

COMMITTEE DISCUSSION AND REVIEW 171

P R O C E E D I N G S

(8:01 a.m.)

DR. BORER: It\'s not quite 8:01, so everybody has had some extra time.
We\'ll begin this morning\'s session which is consideration of NDA
21-188, Vanlev, sponsored by Bristol-Myers Squibb.

The committee is slightly restructured today because of conflict of two
members. So, we\'ll introduce the active members, including our
nonvoting member guest. Before we do that, let me ask you please to turn
off your cell phones, if they happen to be on.

Why don\'t we start on this side. Tom.

DR. PICKERING: I\'m Tom Pickering from the Cardiovascular Institute at
Mount Sinai Medical Center in New York.

DR. CUNNINGHAM: I\'m Susanna Cunningham from the University of
Washington in Seattle.

DR. CARABELLO: I\'m Blase Carabello from the Houston VA and from the
Baylor College of Medicine.

DR. NISSEN: Steve Nissen with the Cleveland Clinic School of Medicine.

DR. ARMSTRONG: Paul Armstrong from the University of Alberta.

DR. BORER: I\'m Jeff Borer, Weill Medical College at Cornell University
in New York City.

MS. PETERSON: I\'m Jayne Peterson. I\'m the

DR. FLEMING: Tom Fleming, University of acting Executive Secretary of
the Advisory Committee. Washington, Seattle.

DR. THROCKMORTON: Doug Throckmorton. I\'m the Director of the
Cardio-Renal Division in the FDA.

DR. BORER: We\'ll have our additional member introduce himself when he
comes in.

Jayne, will you please present the conflict of interest statement?

MS. PETERSON: Thank you.

The following announcement addresses conflict of interest with regard to
this meeting and is made a part of the record to preclude even the
appearance of such at this meeting.

Based on the submitted agenda for the meeting and all financial
interests reported by the committee participants, it has been determined
that all interests in firms regulated by the Center for Drug Evaluation
and Research which have been reported by the participants present no
potential for an appearance of a conflict of interest at this meeting
with the following exceptions.

Dr. Jeffrey Borer has been granted a waiver under 18 U.S.C. 208(b)(3)
for his potential consulting for the sponsor on a competitor to Vanlev
on unrelated matters. Potentially he could receive less than \$10,001 a
year.

Dr. Susanna Cunningham has been granted waivers under 18 U.S.C.
208(b)(3) and 21 U.S.C. 355(n)(4), amendment of section 505 of the Food
and Drug Administration Modernization Act, for ownership of stock in a
competitor to Vanlev. The stock is valued between \$25,000 and \$50,000.

Dr. Thomas Fleming has been granted a waiver under 18 U.S.C. 208(b)(3)
for his participation on two data safety monitoring committees for a
competitor and the parent of a competitor to Vanlev on unrelated
matters. He receives less than \$10,000 per year for each activity.

A copy of these waiver statements may be obtained by submitting a
written request to the agency\'s Freedom of Information Office, room
12A-30 of the Parklawn Building.

We would also like to disclose for the record, because of her reported
interest, Dr. Beverly Lorell, a committee member, is excluded from
participating in all official matters concerning new drug application
21-188, Vanlev, omapatrilat, sponsored by Bristol-Myers Squibb proposed
for the treatment of hypertension.

With respect to FDA\'s invited guest, Dr. Pickering has a reported
interest that we believe should be made public to allow the participants
to objectively evaluate his comments. Dr. Pickering is listed as a
Vanlev consultant for Bristol-Myers Squibb and was paid in 2001. He has
received a research grant from Bristol-Myers Squibb in 2001 for
analyzing their data on 24-hour blood pressure. He has done nothing for
the company in 2002.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from such involvement and their exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose products they may wish to comment upon.

Thank you. Dr. Borer.

DR. BORER: Mike, will you introduce yourself to the company?

DR. ARTMAN: I\'m Mike Artman. I\'m at New York University School of
Medicine.

And I would just like the record to show that Dr. Borer\'s clock,
according to the U.S. atomic clock, is about 3 minutes fast. Thank you.

(Laughter.)

DR. BORER: Well, it means we get through 3 minutes earlier.

Let\'s begin the sponsor\'s presentation then, if we can. Dr. Waclawski.

DR. WACLAWSKI: Thank you, Dr. Borer. Good morning to you, members of the
advisory committee, FDA, ladies and gentlemen.

I\'m Anthony Waclawski with the Regulatory Sciences Group at
Bristol-Myers Squibb. It\'s my pleasure to take a few minutes today and
introduce our presentation.

The purpose of our presentation today is to discuss the data that is
relevant to the use of omapatrilat in hypertension, specifically in
patients with hypertension that is difficult to control with other
agents.

Omapatrilat is a vasopeptide ACE inhibitor. It is the first agent in
this new class of antihypertensive agents to be discussed by this
committee.

As background, I will briefly review the regulatory history of the
application and then give you an overview of this morning\'s
presentation.

The original NDA was filed in December of 1999. This NDA was based on an
extensive preclinical and clinical development program. The clinical
studies were mainly conducted as placebo-controlled or
active-controlled, forced-titration studies.

In April of 2000, Bristol-Myers Squibb withdrew the NDA. This was in
response to questions raised by the FDA regarding the comparative
incidence and severity of angioedema with omapatrilat compared to
existing agents.

In August of 2000, the 6-month, 25,000-patient OCTAVE study was
initiated. OCTAVE stands for omapatrilat cardiovascular treatment
assessment versus enalapril. This study was conducted to more clearly
define the efficacy and safety of omapatrilat compared to the ACE
inhibitor enalapril.

In December of 2001, based upon the review and analysis of the results
of the OCTAVE study, the NDA for omapatrilat for the treatment of
hypertension was resubmitted. The resubmitted NDA included data from
approximately 19,000 subjects treated with omapatrilat, making it
several times larger than recent NDAs submitted for hypertension. The
size and scope of the omapatrilat NDA allowed for the characterization
of the safety and efficacy of omapatrilat in a broad range of patients.

In addition, although not part of the NDA for hypertension, omapatrilat
has been studied in an extensive heart failure program, including the
recently completed OVERTURE study. There\'s a question today about
OVERTURE and its implications for hypertension on the list of questions
today.

With that background, I will now provide an overview of our
presentation.

First, in terms of efficacy, data will be presented to demonstrate that
omapatrilat is an effective antihypertensive agent, more effective as
monotherapy than lisinopril, losartan, or amlodipine. In addition, data
from the OCTAVE study will be presented. These data demonstrate that an
omapatrilat-based regimen is more effective than an enalapril-based
regimen in a broad range of patients under conditions that closely mimic
clinical practice.

In terms of safety, data from the OCTAVE study will be presented that
demonstrate that patients treated with omapatrilat experience angioedema
about three times more frequently than those patients treated with
enalapril. In OCTAVE, life-threatening angioedema occurred in patients
treated with omapatrilat at a rate of approximately 2 per 12,000
patients. In OCTAVE, no patients treated with enalapril experienced
life-threatening angioedema.

In terms of benefit and risk, these data, taken together, present
difficult and complex questions about benefit and risk. How should one
evaluate a compound that may offer superior benefit when it also carries
an increased risk of a potentially life-threatening adverse event? How
should the expected benefit be estimated? What level of risk is
acceptable? And in what patients is perhaps the benefit-to-risk
favorable? Data will be presented today to help address these issues.

Let me tell you about the approach that we have taken.

Since the filing of our NDA in December of last year, we have performed
numerous additional statistical analyses of the OCTAVE data and have had
extensive consultations with medical and regulatory experts and the FDA
aimed at helping us to answer these questions.

In light of the risk of angioedema, we have looked for ways to maximize
the benefit and minimize the risk. Maximizing the benefit means to
target the use of omapatrilat to those patients that are most likely to
benefit from therapy. These patients would have an increased
cardiovascular risk and would have hypertension that is difficult to
control with available therapies. Data will be presented today which
demonstrate that omapatrilat provides substantial blood pressure
reductions in these patients.

Regarding the management of risk, we have initiated discussions with the
FDA about how to manage the risk of angioedema. We have thus far focused
on the identification of the risk factors of angioedema and on the use
of patient education about angioedema to help minimize the risk of
severe outcomes.

You have in your briefing book an FDA review of our proposed risk
management plan. The review points out that risk management will not
likely reduce the risk of angioedema with omapatrilat to that of an ACE
inhibitor. We agree with this, and this is not the objective of the
plan. Rather, the objective is to minimize the risk of life-threatening
angioedema using education. The review acknowledges that this might be
possible, and we are continuing to work with FDA on this plan. We are
confident that if omapatrilat is approved on the basis of the clinical
data, that we can find a mutually acceptable plan with the FDA.

I will now come back to the target population and be a little bit more
specific since our presentation today is focused on these patients.

We\'ll present data that supports the use of omapatrilat in patients
that can be described with two broad criteria. These patients will have
comorbid conditions or characteristics associated with high
cardiovascular risk, such as a history of cardiovascular disease,
patients with target organ damage, those with three or more cardiac risk
factors, or patients with diabetes or renal disease. They would also
have hypertension that is difficult to control with existing agents.

As you\'ll see from our presentation today, black patients and patients
who smoke are at a higher risk of angioedema. Use of omapatrilat in
these patients must be accompanied by particular caution.

This is the target population. We will present data today that supports
the use of omapatrilat in these patients. When evaluating these data, we
recognize that the advisory committee and the FDA will rely upon their
scientific judgment when considering how these data may support a
recommendation for the approval of omapatrilat. We\'ve been working
through these issues for some time and are looking forward to your
deliberations.

Bristol-Myers Squibb has invited several consultants to the meeting
today. They are Drs. Black, Hennekens, Kaplan, Packer, Neaton, and
Weber. These experts are here to facilitate the advisory committee
discussions and deliberations.

Finally, the agenda for the presentation is as follows. Dr. Levy, who
leads the clinical development program for omapatrilat at Bristol-Myers
Squibb, will present the clinical efficacy data. Dr. Kaplan, from the
University of South Carolina, an expert in angioedema and a member of
the OCTAVE angioedema endpoint adjudication committee, will provide a
short background on this event. Dr. Levy will then return to present the
safety data and the benefit-risk summary.

I should note that although Dr. Hennekens was listed on the agenda that
may be in your briefing package, he will not make a presentation today
on risk-benefit, but he is here to answer any questions.

There is also a question about OVERTURE. We have asked Dr. Packer to
come and make a short presentation about OVERTURE. This is also a small
change from your agenda.

Dr. Black will follow Dr. Packer and he will provide a clinician\'s
perspective. I will then return and conclude our presentation.

That ends the introduction. I would now like to introduce Dr. Elliott
Levy who will present the clinical efficacy data.

DR. LEVY: Dr. Borer and members of the committee, thank you for your
attention. My name is Elliott Levy, and I lead the omapatrilat clinical
development team.

Before discussing the efficacy of omapatrilat, I\'d like to reemphasize
a point made by Dr. Waclawski in his introduction. Bristol-Myers Squibb
is asking the advisory committee to consider omapatrilat for use in
patients who have established cardiovascular disease or other
characteristics associated with similarly high cardiovascular risk and
whose blood pressure is difficult to control with existing therapies. In
this population, the benefit of omapatrilat treatment strongly outweighs
the risk of angioedema.

I\'ll present efficacy data this morning in the following order. In four
placebo-controlled trials, including approximately 2,400 subjects,
omapatrilat was shown to reduce systolic and diastolic blood pressure in
dose-dependent fashion.

In six active-controlled trials involving approximately 2,700 subjects,
the maximum intended dose of omapatrilat, 80 milligrams, was shown to
reduce blood pressure more effectively than the maximum labeled dose of
the widely used antihypertensives lisinopril, amlodipine, and losartan.

In OCTAVE, which included about 2,500 subjects, an omapatrilat-based
regimen was shown to reduce blood pressure more effectively than one
based on enalapril. Omapatrilat was also shown to reduce blood pressure
effectively in the proposed target population: patients with high
cardiovascular risk and difficult-to-control hypertension.

In four placebo-controlled, randomized, double-blind, dose-ranging
studies, omapatrilat at doses of 10 to 80 milligrams was shown to reduce
systolic and diastolic blood pressure in dose-dependent fashion. At the
proposed starting dose of 10 milligrams, omapatrilat produced
statistically significant reductions in blood pressure relative to
placebo. At the maximum intended dose of 80 milligrams, omapatrilat
reduced systolic blood pressure by about 16 millimeters of mercury
relative to placebo and 19 millimeters of mercury overall.

These changes in blood pressure were substantially larger than those
historically reported with existing agents, and based on these findings
a series of six active-controlled, randomized, double-blind trials were
performed in which omapatrilat 80 milligrams was directly compared to
the maximal recommended dose for the widely used antihypertensive agents
amlodipine, lisinopril, and losartan. For clarity, I\'ll present the
systolic blood pressure results in these studies. The results for
diastolic blood pressure were similar.

In three of these studies presented here, efficacy was assessed by
measurement of seated blood pressure in the physician\'s office using
standard cuff methodology at the time of trough blood levels, so about
24 hours after administration of the previous dose. Omapatrilat produced
statistically significant reductions in blood pressure relative to
amlodipine, lisinopril, and losartan, ranging from 3 millimeters of
mercury systolic relative to amlodipine on the left-hand side, and
moving right, 5 millimeters of mercury relative to lisinopril, and 7
millimeters of mercury relative to losartan.

You may have noted that in one of these studies conducted versus
lisinopril, reductions in blood pressure were smaller than observed
elsewhere. This study was performed in African Americans in whom the
response to drugs that inhibit the renin-angiotensin system is known to
be diminished. As expected, the response to both omapatrilat and
lisinopril was reduced in this study, but systolic blood pressure was
reduced about 5 millimeters of mercury more with omapatrilat than with
lisinopril.

In three other studies displayed here, efficacy was assessed by
ambulatory blood pressure monitoring. Ambulatory blood pressure has been
shown to correlate more closely with target organ damage than does
office blood pressure. And ambulatory blood pressure also captures the
effect of drug on blood pressure over 24 hours during normal daily
activities, rather than at a single time point in the physician\'s
office.

In these studies, omapatrilat was also shown to reduce blood pressure
more effectively than maximal recommended doses of amlodipine,
lisinopril, or losartan. Here the differences ranged from about 5 to 6
millimeters of mercury relative to amlodipine to about 7 millimeters of
mercury relative to lisinopril and 8 to 9 millimeters of mercury
relative to losartan. These differences between omapatrilat and
comparator were somewhat greater than observed in the office blood
pressure studies previously presented, which is the opposite of what one
might expect since ambulatory pressures tend to be lower than office
blood pressures and to vary over a smaller range.

The course of blood pressure reduction over 24 hours is illustrated in
this representative tracing from the amlodipine comparison study. At
every time point over 24 hours, omapatrilat reduced blood pressure more
than amlodipine, as illustrated by the bottom curves. Similar results
were observed in ambulatory blood pressure trials conducted versus
lisinopril and losartan.

In sum, in these active-controlled trials, omapatrilat at 80 milligrams
produced greater reductions in blood pressure than the maximum
recommended doses of amlodipine, lisinopril, and losartan. A major
objective of OCTAVE was to determined whether omapatrilat would be
superior to another agent in conditions similar to those encountered in
clinical practice where an antihypertensive therapy is titrated
electively to reach blood pressure target and supplemented by other
agents as needed.

OCTAVE used a simple protocol of a large sample size and few exclusion
criteria so that the efficacy and safety of omapatrilat could be
assessed in a variety of demographic and clinical subgroups.

In OCTAVE, 25,000 hypertensive patients were randomized in equal number
to treatment with omapatrilat beginning at 10 milligrams or enalapril
beginning at 5 milligrams. After an initial fourth titration step at
week 2, physicians were instructed to titrate patients as needed to
reach blood pressure target at weeks 4 and 6. At week 8, the end of the
study drug titration phase, the dose of study medication was fixed, and
investigators were instructed to add other antihypertensive agents as
needed in order to reach blood pressure target at weeks 8 and 16. The
dose range selected for omapatrilat reflected the intended clinical dose
range, while the enalapril dose regimen was selected in accordance with
the label and customary clinical practice.

For assessment of efficacy, subjects were assigned at randomization to
one of three prespecified study groups, each representing a potential
manner of use of omapatrilat. Patients not receiving antihypertensive
therapy at enrollment, about 9,000 patients, were assigned to study
group 1 and received omapatrilat or enalapril as initial therapy for
hypertension.

Patients receiving antihypertensive therapy at enrollment but not
controlled were assigned to study groups 2 or 3. Those with mildly
elevated blood pressure, systolic blood pressures of 140 to 159, or
diastolics of 90 to 99, were assigned to study group 2 and received
omapatrilat or enalapril as replacement for existing therapies, all of
which were discontinued at randomization. About 11,000 patients were
assigned to this group.

Study group 3 patients included those with more markedly uncontrolled
blood pressure at randomization, systolic blood pressure of 160 to 179
or diastolic pressure of 100 to 109, and whose baseline regimen did not
include an ACE inhibitor. These patients received omapatrilat or
enalapril in addition to existing therapies which were continued beyond
randomization. About 5,000 patients were assigned to this study group.

Two efficacy objectives were specified as co-primary study endpoints.
The first, change in systolic blood pressure from baseline to week 8,
reflected the effect of study drug on blood pressure, titrated
electively as needed to reach target. The second co-primary efficacy
objective, the use of new adjunctive antihypertensive therapy between
weeks 8 and 24, reflected the extent to which a more effective
monotherapy might reduce the need for additional antihypertensive
therapy.

Important safety objectives included the assessment of the incidence of
adverse events, as well as the incidence and severity of angioedema.
These will be discussed in more detail in the safety portion of the
talk.

The study results at week 8, the end of the study drug titration period,
are summarized here. If omapatrilat had greater inherent efficacy, then
one might expect that subjects randomized to enalapril would be more
likely to be titrated upward in order to reach blood pressure target
than subjects randomized to omapatrilat, and this in fact was observed.
As shown on the right-hand panel of this slide, subjects randomized to
enalapril were more likely to be titrated to top dose of study drug than
subjects randomized to omapatrilat, and this was true whether study drug
was used as initial therapy for hypertension in study group 1, as
replacement for existing therapy in study group 2, or in addition to
existing therapy as in study group 3.

Between 33 and 52 percent of patients randomized to enalapril were
titrated to 40 milligrams, the maximal dose. This pattern of therapy
with robust doses of enalapril is considerably more aggressive than that
encountered in clinical practice. Despite greater use of maximal study
therapy in patients randomized to enalapril, those randomized to
omapatrilat had greater reductions in systolic blood pressure at week 8,
as shown in the left-hand panel. The difference in systolic blood
pressure reduction of about 3 to 4 millimeters of mercury was highly
consistent whether patients received study drug as initial therapy, as
replacement, or add-on therapy.

You might note that the blood pressure reductions with both study drugs
were smaller in group 2 than in groups 1 and 3 because group 2 subjects
discontinued all prior antihypertensive therapy at enrollment. Their
blood pressure changes reflect both the antihypertensive effect of study
drug and the effect of withdrawal of other active therapies.

The results at week 24, the end of the study, are summarized here. It
was hypothesized that if omapatrilat reduced systolic blood pressure
more than enalapril at week 8, it would also reduce the use of other
antihypertensive agents from weeks 9 through 24, and this was observed.
As summarized on the right-hand panel, subjects randomized to
omapatrilat were significantly less likely to receive additional
antihypertensive therapy than subjects randomized to enalapril. Despite
receiving less top-dose study drug and less adjunctive therapy, subjects
randomized to omapatrilat had consistently greater reductions in
systolic blood pressure at week 24 as shown in the right-hand panel,
about 3 millimeters of mercury more than subjects randomized to
enalapril.

Now, these study findings were highly consistent across patient
subgroups. OCTAVE included about 7,000 patients over the age of 65,
2,000 over the age of 75, and 2,500 black patients. Omapatrilat reduced
systolic blood pressure about 3 millimeters of mercury more than
enalapril at study\'s end in each major demographic subgroup as shown on
the right-hand column of this slide. Not surprisingly, reductions in
blood pressure with both omapatrilat and enalapril were smaller in black
patients than in others, but nevertheless blood pressure was reduced
about 4 millimeters of mercury more with omapatrilat than with enalapril
in these subjects.

OCTAVE also included a large number of patients with comorbid
characteristics or other features associated with increased risk of
cardiovascular disease. About 3,300 patients with diabetes and 2,300
patients with established cardiovascular disease were studied in OCTAVE.
Omapatrilat produced consistently greater reductions in systolic blood
pressure than enalapril, on the order of 3 to 5 millimeters of mercury,
as shown on the right-hand side of this chart, in patients with severe
hypertension, those with diabetes, atherosclerotic disease, isolated
systolic hypertension, renal disease, or heart failure.

In summary, OCTAVE demonstrated greater blood pressure reduction with an
omapatrilat-based regimen than with an enalapril-based regimen despite
more use of top-dose enalapril and more use of adjunctive
antihypertensive therapy with enalapril.

The results of OCTAVE were highly consistent, regardless of patient
demographics or comorbidity and regardless of the manner in which study
drug was used.

Lastly, the greater blood pressure reduction observed with omapatrilat
at week 8, the end of the study drug titration period, was preserved to
the end of the trial despite the use of adjunctive therapy in order to
reach a common blood pressure target in all patients.

The advisory committee has been asked to consider why the efficacy
advantage observed at week 8 in OCTAVE was preserved at week 24 and
whether this suggests that an omapatrilat-based regimen provides a
reduction in blood pressure that cannot be achieved with a regimen based
on enalapril or existing therapies.

OCTAVE provides a unique data set with which to answer this question.
While we acknowledge that in many patients hypertension can be readily
controlled with enalapril or other existing treatments, OCTAVE suggests
‑‑ and other clinical trials confirm ‑‑ that hypertension is difficult
to control in many patients, even with multi-drug regimens. Therefore,
for many patients the question is not whether omapatrilat can be used in
place of a combination regimen, but whether omapatrilat should be used
as part of a combination regimen. The results of OCTAVE strongly confirm
that a combination regimen which includes omapatrilat reduces blood
pressure to a greater extent than a combination regimen containing
enalapril because omapatrilat is a more efficacious antihypertensive
agent.

The effect that greater drug efficacy can have on regimen efficacy can
be most clearly appreciated in those most likely to require a multi-drug
antihypertensive regimen, namely those whose blood pressure is difficult
to control with single agents. In this presentation, the blood pressure
changes at week 24 are summarized for study group 1 subjects stratified
according to their baseline severity of hypertension; that is, from left
to right, mild or JNC VI stage I, moderate or JNC VI stage II, severe or
JNC VI stage III.

The difference between omapatrilat and enalapril at week 24 is present
in all three groups, but it is most apparent in those with most severe
hypertension at baseline in whom, as shown on the right-hand panel of
the slide, the rate of use of adjunctive therapy was also the greatest.
This suggests that the benefit of a more efficacious antihypertensive
agent might be greatest in those most likely to require combination
therapy, those with hypertension that is difficult to control.

Another representative group of patients with difficult-to-control
hypertension is those who remained significantly above blood pressure
goal in spite of treatment with existing therapies. In data from
patients randomized to OCTAVE study group 3 who continued to have JNC VI
stage II hypertension in spite of treatment with two or more
antihypertensives or three or more antihypertensives at baseline are
shown on this slide. In these patients, the addition of omapatrilat
provided significantly greater blood pressure reduction compared to the
addition of enalapril, demonstrating the benefit of adding a more effect
agent.

The FDA review has raised the question that the efficacy difference
between omapatrilat and enalapril may be easily overcome with greater
use of adjunctive therapy. I would like to make two important points
here.

First, many of these difficult-to-control patients are already on
multiple treatments and have limited options for additional therapy.

Second, many of these patients remain significantly above goal even
after adding enalapril or omapatrilat, as illustrated here in these 700
patients in whom the rate of control with enalapril on top of three
baseline meds is only 28 percent at the end of the study, and even with
omapatrilat only 42 percent reached target. If there is opportunity to
add more treatment, if there are options, it would occur in both
patients treated with omapatrilat and those treated with enalapril. And
while the use of adjunctive therapy would increase with both drugs, the
blood pressure reduction in the regimen with more effective components
would still be grater.

Hence, in patients with difficult-to-control hypertension, a regimen
containing omapatrilat would be expected to provide persistent benefit
compared to a regimen using less effective agents due to the greater
antihypertensive efficacy of omapatrilat.

To maximize the benefit this drug has to offer, we are focusing on
patients with high cardiovascular risk and hypertension that is
difficult to control with existing agents, and I\'d like to provide you
with some more data in patients not achieving blood pressure goal on
current therapies.

I\'ll now present data collected in another group of patients with
hypertension that\'s difficult to control with existing agents, namely
those who are resistant to ACE inhibitor therapy. This group of patients
is of particular interest since ACE inhibitors are widely used to treat
hypertension and since omapatrilat acts in part through ACE inhibition.
I\'ll review data from two sources, a study conducted specifically in
ACE inhibitor resistant patients, study -73, and the large number of
such patients from OCTAVE.

This slide summarizes the design of study -73, conducted in patients who
remained above blood pressure target despite aggressive ACE inhibitor
therapy. Subjects with systolic blood pressure of at least 140
millimeters of mercury or diastolic pressure of at least 90 millimeters
of mercury despite therapy with an ACE inhibitor at maximal or near
maximal dose for at least a month were enrolled and, after a 2-week
stabilization period, randomized to treatment with either omapatrilat
starting at 20 milligrams and up-titrated to 80 milligrams, or
lisinopril starting with 10 milligrams and up-titrated to 40 milligrams.

The lisinopril arm was intended to reproduce under blinded conditions
the potential effects of continued therapy with maximal ACE inhibitor.
All patients were treated with top doses of omapatrilat or lisinopril
for 4 weeks prior to the final evaluation. Ambulatory blood pressure was
used as the primary method for the assessment of treatment effect.

At study\'s end, 24-hour ambulatory systolic blood pressure was reduced
8.8 millimeters of mercury more with omapatrilat than with lisinopril.
Blood pressure was also reduced more with omapatrilat than with
lisinopril at each time point during 24-hour ambulatory blood pressure
monitoring. While the differences between omapatrilat and lisinopril
were greatest during the daytime hours, a difference of 7 millimeters of
mercury persisted at trough, 24 hours post dose administration.

The results of this study indicate that patients resistant to ACE
inhibition are not equally resistant to treatment with omapatrilat and
suggest that omapatrilat can be used as an alternative to ACE inhibitors
to provide substantial additional blood pressure reduction in patients
failing to reach target with an ACE inhibitor.

Of course, subjects treated with an ACE inhibitor alone could achieve
additional blood pressure reduction through addition of a second or
third agent. This study evaluated not only patients uncontrolled on ACE
inhibitor monotherapy, but also those uncontrolled on ACE inhibitor as
part of a combination antihypertensive regimen. In such subjects, the
ACE inhibitor was discontinued at randomization while other
antihypertensive medications were continued without alteration in dose.

As shown here, reductions in blood pressure were highly consistent
whether subjects entered the study on ACE inhibitor monotherapy, as
shown in the left-hand bars, or on an ACE inhibitor as part of a
combination antihypertensive regimen, as shown in the right-hand bars.
Numerically the reductions in systolic blood pressure relative to
enalapril were greater in those who entered the study on an ACE
inhibitor-containing regimen than those who entered the study on an ACE
inhibitor monotherapy, 11.5 versus 7.6 millimeters of mercury.

Now, OCTAVE also included over 4,000 subjects whose enrollment blood
pressure remained above target despite therapy with an ACE inhibitor or
ACE inhibitor-containing regimens. In these patients, prior treatments
were discontinued at study entry and patients were randomized to either
omapatrilat or enalapril.

Blood pressure was reduced consistently more with omapatrilat than with
enalapril whether patients were receiving an ACE inhibitor alone at
randomization or as part of a regimen containing one or more additional
antihypertensives. Numerically the greatest reductions relative to
enalapril of about 6 millimeters of mercury were observed in those
receiving an ACE inhibitor plus two or more antihypertensive medications
at randomization.

Now, the proposed target indication also includes patients with
difficult-to-control hypertension who have comorbid conditions and other
characteristics that put them at increased risk of cardiovascular
events. As representative data for this population, the results from
OCTAVE in subjects with diabetes and blood pressure above target at
enrollment despite ACE inhibitor therapy are summarized here. About
1,000 patients are included in this analysis.

Omapatrilat reduced blood pressure significantly more than enalapril in
these subjects whether they had been treated with an ACE inhibitor alone
at randomization as shown in the left-hand bars or with an ACE
inhibitor-containing antihypertensive regimen in the middle and
right-hand bars. Reductions in blood pressure with omapatrilat relative
to enalapril ranged from about 5 up to 9 millimeters of mercury, and the
greatest reduction was again observed in those receiving the most
intensive antihypertensive regimen at baseline.

In summary, a large clinical development program has demonstrated that
an omapatrilat-based regimen reduced blood pressure more than the
regimens containing enalapril. This blood pressure advantage was
consistent across patient subgroups regardless of the manner of the use
of the study drug. And OCTAVE further suggested that the blood pressure
advantage observed with omapatrilat in clinical trials can be maintained
under clinical use conditions.

Lastly, data from OCTAVE, as well as data from other trials, indicate
that in patients that cannot readily achieve blood pressure target with
existing drugs, omapatrilat provides further blood pressure reduction
that\'s not otherwise available.

Now, let\'s go on to safety. In a few minutes, I\'m going to ask Dr.
Kaplan to come to the podium to present an overview of angioedema.

DR. BORER: I\'m sorry. Just before you do that, because these are a lot
of data and there will be a lot of questions, maybe if it\'s okay we can
stop here and ask questions to clarify the efficacy data, and then
we\'ll move on to the safety and do the same thing.

Does anybody on the committee have substantive questions about the data?
Tom.

DR. PICKERING: Yes. I have one general question. It\'s well known that
ACE inhibitors\' effectiveness is increased by sodium depletion or
diuretic treatment, and I don\'t think in any part of your presentation
you specifically referred to the use of concomitant diuretics. I don\'t
think I\'ve seen any head-to-head comparison between omapatrilat and an
ACE inhibitor-diuretic combination, which many of us use in clinical
practice. Do you have such data?

DR. LEVY: If I could refer to my backup deck for a moment. Thank you.
Could I have slide HP-8?

What we\'ve done here is summarize the blood pressure reductions at
study end in patients who received a variety of additional therapies
after week 8. On the left-hand panel are displayed the findings in those
who received hydrochlorothiazide in addition to either omapatrilat or
enalapril, as well as those who received a variety of other
antihypertensive agents. As you can see, both omapatrilat and enalapril
have additional efficacy when supplemented by hydrochlorothiazide, but
the blood pressure reduction with omapatrilat remains greater. And the
same is true really regardless of the antihypertensive agent or class
which is added on top of omapatrilat or enalapril.

DR. PICKERING: You are saying that no study has been done with a
randomized direct comparison between omapatrilat and ACE
inhibitor-diuretic combination. Is that correct?

DR. LEVY: Yes. We\'re not proposing that the drug be used in patients
who can readily be controlled with an ACE inhibitor-diuretic
combination. And the patients I\'ve shown you are patients who are
typically already treated with combination therapy in whom the option of
adding a diuretic to an ACE inhibitor is no longer available.

DR. BORER: Are there other substantive issues? Bob.

DR. TEMPLE: This is to some extent the same question. But on slide 25
where you\'re looking at ACE inhibitor plus two or more antihypertensive
meds, what would those antihypertensive meds have been? I ask because it
matters. For example, if they\'re all on beta blockers, you don\'t
really expect too much more. The effectiveness overlaps. Were they all
on diuretics, as they presumably should have been? What were they on?

DR. LEVY: The majority of these patients were on diuretics, and then, of
course, the third med was a variety of medications, in some cases a
calcium channel blocker, in some cases a beta blocker.

DR. TEMPLE: Okay, but again I ask because the question that I\'m sure
will come up repeatedly always is this extra 3 millimeters or 10
millimeters or whatever it is ‑‑ could you have done it just as easily
by adding amlodipine? So, all of these things raise that question. I\'m
just trying to direct it there early because I think that\'s going to
come up repeatedly.

So, those people would have mostly been ‑‑ it\'s not that many, but 169
of them ‑‑ on at least a diuretic, do you think? Do you know exactly?

DR. LEVY: Can we go back a slide? Again, this is a cut of a cut, but the
previous slide, slide 24, is of a larger number of patients who were on
an ACE inhibitor at randomization and failed to reach target. As you can
see, there was almost 600 in the group on two or more antihypertensive
meds. And yes, these patients are in general receiving an ACE inhibitor,
in most cases plus a thiazide diuretic and then a calcium channel
blocker or a beta blocker.

DR. TEMPLE: You don\'t ave a precise breakdown of that.

DR. LEVY: We can provide you with that information later, if you\'d
like.

DR. TEMPLE: Okay.

DR. BORER: Paul.

DR. ARMSTRONG: My question is in the same area. Just to pursue this, if
we\'re going to get more data to see later, not only would I be
interested in the types of adjunctive therapies that were added in
instances where one or other choice of therapy in OCTAVE was perceived
to be inadequate, but the doses of those agents. In other words, were
the doses of those agents pushed to equal intensity in the instance
where it was perceived that the primary therapy had failed?

DR. LEVY: Certainly there\'s a wealth of data on that question. Let me
provide you with the one patient subgroup where the data is most clearly
defined. As mentioned, this was a simple trial. The case report form was
simple, and the amount of information about study drug dosing is
therefore limited. But for a few certain drugs, we do have specific
dosing information, and perhaps I can show you some information there
that will illustrate what happens when omapatrilat is used rather than
enalapril in patients who were receiving high-dose, aggressive
antihypertensive regimens. I think they\'re representative of the whole
study, but for this particular subgroup, we have very detailed
information about dosing.

These would be our slides comparing the efficacy of omapatrilat and
enalapril at week 24 in study group 3 subjects who entered the trial on
a two-drug regimen, including amlodipine and hydrochlorothiazide.

DR. BORER: While you\'re pulling that up and looking for slides, Steve
is our committee reviewer, and he\'ll have a number of questions I\'m
sure. But I had a specific question on the same issue and that was from
your slide number 23 where the addition of lisinopril actually caused no
change, an average .6 millimeter of mercury increase in blood pressure,
when added on to other therapy. And I too wanted to know what the other
drugs were, what their doses were, how you would explain that, what the
population was. Were there some vagaries there that could explain the
absolute lack of any activity of the ACE inhibitor in that population?
So, while you\'re looking all this up, go back to your slide 23 also, if
you would.

DR. LEVY: All right. Let me answer this question first and then I\'ll
return to your question.

Again, in this group we have the most specific information about study
drug dosing and the doses of adjunctive therapy. Now, these are patients
who entered the trial uncontrolled on two or more antihypertensive
agents, which included amlodipine or hydrochlorothiazide, and for those
two drugs we have the dosing information. These patients at baseline had
blood pressures that remained at JNC VI stage II, systolic pressure of
160 to 169 or diastolic of 100 to 109. And their mean systolic pressures
were about 166.

These patients were receiving a minimum of hydrochlorothiazide and
amlodipine. The mean dose of amlodipine was 7 milligrams. The mean dose
of hydrochlorothiazide was 20 milligrams. So, the patients were about
split between amlodipine 5 and 10 and hydrochlorothiazide 12.5 and 25.
About 40 percent of them were also receiving a beta blocker, and 10
percent were also receiving an angiotensin receptor blocker. So, over
half of these patients were actually receiving three drugs at
randomization.

They then received, in addition to their existing therapy, omapatrilat
or enalapril. As I mentioned, these drugs were used very aggressively in
the course of the trial. Over 60 percent of these patients were titrated
to enalapril 40 milligrams, which is a dose that\'s considerably higher
than that generally used in clinical practice, and then some number of
these patients received a fifth or a sixth antihypertensive agent in the
course of the trial.

So, these represent really an extraordinarily aggressively treated group
of patients in terms of the number of drugs and the dosing of those
drugs. And there\'s still an advantage in both systolic and diastolic
blood pressure reduction at the end of the study. So, I present these as
representative. I happen to have the most detailed dosing information
for these patients, but they\'re presented to you simply because you
asked a question about dosing.

DR. BORER: Do you have any idea why 7 milligrams and 20 milligrams was
the average? It\'s certainly not the maximum labeled dose of amlodipine,
and the thiazide dose, though, one can go way up the scale. One might
choose not to because of safety issues, but 20 milligrams is kind of
low. So, why is it that those adjunctive therapies or those initial
therapies were limited in those patients? Do we have any idea at all?

DR. LEVY: Well, you know, in practice physicians tend to prefer the use
of low-dose therapies, particularly for drugs that do have dose-related
toxicity. Amlodipine has a much higher incidence of peripheral edema at
10 milligrams than at 5 milligrams. That may have been a factor in
physicians\' choice of 5 milligrams in some half of these patients, and
thiazide diuretics also have a dose-related adverse effects that may
have influenced the selection of study dose. But these are actually
relatively high doses compared to those encountered in usual practice.

DR. BORER: Right, but that\'s not really the point. What\'s encountered
in usual practice may be reasonable or it may be unreasonable, and I
know that there are many reasons people may do things. That doesn\'t
make them rational or right. The question is, do we actually have
information about why people weren\'t given the higher doses? Maybe you
don\'t, and I\'m not suggesting you had to have such information but
I\'m just asking if you do.

DR. LEVY: No, we don\'t.

DR. BORER: Before you go on with Paul\'s issue, can you go back to your
slide 23? Do you know anything about that group that received lisinopril
on top of something else?

DR. LEVY: Again, this isn\'t OCTAVE. This is a trial that was
specifically conducted in patients who were resistant to ACE inhibitor
therapy. In this study patients who were on combination regimens
discontinued the ACE inhibitor at randomization but continued all other
medications. They were already on maximal or near maximal ACE inhibitor
therapy at randomization. So, that meant lisinopril 20 milligrams,
enalapril 20 milligrams. What you see there reflects the replacement of
their prior ACE inhibitor with study ACE inhibitor, which was titrated
to 40 milligrams.

DR. BORER: Do you have any information about the characteristics of that
population that would explain their relative resistance just for our
edification?

DR. LEVY: Well, there were more black patients represented in this study
and a slightly higher incidence of diabetics, characteristics which
might be associated with diminished response to drugs which inhibit the
renin-angiotensin system. But it was actually a quite representative
hypertensive population.

DR. BORER: Paul, have you completed?

DR. ARMSTRONG: Yes.

DR. BORER: Steve.

DR. NISSEN: First of all, I really want to compliment BMS on one of the
most extraordinary development programs for a hypertensive drug. The
number of patients studied, the robustness of the data is really quite
extraordinary. I think there a lot of insights, obviously, to gain from
a 25,000-patient study.

I also wanted to say I really appreciated the review from Drs. Lawrence,
Stockbridge, and Throckmorton. I think we had a really comprehensive
package. So, we\'ve got a lot of information and I want to go through a
little bit of it.

I wanted to begin by asking something about mode of action, and the
question I want to get at is why does this agent have greater
antihypertensive efficacy. I\'ll offer you a hypothesis, and I want to
know whether there\'s any data to support it.

The hypothesis is that by increasing levels of natriuretic peptides,
that there\'s a weak diuretic effect from the drug. So, what we\'re
looking at here is something that looks like the combination of an ACE
inhibitor with a very weak diuretic. As we all know, when you add a
little bit of diuretic to an ACE inhibitor, you get a lot of bang for
the buck. You get a lot of blood pressure reduction, even 6.25
milligrams of hydrochlorothiazide will add a few millimeters of blood
pressure reduction to ACE.

Is that really what we\'re seeing here that we have in a single compound
a drug that\'s combining a little bit of diuretic effect with an
inhibition of the renin-angiotensin system? And any of your consultants,
if you could shed some light on this, I would be appreciative.

DR. LEVY: If I can just make a few comments. That\'s an excellent
question. Certainly when we began developing the drug, it was a major
question. In our clinical pharmacology program, in which subjects were
actually studied in clinical research units and their intakes and
outputs could be carefully measured, there was no evidence of a
natriuretic or diuretic effect with omapatrilat at doses well above and
below those studied.

In our hypertension development program, as I\'ve shown you, patients
who received a diuretic in addition to omapatrilat, experienced the same
incremental reductions in blood pressure that one sees when adding a
diuretic to an ACE inhibitor, suggesting that its additional
antihypertensive effect is not mediated through diuresis. It appears to
be the vasodilator effect of the natriuretic peptide that contributes to
the antihypertensive effects of this drug. In particular, the drug may
have a unique central vasodilatory effect on the large conduit vessels.

DR. NISSEN: You did formal salt balance studies and that sort of thing.
Are those available for us? Because I think that would be very
interesting to see is, in that first week after you start the drug, what
happens to salt balance, not later on, but as I understand diuretics,
what you see is an initial fall in sodium and then it returns to normal
again. I\'d be very interested in seeing any salt balance studies that
you have.

The reason it\'s relevant I guess is let\'s suppose that that\'s right,
that this is a drug that has weak diuretic properties. Then it still
might be true that adding additional, say, hydrochlorothiazide to the
regimen would produce additional blood pressure reductions. I mean, if
you go from 6.25 to 12.5 to 25 milligrams of hydrochlorothiazide, you
see additional efficacy. It\'s highly relevant in my view because it
speaks to Tom Pickering\'s question, which is, is the real comparator
for omapatrilat ACE plus a little bit of diuretic? Is that really what
we\'re talking about as a comparator?

DR. LEVY: Well, of course, we\'re not recommending that the drug be used
in patients who can be controlled with ACE plus a little bit of
diuretic. We\'re proposing it be used in patients who can\'t be
controlled with an ACE-diuretic combination, and there\'s evidence that
it provides substantial incremental benefit in those patients.

So, with regard to the mechanistic considerations, with a
thiazide-diuretic, one would see a brisk diuresis within hours of
administration of the drug, an excretion of 200 to 300 millimoles of
salt. We don\'t see anything like that with early dose administration.

DR. NISSEN: So, there are salt balance studies that you can provide us
to take a look at?

DR. LEVY: There are studies conducted in which urinary sodium excretion
is measured over the first hours of dosing and the first 24 hours of
dosing, a time period in which the effect of either a thiazide or a loop
diuretic would be unmistakable. And we don\'t see anything at all.

DR. NISSEN: Okay.

I wonder if you could bring up slide 11. There are some things I didn\'t
understand here, and I really want to explore it.

Let\'s look at the add-on group, or group 3. Now, the entry criteria for
group 3 was what entry criteria? What did you have to have to be in
group 3?

DR. LEVY: These patients had to be uncontrolled on antihypertensive
therapy with blood pressures at JNC VI stage II, or a systolic blood
pressure of 160 to 179 or a diastolic blood pressure of 100 to 109.
These patients at randomization continued their existing
antihypertensive therapies and added omapatrilat or enalapril.

DR. NISSEN: I thought that\'s what I heard, and then I was confused
because the baseline blood pressures in this group are actually lower
than the minimum requirement to get in that arm of the trial. When I
read this last night, I just couldn\'t understand how that could
possibly happen.

DR. LEVY: Well, that\'s a very good question. Remember, patients could
enter the trial by satisfying either the systolic blood pressure
criteria of 160 to 179 or the diastolic blood pressure criteria of 100
to 109.

Now, you made a very important observation. The systolic pressure is 166
which is within the target range, while the diastolic pressure is below.
That reflects the difficulty in achieving systolic blood pressure
control in populations. Failure to control systolic blood pressure is
the primary reason for difficult-to-control hypertension. And Dr. Black
is going to address this issue in more detail at the end of this talk.
So, it\'s not a defect the study design. It really reflects the
extraordinary difficulty that physicians have in bringing systolic blood
pressure under control with existing medications.

DR. NISSEN: Well, let me tell you what I\'m concerned about. Again,
we\'re trying to tease out the group that might benefit here. So, this
group 3 was going to be people who were just refractory. They couldn\'t
be controlled on existing medications. When I see a group that\'s 166
over 97, it seems a lot less refractory to me than the entry criteria
would look like. My guess is sometimes when you do a trial of 25,000
patients in less than a year, you\'ve got to get patients in the trial,
and so investigators tend to be a little more aggressive and maybe
initial blood pressures were a little bit lower than you wanted them to
be. So, I\'m not sure how refractory that group 3 is. It does color my
interpretation of the data when I see that the average blood pressures
are pretty low and really below the targets in that group. Do you follow
me?

DR. LEVY: Perhaps I\'ll ask Dr. Black to comment at this point.

DR. BLACK: Yes, thanks very much, Elliott.

Steve, I just want to say that I don\'t think those are really low at
all. That\'s the world through a diastolic window, not through a
systolic window. The problem we have, as I\'ll show you a little bit
later, is not that we can\'t control diastolic pressure. It\'s that we
can\'t control systolic pressure. In fact, arteries get stiffer in
diastolic falls if you leave people untreated. So, pulse pressure widens
and I think that\'s the group you\'re looking at.

DR. NISSEN: Well, the reason this is germane is you\'ve said several
times that you want to target this drug at those people that are very,
very difficult to control with conventional regimens. What I see is in
OCTAVE, a 25,000-patient trial, in each of the three arms the blood
pressures are not extraordinarily elevated. So, I know you have some
people in OCTAVE that were very, very high, but I\'m interested in
understanding whether there is, in fact, a target population identified
here that would be optimally benefitted. It\'s harder when the average
blood pressures in the trial are not as high as one might have expected.

DR. LEVY: Let me return to that point. Again, in these study group 3
patients, the systolic pressure at baseline is at least 27 millimeters
of mercury above target on treatment. In those with diabetes, renal
failure, heart failure where the treatment target is 130 millimeters of
mercury, the blood pressure is 37 millimeters above target. If a patient
walked into your office untreated with those pressures, you might be
able to bring them down with one, two, or three medications. If a
patient was already on two or three medications, the opportunity to
reach target is very, very limited.

Again, we had patients in this group ‑‑ and I\'ve shown you the results
‑‑ patients who were on two drugs at randomization, patients who were on
three drugs at randomization. On three drugs at randomization with blood
pressures in this range, the addition of very high-dose enalapril,
making them on a four-drug regimen, plus other drugs, you still only get
28 percent of them to target.

DR. NISSEN: I agree that group is certainly a target group.

But I did want to look at the group that\'s really much more severe. I
know you did a study, 137-049. I\'m sure you have those slides. I\'d
like to see that study because I think it helps us here.

DR. LEVY: Sure. Perhaps I could just begin by going back to the slide
from our core deck showing the results in patients with severe
hypertension in OCTAVE.

DR. NISSEN: Sure.

DR. LEVY: If I could have the table displaying the results by
comorbidity. That\'s slide 16. Again, for patients who entered the trial
off therapy, we could assess their underlying blood pressure. That\'s
study group 1. And 1,000 of those patients had severe hypertension. If
you were to include, as we did by design, those who entered the study on
treatment on at least two antihypertensive medications, then the number
with severe hypertension goes up to about 7,000. So, it\'s a very large
experience. And the confidence intervals around the estimate of
treatment effect are very narrow.

Now, in 1998 and 1999, we conducted an exploratory study in patients
with severe hypertension. That study included about 160 patients, about
two-thirds of whom were on omapatrilat and a third on enalapril. That
study was designed to determine whether the drug effectively reduced
blood pressure in patients with severe hypertension, and it did. It did
not demonstrate a statistically significant difference between the
groups, and it was not intended or powered to do so.

DR. NISSEN: Do you have a slide with the data?

DR. LEVY: Sure. We can look for that and come to it a little bit later.

DR. NISSEN: I\'d just like to see it because as I recall, the entry
criteria for that ‑‑ there it is. That\'s the study.

DR. LEVY: This was a little bit different study population. The focus in
registrational trials in hypertension has been on diastolic blood
pressure, even though that\'s not the critical variable of the
population. So, this study looked at patients with diastolic pressures
of 115 to 130 off treatment. It\'s actually a very narrow segment of the
severe hypertensive population.

DR. NISSEN: Okay, but nonetheless, these are pretty severe. So, it
obviously does send us a signal that we\'d like to see. Show us what
happened with this group.

DR. LEVY: Can we see the primary efficacy results in this study? These
are results at week 10. These are regimen comparisons. Virtually every
patient was on multiple drugs by this time, many on three drugs, and
blood pressure was reduced with both drugs. It\'s reduced about a
millimeter of mercury more with omapatrilat than with enalapril in
systolic blood pressure and about 2 millimeters of mercury more
diastolic with omapatrilat than with enalapril.

DR. NISSEN: Did that result surprise you?

DR. LEVY: No. It\'s a small study and it was designed to compare regimen
versus regimen. It wasn\'t designed to determine if omapatrilat reduced
blood pressure more than enalapril. In fact, there was no planned
statistical comparison in this study and it wasn\'t powered to make one.

DR. NISSEN: All right, fair enough.

DR. TEMPLE: Before you leave that, that\'s a pretty large
antihypertensive study. It\'s not a small study.

DR. LEVY: I don\'t think that 60 patients in the enalapril arm is very
large. In any case, it\'s a lot less than the 1,000 we have in OCTAVE.

DR. NISSEN: Actually there is a little discrepancy, Bob. In the FDA
briefing package, the endpoints are shown, but they\'re actually
opposite to that. They show actually that there was a little bit greater
efficacy with enalapril than omapatrilat. I\'m not sure which is right.

DR. THROCKMORTON: In this study?

DR. NISSEN: Yes, I think so. I\'ll pull it.

DR. THROCKMORTON: I don\'t think I included this particular study review
from the original efficacy. I\'m looking at my original package, and I
don\'t remember doing that because that study, as Elliott said, when we
looked at it originally, was very small and had no statistical plan even
associated with it. So, we did relatively less with it. But we can
double check that.

DR. NISSEN: Fair enough.

I\'m exploring with you because obviously one of the things that we\'re
trying to weigh here is risk versus benefit.

DR. BORER: Excuse me just one second. There is a mention of numbers and
they do appear to be in the opposite direction.

DR. NISSEN: I thought so.

DR. BORER: Severe hypertension in CV137-049. These pages don\'t have
numbers on them, so I can\'t tell you where in the review it is. But it
does say that the change from baseline seated diastolic blood pressure
was similar for the two groups, minus 26 for omapatrilat and minus 29
for enalapril.

DR. NISSEN: So, they\'re reversed from what\'s in there. I understand
the limits of the statistical comparison here. Your point is well taken.

Let me tell you what I\'m trying to explore with you. We\'re trying to
weigh here risk and benefit, and obviously showing that in the very
severe hypertensive, you can get them a much better chance to get them
to goal has a real impact on our thinking about the relative risk and
benefit of a drug. So, I was interested in 137-049, and I wanted to look
at it with you because we just had one paragraph about it in our
briefing book. And I wanted to understand what was done there, and I
understand it wasn\'t a huge study. It doesn\'t compare to the 25,000
patients in OCTAVE, but I wanted to at least understand what it was all
about.

Now, the next issue I wanted to go into ‑‑ and, Jeff, I won\'t take much
longer because I think we want to move on ‑‑ is you compared to
once-a-day enalapril. We had a rather extensive discussion yesterday on
the issue of once-a-day versus twice-a-day drug dosage.

Now, the differences were about 3 over 2 millimeters, something like
that, between once-a-day omapatrilat and once-a-day enalapril. One of
the questions that I needed to have answered was, what might we have
expected if the enalapril had been given as 20 milligrams b.i.d.?
Remember now, we\'re going to try to calculate a benefit versus a risk.
So, the differences between those two regimens is very, very important.
What would the difference have been if we had given enalapril 20 b.i.d.
rather than, say, 40 milligrams once a day? Any information about that?

DR. LEVY: That\'s a very good question. I really can\'t speculate about
that. We didn\'t do a study versus b.i.d. enalapril. We chose an
enalapril dose regimen that reflects the way physicians give chronic
therapy to patients in practice, which is once a day.

Now, we do have a variety of studies against other agents, studies in
which the optimum effect of omapatrilat was compared to the optimum
effect of those agents, and that includes comparisons with not only
lisinopril and losartan, but also with amlodipine which is an extremely
long-lived, once-a-day drug. There again there is superior efficacy.

DR. NISSEN: Well, let me tell you what triggered me to ask the question.
Since you\'re going to present OVERTURE and I don\'t want to presage
that, it\'s interesting that in OVERTURE you gave the enalapril b.i.d.
and in the hypertensive patients, there was exactly the same blood
pressure reduction between omapatrilat and enalapril given b.i.d., 12.6
and 12.7 millimeters. So, I was left saying, gee, what if OCTAVE had
done that? Could that have completely erased the blood pressure
differences between the two regimens?

DR. LEVY: Again, it\'s hard to imagine it would do that in patients
whose blood pressure remains uncontrolled. It\'s difficult to control
with regimens like twice-a-day enalapril or twice-a-day enalapril plus a
thiazide diuretic patients who need more therapy.

DR. NISSEN: Michael, you look like you have some thoughts about that.

DR. WEBER: I was going to suggest, Steve, that we take a look at the
ABPM data because, in fact, that does show pretty good 24-hour efficacy
for the ACE inhibitors as well. Do you have the ABPM data with the
lisinopril study? Slightly different than enalapril.

DR. NISSEN: Wasn\'t lisinopril a bit longer-acting?

DR. WEBER: Yes. Do we have ABPM data for enalapril in the resistant ‑‑

DR. TEMPLE: Lisinopril I think is labeled for once-a-day only because
it\'s got a very long half-life.

DR. NISSEN: So, I guess the lisinopril ambulatory blood pressure data I
wouldn\'t consider relevant.

You know, it\'s really an important question, and I know I\'m kind of
being a stickler here. But if I\'m going to calculate the potential
benefit versus the potential risk, I\'ve got to know how much the
difference between enalapril and omapatrilat is. If enalapril is given
in an optimal way, that might be b.i.d.

DR. PACKER: Steve, I think you\'re asking a very important point. I was
in the audience yesterday and I know the committee was discussing what
constitutes a fair comparison. Would it be appropriate to compare a
once-a-day drug which is being proposed for once-a-day use against a
drug which is most commonly used and includes a labeling for once-a-day
use.

Having said that, there is an extensive experience with the comparison
of once-a-day omapatrilat to twice-a-day enalapril in OVERTURE. I\'ll be
reviewing OVERTURE, but I just wanted to address the question about
blood pressure.

OVERTURE was a heart failure trial, not a hypertension trial. I think it
would be fair to say that hypertension specialists tend to pay more
attention to how they measure blood pressure than heart failure
specialists who tend to think of blood pressure as being a general
phenomenon and generally estimated. That creates a lot of noise in
clinical trials.

Second is that the blood pressure measurements were made at trough in
OVERTURE before the next dose of the drug, and there are considerable
data from another heart failure trial called the IMPRESS study comparing
omapatrilat once a day with lisinopril once a day, which is also
approved once a day for heart failure, showing that, yes, the blood
pressures with omapatrilat and lisinopril come together at trough, but
there\'s a huge difference during the day. Therefore, if you look at the
cumulative effect over 24 hours, there\'s still a major difference
between omapatrilat and the comparator ACE inhibitor. We couldn\'t
document that in OVERTURE because we only have trough blood pressures.

DR. NISSEN: Would it be safe to say, Michael, whoever ‑‑ let me ask you
this. Would it be safe to say that a regimen of 20 milligrams b.i.d. of
enalapril might reduce blood pressure over the 24-hour period more
effectively than 40 milligrams once a day? Would it likely narrow that
gap of 3 over 2 millimeters or would it not?

DR. WEBER: It probably could, but I can\'t be certain of that, Steve,
because certainly there have been plenty of other trials with enalapril
given once a day where, in fact, I thought it did rather well throughout
the 24-hour period. In fact, our experience with ABPM would suggest that
enalapril may be fractionally better twice a day, just as you could say
the same with losartan. In fact, we know that would be true. But still,
we\'re talking about a very, very minimal advantage.

DR. NISSEN: 1 or 2 millimeters?

DR. WEBER: 0 to 1, .5 to 1.

DR. NISSEN: I guess the answer is we really don\'t know. Is that a fair
answer?

DR. WEBER: Yes.

The other thing too is omapatrilat is a long-acting drug. It gives you
24-hour efficacy, but you might have noticed from the ABPM data that
towards the end of the dosing interval its advantage compared with the
ACE inhibitor is getting less. You could argue that omapatrilat twice a
day would be significantly better than omapatrilat once a day as well.
So, I\'m not sure how far we would want to take this particular
argument.

DR. NISSEN: Well, I guess I wouldn\'t buy that necessarily, Michael, and
the reason I wouldn\'t is that I\'m a clinician and I\'ve got a choice.
I can give an agent with a more adverse safety profile once a day and
take a risk of angioedema, or I can give a drug that\'s got a better
safety profile twice a day. That\'s a very relevant consideration
regarding approvability because if I could get the same blood pressure
reduction by giving a safer agent twice a day, it would be hard to argue
in favor of the less safe agent once a day I think.

DR. WEBER: Yes, but let me remind you of the patients who are resistant
to ACE inhibitor, the study that Elliott showed before. The difference
was really quite considerable between omapatrilat and enalapril in that
setting, and I don\'t think giving enalapril twice a day there would
have really compensated for those kinds of millimeters of mercury.

DR. NISSEN: I have two other brief questions, Jeffrey, if you don\'t
mind. A couple of interesting things.

I was very struck by your slide number 6, if you want to show that.
There\'s an interesting question that it raises. So, in 037 you were
studying African Americans, and in 030 the comparison was amlodipine.
So, given the fact that lisinopril didn\'t work as well in African
Americans ‑‑ and neither did omapatrilat ‑‑ I\'d be interested in
whether you have any comparative data comparing omapatrilat to
amlodipine in African Americans. Did you do any of those comparisons?

DR. LEVY: Well, there were small subset comparisons within each of these
trials that are done, and about 10 percent of the subjects in each of
the trials in unselected populations tend to be African Americans. In
general, all those subgroup cuts are very consistent with the overall
study results. There\'s a superior efficacy for omapatrilat.

DR. NISSEN: I seem to remember somewhere in Dr. Throckmorton\'s review
some studies where that comparison was made where, in fact, in that
subgroup omapatrilat actually produced less effect than amlodipine in
the African Americans. I\'m not surprised by that, but it\'s an
interesting issue about choice of drugs in patients. There the
risk-benefit really does shift quite a bit.

Doug, didn\'t you review that somewhere? Do you have that, Jeff?

DR. BORER: I think the statement is correct that in general the results
look qualitatively similar by race. There may be a little bit more
effect in non-black than black, but the results are qualitatively
similar.

DR. LEVY: If I could comment, though, it\'s not our intention that
omapatrilat should be used in patients who can readily be controlled
with a safer agent. Particularly in black patients, we surely are not
suggesting this drug should be used in place of a dihydropyridine
calcium channel blocker in a patient who could be controlled on those
drugs.

DR. NISSEN: I have one more brief question. The other questions I have
on efficacy really relate to the issue of target organ protection, but I
think I\'m going to wait on those, Jeff, until after we hear from Henry
and so on.

So, the one final question I had was on your slide number 3. I want to
make sure I understand the entry criteria. So, this is the group you\'re
proposing the drug is most likely to benefit. Was this criteria of
presence of cardiovascular disease an entry criteria for OCTAVE?

DR. LEVY: It was not an exclusion criteria.

DR. NISSEN: But it wasn\'t necessarily an explicit one.

DR. LEVY: Well, I\'ve shown you about 2,300 subjects had a history of MI
or stroke or overt atherosclerotic disease at baseline. Heart failure
was a small number, but there\'s of course a much larger number in the
OVERTURE study.

DR. NISSEN: I want to come back to this later, but I do want to know
subsequently. Since this is the population you\'re suggesting we should
target with this drug, I will want to know more about studies done in
such subgroups because, obviously, if you want to use a group in a
subgroup, you\'ve got to know a lot about it. So, I\'ll be interested
later to hear about those people with known target organ damage, those
people with post-MI, those people with three or more cardiovascular risk
factors because, again, looking at risk-benefit, we need information
about those groups if those are going to be the target groups that
we\'re going to want to treat.

DR. LEVY: Right.

DR. BORER: Two final questions that I have for you. Again, you may not
have specific information about this, and if so, you don\'t. But why
were patients who were not adequately controlled stopped at two drugs?
You had a number of patients who were given one additional drug, two
additional drugs, or three additional drugs. And if they were not
adequately controlled with two drugs, still a fair number continued on
two drugs. Why was that or am I misunderstanding?

DR. LEVY: I\'m not sure I understand the question. If you could point to
a specific slide.

DR. BORER: Why if somebody\'s blood pressure isn\'t controlled would you
not add additional drugs to try to control them? Was there something in
the protocol that would have precluded that? Was there some suggestion
in the selection algorithm that would have influenced that? I mean, if
somebody\'s blood pressure isn\'t controlled, in general you\'d want to
continue to push the dose or push the number of drugs until you get it
controlled. But I inferred from your slide ‑‑ and I\'m sorry I didn\'t
write down the slide number ‑‑ that a number of patients were given one
additional drug or two additional drugs and still weren\'t controlled
but continued on that regimen rather than being given an additional
drug.

DR. LEVY: You don\'t know the slide?

DR. BORER: No.

DR. LEVY: I think there may be a misunderstanding, but I\'ll try to
clarify that.

DR. BORER: I can probably find it easily enough here.

DR. LEVY: What I\'d like to see is the slide from the core deck ‑‑ not
this slide. Bear with me for a moment.

DR. PICKERING: I think it may be the protocol design. There were only
two visits after week 8 ‑‑ is that right ‑‑ at which they could add
additional drugs.

DR. LEVY: Let me first go to slide 20 in the core deck. I don\'t know if
there\'s a misconception here. The number of meds. Those are the
medications which the patient was receiving at study entry. Now, of
course, there was no restriction on the number of medications that a
patient could receive during the study.

And your point is a good one, though. If patients remain uncontrolled,
physicians will continue to add drugs, and that\'s a very important
point. They would do that. Obviously, most of these patients are not
reaching target at the end of the study regardless of therapy. So,
physicians would add drugs to both omapatrilat and enalapril.

DR. BORER: But did they? What I\'m asking you is were there patients
whose blood pressure didn\'t meet the target who were not on three drugs
or more?

DR. LEVY: Yes.

DR. BORER: And why was that?

DR. LEVY: This is a 24-week trial. There are a discrete number of
opportunities to add adjunctive therapy. Not every patient was brought
to a three-drug regimen. Not every patient could be.

DR. PICKERING: Again, I think it was only weeks 8 and 16 that they had
the opportunity to do that, so there was a limit to how many additional
drugs you\'d be able to add or dose-titrations you\'d be able to do.

DR. LEVY: I think the larger question, though, is what can be
accomplished with addition of a fourth, a fifth, or a sixth drug in
patients who are multi-drug resistant. Maybe Dr. Black can speak to this
question.

DR. BLACK: If I may, Jeff. This a practice-based study. You can, when
you\'re doing a protocol, just encourage. You can\'t force necessarily a
lot of physicians ‑‑ and there were lots of physicians in this ‑‑ to
continue to add drugs. I\'ll show you some data late from our CONVINCE
trial about what people used and where we ended up, another
practice-based study with a fairly strict protocol, but we could not, in
fact, insist that people went on. I think it\'s much like the question
of why 7 milligrams of amlodipine and 20 of hydrochlorothiazide. I think
people in practice dealing with individuals won\'t necessarily go to the
top dose.

DR. BORER: No, I understand, and that\'s a very reasonable response.

My point only is that the fact that people don\'t ‑‑ and this is not a
value judgment here, but you\'re proposing a very extensive and
intensive education effort ‑‑ it\'s laudable; it\'s wonderful ‑‑ to try
to make sure that pharmacists, patients, and doctors all know about the
risks and minimize their impact, and I think that\'s wonderful. I\'m
just wondering if that same kind of intensive effort were used with
regard to managing high blood pressure in the first place, we wouldn\'t
have so many people on 7 milligrams or 20 milligrams of adjunctive drug
and might have better blood pressure control.

And that\'s not your responsibility or anything like that, but I don\'t
think we should judge the results here based on the fact that, well,
this is a practice-based study and doctors don\'t always do what would
be done in an academic medical center. That may not be the appropriate
conclusion from all this.

But I\'m sorry. Go ahead.

DR. BLACK: Yes. I think you reflect the frustration we had when we wrote
the Joint National Committee report in 1997, looked at data on how poor
control was in spite of a 25-year history of a very effective program.
We did increase things. We\'ve stopped and we need a much more
aggressive physician and patient and pharmacist education program to
improve control in general. We\'re not at all happy with 27 percent.
NHANES IV looks as if we\'ve improved things extremely little in spite
of our awareness from JNC VI that this wasn\'t getting anywhere. We made
some adjustments in JNC VI to try to make that more obvious, concentrate
less on what drugs people use, but getting to a goal.

DR. BORER: Steve.

DR. NISSEN: Jeff, just to answer, I did find the comparisons that I was
looking for with African Americans. If you want to see it, it\'s FDA
table 7.12G.3. And I can\'t give you a page number, because there
aren\'t any page numbers on there. But John Lawrence did the analysis.

What it shows is is that in the study 137-030, which was the amlodipine
comparison, in black females omapatrilat was 7.9 millimeters worse than
amlodipine with a p value of .01, and in black males it was 1 millimeter
worse with no significant p value. So, there does appear, in fact, to be
a racial difference, at least in the amlodipine comparisons, with
omapatrilat being nominally worse in African Americans, but better in
white males and females. So, it\'s a consideration here that I think
probably needs to be out and discussed because obviously it\'s exactly
that population where the risks of angioedema are the greatest.

DR. BORER: Okay, if there are no more questions, thank you that was very
informative.

DR. FLEMING: On slide A-5, you\'re defining this configured target
population. Can you show us ‑‑ because this, in essence, now is going to
create a focal data set, I assume, from your perspective ‑‑ the
population that meets these criteria in OCTAVE, baseline characteristics
for the two arms and what the actual results were in terms of blood
pressure control, as well as what the differences are in overall
clinical endpoints in this group of patients in OCTAVE?

DR. LEVY: We\'ve not prepared a pooled analysis in which all these
patients are put together. I\'ve shown you data regarding efficacy in
patients with severe hypertension and data in patients with diabetes
whose blood pressure is difficult to control with existing agents. We
have data on efficacy in some of these other populations, which I\'d be
happy to show you as well.

DR. FLEMING: This is your target group that you\'re going to request be
viewed as a group in which we will, hopefully, have a favorable
benefit-to-risk. Correct? So that basically is it correct to say you
would like to label the drug with this as the target indication?

DR. LEVY: The label is something that will be developed through
discussions with the FDA. This is the intended target population.

DR. FLEMING: So, after the break, could you provide us, for this
subpopulation of the trial, what the primary analysis would show for
blood pressure control, differences in clinical events, and
comparability at baseline?

DR. LEVY: Just to be clear, we\'ve not done a pooled analysis in which
we select all patients.

DR. FLEMING: I\'m asking could you do so.

DR. LEVY: I don\'t know if we can do that between now and the break.

DR. FLEMING: Not between now and the break. Could you sometime after the
break prepare that?

DR. LEVY: We\'ll certainly do our best.

DR. FLEMING: Have you not done this at all?

DR. LEVY: We have not prepared a pooled analysis of all these patients.
I\'ll consult with the team. We\'ll do the best we can.

DR. BORER: What about each group individually? You\'ve got four groups.
Do you have data on each of the four groups?

DR. LEVY: Yes. I\'ve shown you patients with severe hypertension who are
represented here. I\'ve shown you data for those with diabetes. There\'s
data for other patient populations as well. I\'d be happy to walk
through all of that in detail. We have an enormous database. But as I
say, we haven\'t put them all together.

DR. BORER: Would you accept that, Tom, looking at each subgroup
individually?

DR. FLEMING: It\'s perplexing to me that we\'ve done a major trial here.
We\'re recognizing that risk was in excess of what we had anticipated.
We make the logical conclusion that it might be that there is an
important subgroup for which benefit could be particularly substantial.
So, we define that subgroup, and we propose that this group be what we
focus on as a retrospectively defined subgroup. And yet, we\'re not able
to show what the overall benefit is and what the risk is in that
subgroup. I\'m assuming we can define whether or not the 25,000 patients
individually would fit into this subgroup, so we ought to have been able
to, in a fairly straightforward fashion, define what would be the
primary efficacy outcomes and the safety outcomes in the subgroup.

DR. BORER: Doug?

DR. THROCKMORTON: Jeff, a minor thing. I looked back at the study 049,
which was the relatively smaller study on resistant populations, and in
fact, those two numbers that are in your briefing document are reversed.
Again, I wouldn\'t make terribly large amounts out of them, but for what
it was worth, the directionality was not different. That is, omapatrilat
had the directionality towards a greater reduction than enalapril in
that trial, which is the opposite of what\'s in the briefing document.

DR. BORER: Why don\'t we go ahead with the safety data and we\'ll come
back to some of these efficacy issues later in the presentation.

DR. LEVY: In a moment, I\'m going to ask Dr. Kaplan to come up to
provide you with an overview of angioedema, but before I do, I\'d just
like to briefly provide a summary of the safety database.

The safety of the drug was characterized, as you know, in an extensive
clinical development program, including about 35,000 hypertensive
patients, 19,000 of whom were treated with omapatrilat. This, as you
know, represents about 5 to 10 times the experience typically described
in a hypertension new drug application. Large numbers of subjects were
exposed to each of the proposed target doses. 13,000 were exposed for
more than 3 months and about 1,500 for more than a year.

This extensive experience has provided an unusually clear profile of the
safety of the drug. The overall incidence adverse events, serious
adverse events, and discontinuation due to adverse events has been shown
to be comparable for omapatrilat and enalapril. The risk of angioedema
has also been clearly characterized and shown to be three times higher
than with enalapril.

Because of the importance of angioedema in the assessment of
omapatrilat, I\'m going to ask Dr. Kaplan to come to the podium now. Dr.
Kaplan is an angioedema expert who will provide a brief presentation on
the pathogenesis and clinical spectrum of this entity before I return to
complete the safety presentation. Dr. Kaplan.

DR. KAPLAN: Thank you very much, Dr. Borer, members of the advisory
panel, and guests. It\'s a pleasure to be here today. What I\'m going to
try to do is give you a little overview about what angioedema is and
what are some of the agents and circumstances in which it occurs.

I\'m Professor of Medicine at the Medical University of South Carolina.
I\'m a clinical allergist, so I see angioedema all the time. And my
research for 30 years involves the mechanisms of formation and
destruction of bradykinin, which is directly germane to the drug that we
are discussing today.

Now, angioedema is due to dilatation of small venules in the deep dermis
of the skin. It\'s caused by a variety of vasoactive substances, but the
vessels dilate, leak fluid, and cause swelling. And that\'s the common
denominator of angioedema.

It has a predilection for various sites in the body, the most common of
which are typically the face, particularly where tissues have low
turgor. The most common site is the lip, but it often involves the
eyelids, with periorbital edema, the cheek with an asymmetric swelling
of the face. It can affect the tongue and it can affect the pharynx.
When people have pharyngeal swelling, they will feel as if they are
choking, even though their airway is not compromised. They will have
difficulty swallowing and difficulty eating. On occasion angioedema will
affect lower down and hit the larynx, and particularly we\'re concerned
about vocal chord edema because then you\'re at risk of asphyxiating.
It\'s uncommon but, nevertheless, there\'s a finite percentage who will
have it. Other sites of angioedema are hands, feet, and genitals.

Among the common etiologies that we see of angioedema solo, without
hives and without other manifestations, are a hereditary disease known
as hereditary angioedema because the patients are deficient in a blood
protein known as C1 inhibitor. In the absence of that C1 inhibitor, they
overproduce bradykinin and that has now been proven to be the cause of
the swelling and the hereditary disorder.

Similarly, the most common cause of angioedema that is exogenous ‑‑ that
is, drug induced ‑‑ currently are ACE inhibitors. When you inhibit the
angiotensin-converting enzyme, you not only prevent the conversion of
angiotensin I to angiotensin II, but you\'re inhibiting one of three
enzymes that are involved in the degradation of bradykinin. Therefore,
by inhibiting degradation, bradykinin levels will tend to rise.

I should add that of those three enzymes are ACE, a plasma
carboxypeptidase that is called carboxypeptidase N, and neutral
endopeptidase. This drug inhibits two out the three, and that does
distinguish it from ACE inhibitors because, given that information, the
likelihood of bradykinin levels rising even more than you would see with
an ACE inhibitor is at least theoretically possible and could account
both for efficacy, as well as side effect.

Anaphylaxis and angioedema are different, and the reason I\'ll make a
few particular comments about that is because they\'re often confused,
and when patients present to the emergency room with angioedema, they
often are treated for the other entity.

Angioedema, when it is due, let\'s say, to bradykinin in particular ‑‑
and that is in the hereditary deficiency, in the drug-induced ‑‑
typically evolves over several hours. An average might be 2 to 4 hours.
But particularly severe cases may be more rapid and progress within an
hour or two. We are not, however, talking a few minutes as is the case
with anaphylaxis.

If you have facial swelling, in particular, I want to point out that
patients typically are keenly aware of this even if they\'ve never
experienced it before in their life. A little lip swelling, a little eye
swelling, just a little tongue swelling has people complaining early on.
It\'s important because if we\'re going to talk about education, then
it\'s important to have patient awareness early on to know that
something is going wrong and be prepared for that eventuality.

How do you treat angioedema if it is due to bradykinin? Well, there are
very few things that work and none of them are specific. People are
often given antihistamines. That\'s, of course, worthless. They\'re
given steroids, almost equally worthless, and it takes five hours for
them to work. Epinephrine will work because it\'s nonspecific. It will
constrict the vessels that are leaking and it will retard the angioedema
from continuing. It will not take it away. It is just gradually then
reabsorbed. So, the goal is to stop progression.

It is important also to note that the one that we\'re really worried
about is laryngeal edema because it\'s the only one that causes airway
compromise. I don\'t think I\'ve ever seen a case of laryngeal edema
that occurred solo without some other angioedema manifestation occurring
with it. Usually lip swelling starts it. You may get tongue swelling,
some pharyngeal swelling, and then the person complains of respiratory
distress, first usually hoarseness, and then if it progresses, stridor.

In this last slide, I\'m contrasting anaphylaxis with a drug-induced or
hereditary angioedema, meaning the bradykinin-induced process.
Anaphylaxis can occur in minutes. Infuse somebody with penicillin who\'s
allergic to it, be stung by a bee while you\'re gardening and you\'re
allergic to bee venom, and within a minute or two symptoms can begin,
are often with generalized pruritus, followed by urticaria, angioedema,
and then other manifestations. The patient will also often complain of
like something really bad is about to happen, and we call it an
impending sense of doom, if you will. But angioedema of the sort we\'re
talking about doesn\'t evolve in quite that way.

In addition to the cutaneous manifestations, the key to anaphylaxis is
that you now have cardiovascular manifestations and the hypotension and
shock. That does not occur in the hereditary angioedema, nor does it
occur in the drug-induced swelling.

Anaphylaxis can cause two syndromes, if you will, with regard to
respiratory embarrassment: classical asthma where the person starts to
wheeze and really has difficulty expiring; and laryngeal edema.
Laryngeal edema is theoretically common to both. Bradykinin can do that
solo. You don\'t get asthma in patients with this, but as you know, you
get cough with ACE inhibitors.

To our knowledge, bradykinin is the only mediator of the angioedema that
we are talking about whereas in anaphylaxis you release histamine,
leukotrienes, platelet-activating factor, an array of cytokines, and
just multiple vasoactive factors.

The treatment for anaphylaxis is, of course, epinephrine. Anaphylaxis
tends to rebound. You can have somebody that has anaplylacted, but
they\'re in the emergency room and they\'re making it. You\'ve given
them treatment, they start to feel better. You can be seduced to think
that they\'re okay and stop treatment, and then five hours later, the
syndrome may come back, not quite as bad, but it\'s there. Steroids stop
that which is why it should be given, but it\'s not the first thing that
you do. They also need to receive IV fluids and, of course, IV
antihistamine such as Benadryl which does counteract the histamine.

In the drug-induced, if they receive all of these things, the only one
that does anything is the epinephrine. Therefore, as you\'ll probably
see, many patients that recover, even in an emergency room setting
because they have gone there, who do not receive epinephrine but
received all those other drugs, have spontaneously resolved without any
treatment.

Thank you.

DR. BORER: Does anyone have any questions? Yes.

DR. NISSEN: Given what you said, there\'s an obvious strategy here for
risk limitation that I had wanted to explore with you. If you had a drug
that you knew had the potential to produce this, would it be prudent to
give these patients an Epi-Pen? I know many of my patients who have had
reactions to bee stings and so on carry that around. Could the sponsor
here mitigate against this by giving every patient who is given
omapatrilat an Epi-Pen so that they could self-inject with epinephrine
if they get stridor?

DR. KAPLAN: Number one, of course, it would be a possibility which would
theoretically be helpful and, if you had a reaction, would certainly
tend to stop it.

There you have to balance. Now, the patient population that you\'re
dealing with, if we\'re going to talk about the use of this drug in the
most severe hypertensive who may have heart disease, arrhythmias, and
who knows what else, now having them self-administer epinephrine has
some risk associated with it. You might not want to willy-nilly give it
to everybody, and if you\'re going to do it at all, it\'s either all or
none. Therefore, you\'d have to somehow rationalize how many people
would have the side effect of the epinephrine that was worse than what
was happening to them. Perhaps it would be ‑‑ I\'m just giving you the
counter-argument ‑‑ better to select out those who have the most severe
swelling, get them to the emergency room promptly and let some physician
make a decision as to whether it\'s appropriate to give epinephrine or
not. But I think it is a point well taken, and it is at least one of the
things that could be considered.

DR. NISSEN: Suppose a patient is ‑‑ let\'s say, African Americans who
had, I think, about a 1 in 18 or 1 in 19 chance of developing angioedema
in OCTAVE. Would that be a high enough risk group that you might think
about it?

DR. KAPLAN: Yes.

DR. NISSEN: And smokers again, it was about 1 out of every 27 smokers
got angioedema. That might also be a good target population.

DR. KAPLAN: Yes. And I wouldn\'t argue the point with you. My only
concern would be that I\'m sure among the smokers and the black
hypertensives are people with some of the most complicated other things
that are cardiac that you would have to deal with.

DR. BORER: Let\'s go Tom and then Susanna and then Paul. Tom.

DR. PICKERING: Thank you. I wondered if anything is known about C1
inhibitor deficiency in African Americans as compared with whites.

DR. KAPLAN: A C1 inhibitor deficiency is slightly less statistically of
African Americans than in caucasians. Of course, it\'s rare to start
with. That\'s in the hereditary disorder. There\'s a second form that is
acquired and there the incidence is equal. It relates mainly to
lymphoma. There are some people with lymphoma who express tumor antigens
to which you make antibody. So, you have an immune complex and you
fix-complement, and you can do so in massive fashion. You can fix so
much of the first component of complement that the C1 inhibitor, which
is the inactivator now binds to the activated first component and gets
consumed. If the level of C1 inhibitor drops below 25 percent of normal,
you\'re now at risk for having angioedema. So, the acquired form in
lymphoma is a second type ‑‑ a third, if you will ‑‑ of
bradykinin-induced angioedema, and there the incidence would be
proportional to the incidence of the lymphoma in the population.

DR. CUNNINGHAM: I was wondering what you know about why smokers and
African Americans are at greater risk for angioedema.

DR. KAPLAN: Knowing what I do about bradykinin, I certainly have thought
about it and I could not answer the question. I don\'t know.
Particularly the smokers. There are some data comparing blacks and
whites with regard to end organ responsiveness to bradykinin with some
interesting data that might explain that, at least in part, but there\'s
nothing on smoking.

DR. BORER: Paul and then Doug.

DR. ARMSTRONG: Dr. Kaplan, first of all, thank you for contributing to
my continuing medical education.

I\'m interested in your thoughts about the epidemiology of angioedema in
the general population, especially in the aging general population. I\'m
interested in your comments about the frequency of new onset allergy in
the aging population such as, for example, fish or medicines or pollens,
and the implications of those phenomenon in a patient taking a medicine
that would inhibit bradykinin.

DR. KAPLAN: The incidence of a food allergy goes down in an aging
population and therefore allergic urticaria and angioedema due to a food
allergy is actually lower.

The most common disorder that we see that is not related to a specific
allergen ‑‑ somebody walks into your office and says I\'ve had hives and
swelling for five months. I have no idea what\'s going on. I saw my
internist, and they find nothing wrong with me. That turns out to be an
autoimmune disorder due to, in part, at least in half the people, of a
circulating antibody to the IgE receptor. So, the antibody cross links
the IgE receptor just as if you had an allergen and they have waves of
urticaria and angioedema that can last months to years. That is common
throughout the population in all age groups, but I think in terms of
allergy per se, even though it\'s going up in incidence in our
population, it\'s almost all hayfever and asthma. It\'s not allergic
urticaria or angioedema, and foods, in particular, goes down as we age.

DR. ARMSTRONG: So, a patient who develops late allergy for whatever
reason who\'s taking an agent that inhibits bradykinin is no more likely
to develop angioedema?

DR. KAPLAN: That\'s a tough question, but it has to be focused now only
on an allergen for which angioedema is one of the manifestations. In
other words, if you have hay fever and asthma, it\'s no more or less
likely to be affected by an ACE inhibitor, nor will the allergen cause
angioedema per se just because you\'re on the drug. On the other hand,
if you give me a circumstance in which angioedema might otherwise occur
anyway and you are on an ACE inhibitor, you\'d be more likely to get it,
even though the pathogenesis then would be multifactorial.

DR. ARMSTRONG: Do you think that the exclusion criteria in OCTAVE ‑‑ and
there was some exclusion criteria associated with a history ‑‑ I was
looking for exactly the criteria. I can\'t find them at hand, but what
I\'m trying to get at is how effective the exclusion criteria in OCTAVE
precluded a higher incidence of angioedema in a hypertensive treated
population then would otherwise have been the case, if you follow my
drift.

DR. KAPLAN: I know there\'s no way of predicting, which is ideally what
you\'d like to do, as to who will have angioedema to any of these drugs.
I\'m sure there\'s an explanation. It could be some subtle, genetic
polymorphism in ACE or other things that are involved with bradykinin,
but we just don\'t know. So, I\'m not sure whether I can be more
specific in answering your question. Others involved with the study
might be able to chime in because I\'m not that close to it.

DR. ARMSTRONG: There\'s a statement about any drug-induced rash of any
kind would have been an exclusion criteria in OCTAVE, for example.

DR. LEVY: I\'d like to clarify that because that\'s not correct.
Patients with a history of multiple drug sensitivities with a history of
drug rash to two or more drug classes were excluded with the study, not
patients with a history of a rash to any medication.

DR. ARMSTRONG: Do we know how many patients were excluded for that
reason, Dr. Levy?

DR. LEVY: There\'s no way to know.

DR. KAPLAN: I could comment on that. There is a syndrome not well
understood, a multiple drug hypersensitivity syndrome. A patient comes
in and gives you a list of 10 medications. They get rashes to all of
them. They go from one antibiotic to another, phenobarbital, an
antihypertensive, and it cuts across classes of compounds and so on.
It\'s reasonable in a study to eliminate them because they always come
in and react to something, and you\'re just going to get into trouble.

DR. BORER: Doug.

DR. THROCKMORTON: Just one quick question. The statistical reviewer from
the FDA appropriately pointed out that the number of cases of angioedema
in this data set offers an unparalleled opportunity to look at
angioedema and did some modeling as far as risks and things like that. I
wonder if you could comment ‑‑ and you may be talking about this later,
in which case it can come up later. Is there anything about the
angioedema that you saw in this data set that suggests that it\'s of a
sort that\'s different than the kinds of angioedema that you\'ve been
talking about up to now?

DR. KAPLAN: It\'s a very important question, and the details you\'ll
hear in a few minutes by Dr. Levy. The differences are quantitative but
not qualitative. A severe patient on enalapril looks like a severe
patient on omapatrilat. A mild patient looks like a ‑‑ I could not
qualitatively ‑‑ and as a member of the review group, we tried to
determine who has angioedema, is it drug-related, blah, blah, blah. I
see angioedema due to ACE inhibitors all the time. That I could not
distinguish. So, it\'s not qualitatively different, but it may be
quantitatively different.

DR. BORER: Can I just follow that up? Because I was struck by the model
also in reviewing this and I was going to ask the question later, but I
think you\'re the right guy to ask.

When I looked at that model, my inference was if only we knew how, we
could identify the people at risk. It was a three-group fit that best
fit the curve. I\'m inferring from what you said earlier, that we have
no basis ‑‑

DR. KAPLAN: No marker.

DR. BORER: ‑‑ to identify risk. I don\'t know if any work is going on
within the company to try to do that. I assume there is, but right now
there is no basis. Is that correct?

DR. LEVY: Let me just mention that we\'ve had some ongoing work in that
area, and perhaps once you\'ve seen the safety data, we can share some
of that work with you.

DR. BORER: Tom.

DR. PICKERING: As a follow-up to Dr. Throckmorton\'s question, is there
any suggestion that the rate of progression of symptoms might be
different in the omapatrilat than enalapril patients?

DR. KAPLAN: I don\'t think so. I think that when you see the data, the
number that were considered \"severe\" was greater, but in terms of rate
of progression, they looked exactly like what I\'m used to seeing with
any ACE inhibitor.

DR. BORER: Why don\'t we go ahead then. Thank you very much, Dr. Kaplan.

DR. LEVY: I\'d like to thank Dr. Kaplan for that very interesting
presentation and go on and describe for you in more detail the safety
and particularly the problem of angioedema with omapatrilat.

Because the procedures used to assess angioedema in studies prior to
OCTAVE and in OCTAVE were different, I\'ll describe the findings
separately.

In studies prior to OCTAVE, angioedema was reported using standard
procedures for reporting adverse events. The investigator typically
provided a brief text description of the event which was then assigned a
diagnostic code for the purpose of tabulation. The diagnostic codes were
assigned using a dictionary based on the International Classification of
Disease, or ICD-9. These procedures for reporting and classifying
angioedema, which were identical to those used for the classification of
all other adverse events, introduced certain limitations.

The ICD-9 based coding system assigned potential angioedema events to
several different coding terms, depending on the actual verbatim text
provided by the investigator. The most commonly used terms are
\"angioedema\" and \"head and neck edema.\" And while the term
\"angioedema\" appeared to be quite specific for the event angioedema,
the term \"head and neck edema\" was not specific, and the adverse event
reports themselves didn\'t provide sufficient additional detail to
further assess these potential cases.

The findings of studies conducted prior to OCTAVE are summarized here. A
total of 44 cases of angioedema were reported. An additional 40 cases of
head and neck edema were reported, which may have been angioedema. These
are shown on the right. 4 subjects experienced angioedema with airway
compromise which required mechanical airway protection, and it was these
findings reported in the prior new drug application which prompted the
FDA to ask if the incidence and severity of angioedema were greater with
omapatrilat than that historically reported with ACE inhibitors.

In reviewing these data, we observed that the rate of angioedema
appeared to be lower in subjects who began treatment with a dose of
omapatrilat of less than 20 milligrams compared to those who began
treatment with a dose of 20 milligrams or greater, in this case .45
versus 1.35 percent. Moreover, all four cases in which angioedema
resulted in airway compromise occurred in subjects who began treatment
with a 20 milligram starting dose, shown here. This analysis suggested
that the incidence and severity of angioedema, particularly angioedema
with airway compromise, might be reduced if patients were to begin
therapy with a lower starting dose of omapatrilat.

The four cases of angioedema with airway compromise observed prior to
OCTAVE are summarized here. All occurred in patients who had begun
therapy with a 20 milligram starting dose. Two occurred on the first day
of treatment, one on day 6 and one on day 11. All occurred while
patients were receiving treatment with omapatrilat 20 milligrams prior
to any dose titration. None of these cases presented in a fulminant
manner; however, all required mechanical airway protection prior to
resolution and all patients recovered without residual sequelae.

In the presentation that follows, I\'m going to identify black race and
current smoking as the two major risk factors for angioedema associated
with omapatrilat, and one or both of these risk factors was present in 3
of the 4 subjects who experienced angioedema with airway compromise
prior to OCTAVE.

Based on the observation that the incidence of angioedema appeared to be
lower in patients who had begun therapy with doses of omapatrilat less
than 20 milligrams, OCTAVE was designed in part to determine whether the
incidence and severity of angioedema with omapatrilat could be reduced
to a level comparable to that seen with ACE inhibitors if the starting
dose of omapatrilat were reduced to 10 milligrams. Enalapril was chosen
as a representative ACE inhibitor. And of note, the study wasn\'t
designed to directly compare the incidence of angioedema with
omapatrilat at starting doses of 10 and 20 milligrams.

Because of the difficulty encountered in previous studies in the
accurate classification and counting of potential angioedema events, a
special evaluation process was created for OCTAVE. Investigators were
actively solicited to report all potential angioedema events using a
special case report form page, and then detailed follow-up information
on each potential case was collected on a structured questionnaire to
ensure a consistent and complete database. Potential angioedema cases
were adjudicated by an expert committee without knowledge of treatment
assignment. The analyses that follow are based on cases confirmed as
angioedema by that expert committee.

As you know, angioedema occurred in 274 omapatrilat treated subjects, or
2.17 percent, as compared to 86 enalapril treated subjects, or .68
percent. And the relative risk of angioedema with omapatrilat versus
enalapril was 3.17.

Corresponding to the scientific hypothesis that reduction in the
omapatrilat starting dose would result in a rate of angioedema
comparable to that of enalapril, a statistical hypothesis was
prespecified in which a significant increase in the incidence of
angioedema with omapatrilat relative to enalapril would be excluded if
the upper bound of the 95 percent confidence interval for relative risk
was less than 2. And clearly, this hypothesis was not confirmed, but
nevertheless a fairly precise estimate of the relative risk of
angioedema with omapatrilat relative to enalapril was provided with
reasonably narrow confidence limits.

An important secondary objective of OCTAVE was the assessment of the
severity, as well as the incidence, of angioedema. Because no
established classification systems for angioedema severity existed, a
classification system was created for OCTAVE. Since it\'s not possible
to obtain direct assessment of severity as these events occur, this
system utilized treatment rendered as a proxy for severity.

The assignment of subjects to severity classes was performed by the
event adjudication committee as part of their blinded review of
angioedema cases. In this system, subjects receiving no treatment were
assigned to severity class I, as were subjects treated only with
antihistamines. Subjects treated with corticosteroids or epinephrine but
not hospitalized were assigned to severity class II. Those who were
hospitalized but did not require mechanical airway protection were
assigned to severity class III, while subjects who required mechanical
airway protection or subjects with fatal airway compromise were assigned
to class IV.

It became apparent early in the trial that hospitalized patients were
not consistently more ill than nonhospitalized patients treated with
steroids or epinephrine and that at times patients were hospitalized for
observation or other reasons. As a result, we asked the adjudication
committee to identify patients hospitalized with serious angioedema by
determining if airway compromise was present and assigning patients to
class IIIa or class IIIb accordingly.

As you know, in OCTAVE angioedema ranged in severity from mild and
self-limited to life-threatening. No deaths occurred from angioedema in
OCTAVE. The majority of patients, about 60 percent, who experienced
angioedema with omapatrilat received no treatment or antihistamines only
and were assigned to severity class I. One subject treated with
omapatrilat experienced angioedema with airway compromise requiring
mechanical airway protection and was assigned to severity class IV. A
second omapatrilat treated subject experienced anaphylaxis with
associated angioedema and transient airway compromise which resolved
without mechanical airway protection, and this subject was assigned to
severity class IIIb. No enalapril treated subjects angioedema with
airway compromise. 17 omapatrilat treated patients and 2 enalapril
treated patients were hospitalized for angioedema without airway
compromise.

Analysis of the relationship between severity class and treatment group
showed that patients who developed angioedema on omapatrilat had higher
severity classes indicative of a more intensive treatment pattern than
those on enalapril. And in our review of the clinical manifestations of
angioedema, we found that an appreciable difference between omapatrilat
and enalapril events was the somewhat more frequent occurrence of tongue
swelling and associated symptoms of difficulty speaking or swallowing
with omapatrilat. And the more frequent occurrence of this highly
symptomatic presentation may have led to this more intensive pattern of
treatment.

Of greatest concern, of course, were the cases in which angioedema
resulted in airway compromise. The rates of angioedema with airway
compromise in OCTAVE and in all omapatrilat studies including OCTAVE are
summarized in this slide. In OCTAVE, 2 patients, or 1.6 per 10,000
treated, experienced angioedema with airway compromise. If one places 95
percent confidence intervals around this rate, an upper confidence limit
of 5.7 is seen, suggesting a rate of 6 per 10,000 as a worst case
estimate. If one were to include all cases of airway compromise observed
with omapatrilat, regardless of starting dose, a point estimate for the
rate of angioedema with airway compromise would be 3.2 per 10,000 and
the upper bound of the 95 percent confidence limit 7.0.

Now, it should be noted that the rate of angioedema with airway
compromise observed in OCTAVE with the 10 milligram starting dose was
distinctly different from the rate of angioedema observed in prior
studies with the 20 milligram starting dose. In OCTAVE, angioedema with
airway compromise occurred in about 1 per 6,000 treated. In prior
studies with the 20 milligram starting dose, angioedema occurred in
about 1 in 600 treated.

While not definitive and not a direct comparison, these data do suggest
that the rate of life-threatening angioedema is lower with the 10
milligram starting dose and that the estimate of angioedema risk
obtained from OCTAVE is perhaps the most relevant estimate for
considerations of benefit and risk based on the recommended dosing. But
whether one uses the OCTAVE estimate or the estimate from the entire
clinical development program, the worst case estimate that runs 6 to 7
per 10,000 is not meaningfully different.

The two cases of angioedema with airway compromise that occurred in
OCTAVE are summarized here. The first occurred in a white female who
developed edema of the eyelids, lip, and neck, difficulty speaking and
swallowing, hoarseness, hypotension, and cyanosis within 15 minutes of
the first dose of omapatrilat. This presentation with systemic
manifestations, including cardiovascular collapse, as well as
angioedema, within minutes of exposure to the drug is characteristic of
anaphylaxis and was diagnosed as anaphylaxis by the treating physicians.
No other cases of anaphylaxis have been reported in the omapatrilat
clinical development program. This subject was treated with epinephrine
and recovered promptly. She was admitted to the hospital for observation
and discharged the following day with no complaints.

A second case occurred in a black female during the 10th week of
treatment with omapatrilat. She had been treated with omapatrilat 80
milligrams for about 4 weeks prior to the event without difficulty or
dose interruption. Over a period of several hours, she developed diffuse
and massive swelling of the face and oropharynx, as well as difficulty
speaking and swallowing. She presented to the hospital emergency room
within 2 hours of onset of symptoms and, about 3 hours after symptom
onset, underwent tracheostomy for mechanical airway protection, and
subsequently recovered completely.

Of note, both cases of angioedema with airway compromise in OCTAVE
occurred in subjects with major risk factors for angioedema.

Now, 17 other omapatrilat treated patients and 2 enalapril treated
patients were hospitalized for treatment of angioedema. Upon review by
the adjudication committee, none of these patients were felt to have
airway compromise. As discussed previously, many of these patients had
highly symptomatic and visible presentations of angioedema, including
tongue and lip swelling, and in many cases angioedema was not the sole
consideration in the decision to admit to hospital. None of these
subjects had progression of their symptoms while in the hospital. 14
were discharged after 1 day, and 3 after 2 days in hospital. Thus, while
the number of omapatrilat treated patients hospitalized for angioedema
substantially exceeds the number of enalapril treated patients
hospitalized for angioedema, the level of severity of these cases
appears to be low.

Now, the rate of progression of angioedema, once it begins, is an
important question. One case of anaphylaxis with associated angioedema
was observed in OCTAVE, and this case progressed within a matter of
minutes to a life-threatening condition. In general, as you\'ve heard,
angioedema that occurs outside of the syndrome of anaphylaxis progresses
over hours rather than minutes.

To determine whether the rate of progression of potentially serious
angioedema in OCTAVE with omapatrilat was consistent with that described
for angioedema in other settings, we examined those cases that were
considered serious enough to receive treatment with epinephrine or
corticosteroids. We then characterized the length of time between the
onset of symptoms and the receipt of treatment, and since no treatment
was received during that period, any progression would reflect the
natural course of the episode. Other than the two cases with airway
compromise discussed before, no patient had progression of angioedema to
airway compromise.

And while about 20 percent of angioedema events treated with epinephrine
or corticosteroids occurred in the doctor\'s office and therefore
received immediate or near immediate medical attention, about 80 percent
occurred outside of the physician\'s office. Of these, about two-thirds
were associated with an elapsed time of at least an hour between the
onset of symptoms and the patient\'s arrival at medical facilities,
while in a substantial proportion of patients, more than 6 hours elapsed
between the onset of symptoms and the patient arriving at medical
facilities. The lack of rapid progression to airway compromise during
the period from onset of symptoms to presentation at a medical facility
is consistent with a rate of progression of the underlying disease
measured in hours and not minutes.

A related question is whether angioedema with omapatrilat is
sufficiently symptomatic and characteristic to be recognizable by the
patient and prompt them to seek medical attention. In general,
angioedema that might result in airway compromise is a highly
symptomatic event with visible and diffuse swelling. In OCTAVE, both
patients who presented with angioedema and airway compromise were highly
symptomatic with diffuse visible swelling and a constellation of other
symptoms.

We examined the clinical presentation in all other cases to determine if
there were any patients who presented with angioedema and potential
airway compromise in an occult rather than clinically overt fashion.
Perhaps the most worrisome presentation would be the patient who
presented with nonspecific throat discomfort and no other signs or
symptoms. In OCTAVE there were no patients who presented in this
fashion. Every patient with angioedema had a clinically overt
presentation with visible swelling. Many had accompanying functional
complaints, such as difficulty swallowing or difficulty handling oral
secretions attributable to the swelling, and no patients with angioedema
had nonspecific lower airway complaints such as stridor, dyspnea, or
hoarseness alone.

The time course of angioedema with omapatrilat is illustrated here. The
risk is greatest during the initiation of therapy. 88 cases, about
one-third of all cases, of angioedema with omapatrilat occurred on the
first day of treatment, as opposed to only 3 cases on the first day of
treatment with enalapril. Many of these occurred within 2 hours of
administration of the first dose. Nevertheless, angioedema continued to
occur although at much lower rates through the trial. In the last weeks
of the trial, the rate of angioedema was low with both drugs, though
still about twice with omapatrilat compared to enalapril. Based on the
observed incidence of angioedema in the last weeks of OCTAVE, one might
predict that the rate of angioedema of any degree of severity during
chronic treatment to be about 1 or 1.2 percent per year.

Now, data from studies prior to OCTAVE identified two potential risk
factors for developing angioedema with omapatrilat: black race, which
has also been described as a risk factor for ACE inhibitor-associated
angioedema, and smoking.

An exploratory analysis of the OCTAVE data was performed to determine
the effect of demographic characteristics, comorbidities, treatment
history, and personal habits on the risk of angioedema with omapatrilat.
The results of these analyses are summarized in this figure. On the
left, is the multivariate relative risk of angioedema with omapatrilat
in subjects with the stated characteristic compared to those without
those characteristics. For example, the relative risk for angioedema in
omapatrilat patients who currently smoke is 2.58 times that seen in
patients who never smoke. On the right side is the observed incidence of
angioedema in patients with these stated characteristics.

These analyses confirmed the importance of black race and smoking as
risk factors for developing angioedema with omapatrilat. These two
characteristics were associated with at least a doubling in risk of
angioedema shown here, and the observed incidence of angioedema in these
patients was 5.5 percent in black patients and 3.9 percent in current
smokers.

Several other characteristics shown here, not identified as potential
risk factors in the prior database, were found to be associated with
either modest increases or modest decreases in the risk of angioedema.
Of note, while it was expected that a history of treatment with and
tolerance of ACE inhibitors might be associated with decreased risk of
angioedema, this was not observed.

In sum, through an extensive clinical development program, the safety of
omapatrilat has been very well characterized. This program has
identified an incremental risk of angioedema relative to ACE inhibitor
treatment which must be weighed against the potential benefit of greater
blood pressure reduction.

With omapatrilat, as in other clinical settings, angioedema has a wide
spectrum of severity. Current smokers and black patients have been shown
to have a substantially higher risk.

In OCTAVE, the rate of life-threatening angioedema was 1.6 per 10,000
patients treated, and the upper bound of the 95 percent confidence
interval for this estimate was about 6 per 10,000.

With omapatrilat, as in other clinical settings, angioedema was a
symptomatic event with a characteristic presentation. In those with
severe symptoms, the rate of progression was rapid but not fulminant,
and all patients who developed angioedema with omapatrilat were
successfully treated.

Bristol-Myers Squibb has proposed a risk management plan for omapatrilat
that would minimize the risk of life-threatening angioedema through a
comprehensive system of education. As I\'ve noted, angioedema is a
condition with clinical features which facilitate its management through
education. It has a symptomatic and recognizable clinical presentation,
rapid but not fulminant progression, and effective therapy can help to
prevent poor outcomes.

The objective of the plan is to ensure a favorable benefit-risk ratio
for patients taking omapatrilat. The cornerstone of the plan is a
multifaceted and comprehensive program of education for prescribers,
pharmacists, and patients. The approved labeling and other educational
modalities will be used to educate physicians about the appropriate use
of omapatrilat. Unit-of-use packaging will reinforce key risk messages,
and the plan includes a novel and mandatory risk counseling program for
patients.

A post-marketing surveillance plan would include a prospective
observational cohort study and a plan for ongoing assessment of program
effectiveness, including the use of an expert panel. We\'re also
committed to providing extensive pre- and post-marketing testing of risk
message comprehension and are confident that the proposed plan would be
effective in minimizing the risk of life-threatening angioedema.

At this point, I\'d like to make a few comments on benefit-risk. In
general, the target population proposed for this drug would include
those identified by the WHO IHS classification system as being at very
high risk for cardiovascular disease or at high risk for cardiovascular
disease, with an absolute risk of major cardiovascular events of at
least 2 to 3 percent per annum and perhaps higher.

In these patients, a greater reduction in blood pressure by 3 over 2
millimeters of mercury, such as that observed with omapatrilat relative
to enalapril in OCTAVE, would be projected to be associated with a 10
percent relative risk reduction, which would correlate to the reduction
of 20 to 30 major cardiovascular events per 10,000 treated per year. A
greater reduction in blood pressure by 5 over 3 millimeters of mercury,
such as that observed with omapatrilat over other agents in other
studies would be associated with at least a 15 percent relative risk
reduction, which correlates to a reduction in 30 to 45 major
cardiovascular events per 10,000 patients treated per year. As I\'ve
described, the observed incidence of angioedema with airway compromise
over 24 weeks in OCTAVE was 1.6 per 10,000, with a 95 percent confidence
interval of 0.2 to 5.7.

Now, these observations suggest that at those at high or very high
cardiovascular risk, the projected number of life-threatening
cardiovascular events prevented would substantially exceed the number of
life-threatening angioedema events caused by at least an order of
magnitude and perhaps more. If one takes the worst case estimate, the
upper bound of the 95 percent confidence interval, as the basis for
comparison, the benefit-risk relationship is still favorable.

Special consideration needs to be given to black patients and to current
smokers as the overall risk of angioedema is higher in these patients.
While BMS recognizes the increased risk in these patients and recommends
that omapatrilat be used with special caution, we believe that carefully
selected black patients and current smokers may benefit from omapatrilat
treatment.

To conclude, in patients at high risk for cardiovascular events, the
number of major cardiovascular events prevented would be projected to
exceed the number of life-threatening angioedema events caused by at
least an order of magnitude and possibly much more.

Now, when projecting cardiovascular benefit based on blood pressure
reduction, there may be a concern about any unintended cardiovascular
consequences of the therapy which could undermine or diminish the
benefit. In this regard, I\'d like to introduce Dr. Packer to review
available CV event data with omapatrilat.

DR. BORER: Let\'s hold that just for a second, if we can. First of all,
we\'re going to want to ask you some questions before we hear from
Milton about heart failure. But it is 10:13 and 32 seconds, not by the
satellite, and we\'ll take a break until 10:25 right now and then come
back, ask you some questions, and then we\'ll go on with the
presentation.

DR. LEVY: Thank you.

(Recess.)

DR. BORER: Before we begin the questions, there are two issues we need
to deal with. There were no requests for public comment, but I want to
determine that there is no one here who wants to comment about the
issues that we\'re discussing today.

(No response.)

DR. BORER: If not, one other matter. The statement about Dr. Beverly
Lorell\'s involvement and the reason for her exclusion wasn\'t really
precisely stated. She is one of the principal investigators in the
OVERTURE trial. She has no direct financial interest. For reasons of
public disclosure, I think it\'s useful to know that.

Let\'s go on then with questions about safety. I\'d like to begin with a
request for clarification on two slides, and then we can get into more
substantive safety issues.

Slide number 43. The issue here is that the female patient is listed as
having become hypotensive. Can you give us a little bit of detail here?
How hypotensive? Was this a clinically evident problem or did somebody
measure a low blood pressure and record the patient as being
hypotensive? What happened there?

DR. LEVY: She lost consciousness and didn\'t have a measurable blood
pressure, and with an initial epinephrine injection, she regained
consciousness. She received a second subcutaneous epinephrine injection,
and over about 3 to 5 minutes, she regained a blood pressure of 110.

DR. BORER: This was not presumably ‑‑ or was it ‑‑ one of the patients
who would have been your high-risk groups that\'s being targeted for the
drug in the proposed labeling, or in your proposal I mean.

DR. LEVY: No, she wouldn\'t have been.

DR. BORER: Just for my information, were there other patients who
developed hypotension or lost consciousness with the drug?

DR. LEVY: The rate of hypotension was extremely low with the drug. It
was on the order of a 10th of a percent of all patients.

DR. BORER: And how did that compare with the comparator?

DR. LEVY: They were very similar.

DR. BORER: And then a comment more than a question. The risk factors
that you defined in your last slide included seasonal allergies. Now,
that\'s not overwhelmingly surprising, but a little surprising in view
of the information that Dr. Kaplan gave us. I don\'t expect that you
could possibly have an explanation for it, but it suggests that the
biology we\'re dealing with here is more complex than perhaps we fully
understand at this point. Is there any comment you want to make about ‑‑

DR. LEVY: Can I have that slide again?

DR. BORER: And perhaps Dr. Kaplan wants to comment on it.

DR. LEVY: As I mentioned, there was a prior hypothesis, a relatively
strong one, regarding black race based on both our experience and ‑‑

DR. BORER: I\'m specifically talking about seasonal allergies.

DR. LEVY: Right, I understand. My point is that there was no prior
hypothesis for seasonal allergies, nor was there a reason to believe
that this would be identified as a risk factor. We looked at a wide
variety of characteristics and showed these modest changes, increases or
decreases, in risk in some. The information that\'s reported here makes
no attempt to correct for multiplicity of analyses. The confidence
intervals are nominal, 95 percent confidence intervals. And in the
absence of some pathophysiologic rationale or prior hypothesis, this
should really be regarded as hypothesis-generating.

I\'ll ask Dr. Kaplan to comment on it, if he would.

DR. KAPLAN: I think in terms of the issues there in terms of where the
relative risk was higher or lower, I don\'t think I could have predicted
any one of them in particular. The incidence, if you look at the
seasonal allergies, was a little bit higher, but I don\'t know I could
have related the two or necessarily predicted that the risk would be
somewhat higher.

Female gender. The incidence of angioedema, irrespective of cause, is
higher in women. That might be consistent with it.

Nor could I tell you why somebody with diabetes or atherosclerosis would
have lesser risk. So, I can\'t help much with the way those data came
out in terms of what we know or what we could have predicted.

The only possible one would be in terms of blacks perhaps having more
risk for angioedema. The only data related to that is responsiveness to
intradermal bradykinin seems to be heightened blacks. Therefore, they
may have end organ responsiveness that\'s a little bit higher than
caucasians, and that would predispose to more angioedema.

DR. BORER: Thank you.

Tom, do you have any specific safety issues before we go on to Susanna
and to Steve?

DR. PICKERING: Well, there are some questions I\'d like to ask relating
to the generalizability of the findings and the OCTAVE design.

I wonder if you could tell us a bit more about how the centers were
selected. I believe there was something about being close to a major
medical center.

Also, were any of the episodes occurring during the first 2 hours while
the patient was still in the hospital setting? And finally, what
information was given to the patients about the risks and symptoms that
they might expect?

DR. LEVY: Well, those are very good questions. The first question
regarding selection of study centers, this is an enormous trial with
3,300 centers in 12 countries. They represent both experienced clinical
trialists as well as physicians skilled in the treatment of
hypertension, but without prior experience in clinical trials. The issue
you\'ve just cited, in prequalifying we did require that they be within
1 hour of a medical facility with resuscitation equipment.

Your last question, if I could ask you to restate it.

DR. PICKERING: What information were the patients given about expected
symptoms or side effects?

DR. LEVY: Patients were provided with a detailed informed consent, and
that informed consent described the phenomenon of angioedema, swelling
of the anatomic sites, provided rather detailed information about the
quantitative risk of angioedema, as it was known at the time so they
could evaluate the risk of study participation, and concluded with a
sentence instructing them to seek medical attention should it occur.
It\'s very consistent with what\'s done in trials. We propose in our
risk management program a level of patient education that goes very far
beyond that.

DR. PICKERING: The third part of the question was relating to episodes
during the first 2 hours after the dose.

DR. LEVY: Yes. As I showed you, a total of 88 episodes occurred on the
first day of treatment. 56 of those occurred within 2 hours of
administration of the first dose.

DR. BORER: Susanna.

DR. CUNNINGHAM: You\'ve defined the target population that you
anticipate using this drug in. I want to know what percentage of that
target population is African American, what percent are current smokers,
have renal disease, seasonal allergies, et cetera. So, what\'s the risk
profile going to look like in your defined high risk population?

DR. LEVY: I can certainly refer you to the trial data. Those are
excellent questions.

For instance, overall, 10 percent of subjects in the study were black,
13 percent of those with diabetes were black. So, there is some
association, but overall, the vast majority of patients with diabetes
who would be candidates for the drug are not black.

Prevalence of smoking overall in the study was about 18 percent, and it
was fairly consistent across all study subgroups, including those that
we\'ve identified as potential target populations for the drug.

So, I guess the short answer is that blacks would probably be
represented somewhere between 10 to 13 percent in the potential target
population, perhaps a little bit greater than their overall prevalence
in the population, and smoking probably around 18 percent.

DR. CUNNINGHAM: And how about those other potential new risk factors
that we don\'t know for sure about, the other ones, the seasonal
allergies, the former smokers?

DR. LEVY: The population is 51 percent women; former smokers, maybe
another 20 percent. Again, those are characteristics that are, at this
point, hypothesis-generating associated with small differences in risk.

DR. BORER: Blase.

DR. CARABELLO: You indicated the proportion of patients that developed
angioedema at which dose and that it was much higher at 20 milligrams
than at 10. But of the patients that developed angioedema, how many did
not have it at lower doses and then subsequently developed it as the
dose was up-titrated?

DR. LEVY: Well, it\'s a great question, general question about the dose
relationship of angioedema. This study, of course, was not designed to
really characterize the relationship of incidence to dose. You\'d need a
true parallel group study to do that, in which patients started off at
each dose and were titrated upwards, so you didn\'t filter people.

What we saw is that over time the incidence of angioedema decreased
despite the up-titration of patients to higher levels of drug. But there
were a significant proportions of patients who did develop angioedema on
80 milligrams, having tolerated 10, 20, 40 milligrams.

DR. BORER: Steve.

DR. NISSEN: I want to explore one of the principal hypotheses of the
trial which was that by starting at a low dose and then gradually
working our way up, that we could avoid the more catastrophic problems.
It\'s difficult to answer that question obviously because the way that
the angioedema was adjudicated is different in the two trials, but help
me a little bit, if you will.

The raw rate of angioedema in percent in the pre-OCTAVE trials I have at
about 1.96 percent. Do you agree with that? It looks like angioedema
1.03 and then head and neck edema, another .93. So, your slide number 36
would suggest that the rate of was around 1.96 percent pre-OCTAVE. Is
that right?

DR. LEVY: Well, we didn\'t know exactly what it was pre-OCTAVE because
not all those head and neck edema cases were angioedema, and conversely,
there might have been other events that were called allergic reactions
that were angioedema. But to the best of our knowledge, that\'s a
reasonable, very rough estimate.

DR. NISSEN: Do you think that\'s a high estimate?

DR. LEVY: If we knew exactly what the incidence was before OCTAVE, we
wouldn\'t have done OCTAVE. I think it\'s a reasonable rough estimate.

DR. NISSEN: All right.

And then in OCTAVE, the rate was 2.17 percent. So, again, obviously
there\'s an issue here, but it looks to me like the actual incidence,
about 1 in 50 patients pre-OCTAVE had angioedema and about 1 in 50
patients in OCTAVE had angioedema. So, it looks like the strategy of
starting low and working up may not have been effective. Is that a
reasonable assumption?

DR. LEVY: I think that\'s quite possible. Just bear in mind that the
study wasn\'t designed to compare 10 and 20 milligram doses. There\'s an
enormous difference in the way in which physicians were solicited to
provide angioedema reports in OCTAVE. We know from other trials, like
the SOLVD trial, what when you ask physicians to report this event, the
reporting rate goes up dramatically.

DR. NISSEN: Yes. The reason I think it\'s relevant is that there was a
difference in the number of very severe cases pre-OCTAVE and in OCTAVE.
But because those numbers are so small, the confidence intervals are
quite wide. So, I wanted to go back and look just at the raw rates of
any angioedema to get a sense for whether the strategy of starting low
would be protective or not. To me, there doesn\'t look like there\'s any
evidence that that strategy is going to work in protecting patients, at
least not from what we can see in the data.

Now, just before we broke, you said that you thought that this drug
would be acceptable in smokers and blacks. The word you used is you said
in \"selected\" smokers and blacks. What I guess I would like to know is
how are we to select those people. The incidence was about 1 in 18 or 1
in 19 in blacks. So, what criteria should I use to select those African
American patients that can successfully be given omapatrilat?

DR. LEVY: They would be patients with very high cardiovascular risk and
hypertension that can\'t be controlled with existing medications.

DR. NISSEN: But that\'s the same criteria you told us for the rest of
the population. So, you\'d apply the same criteria to the African
Americans that you would to the non-African Americans.

DR. LEVY: The same principles, but one might set the bar higher.

DR. NISSEN: All right, fair enough.

Now, I guess I had a question for Mike Weber because you obviously spend
your life treating this, and I know you deal with this. The issue
relates to compliance in a clinical trial versus compliance in practice.
In the great State or country of Brooklyn ‑‑

(Laughter.)

DR. NISSEN: ‑‑ what are compliance rates like?

DR. BORER: Tread lightly there.

(Laughter.)

DR. NISSEN: As we know from those who live in the great State of
Manhattan.

(Laughter.)

DR. NISSEN: But what are compliance rates like among populations with
severe hypertension in your setting?

DR. WEBER: Well, as you know, Steve, the largest population group by far
in our setting happens to be African American or Caribbean American.
They do actually extraordinarily well with hypertension treatment
because the African American community is, in fact, highly educated
about hypertension and takes it very seriously. In fact, even if you
look at NHANES data, there is a suggestion that blacks overall have very
comparable adherence to treatment as compared with non-blacks.

So, I would say compliance is good. Now, what do I mean by good? I would
say that about 50 percent of patients who start on a medication are
still taking it about 6 months later or taking some sort of appropriate
treatment 6 months later.

DR. NISSEN: How frequently, in your experience, do patients miss a few
doses, skip a weekend, go off somewhere, and stop the medication, and
then restart it again?

DR. WEBER: I would say about 70-75 percent of hypertensive patients make
those sorts of errors or omissions.

DR. NISSEN: The reason I get to that is because I\'m worried about a
risk here, and the risk is you\'ve titrated somebody up to 80 milligrams
of omapatrilat. They take a long weekend with their spouse somewhere and
they forget to take their medicines with them. They\'ve been off the
drug for three or four days. They come back home and they restart it.
I\'m trying to assess what the risk is going to be in clinical practice
compared to the risk in a clinical trial. So, I need your thoughts about
that.

DR. WEBER: Well, it is going to happen and it does happen all the time
in clinical trials as well as in regular clinical practice. So, we do
know that starting almost de novo on an extraordinarily high dose of a
treatment, omapatrilat or anything else, is happening all the time,
presumably with relatively little side effects or adverse effects that
we are aware of.

We had quite a few people in the early omapatrilat experience who, in
fact, did start directly on higher doses or were accelerated quite
quickly to higher doses in the parallel group studies, and to the best
of my knowledge, with the exception of some people who had some
hypotension ‑‑ and there were not many of those ‑‑ in fact, it was
pretty well tolerated.

DR. NISSEN: But you made the case that the incidence of those severe
cases was worse in the pre-OCTAVE experience, and the suggestion is here
that we can prevent those. I guess I\'m worried here that in the general
population where people start and stop drug, that the risk of somebody
being off the drug for a few days and then going back to an 80 milligram
dose might be pretty significant over a period of years. See, the
question is whether the risk of angioedema is going to tail off with
time and kind of get vanishingly small or whether we\'re going to see
year after year an ongoing risk of this. And that relates to whether
intermittent therapy is likely I think.

DR. WEBER: I don\'t think there\'s an answer to that question, Steve.

DR. LEVY: I might just provide a few facts from the trial that you might
find helpful. We did ask patients at each visit if they had been
compliant with medications. Compliance was defined essentially as taking
at least two-thirds of their prescribed medication from the previous
visit, and at each visit about 3 percent of patients admitted that they
hadn\'t been compliant, which is a small number, but it\'s still 300 to
400 patients at each visit on omapatrilat who admitted they had missed
at least a third of their medication from the previous visit.

We very carefully characterized dose interruptions in subjects who
developed angioedema, and we found 3 subjects who developed what was
essentially mild angioedema following a period of dose interruption. So,
there certainly is no signal that there\'s an increased risk in patients
who take their drug intermittently.

DR. NISSEN: The reason I ask is one of your really bad cases was a
patient that missed a dose. One of your severe cases of angioedema in
the database that I reviewed, the patient took a dose about 8 hours late
and immediately got into trouble. I can refer you to that.

DR. LEVY: No. That is the subject in OCTAVE. She typically took her dose
at 8:00 in the morning. She reported she took it at 4:00 that afternoon
instead. I think given the half-life of the drug, 14 to 19 hours, it
would be difficult to link those two.

DR. NISSEN: A second question I guess relates to how to assess the risk
in general use. I\'m sure many other members of the panel have the same
concern, that when you administer a drug in a clinical trial, there\'s a
certain kind of a protected environment that\'s involved. You know, you
strictly mandate that the patients stay for 2 hours after every dose
titration. The physicians know they have to look for this side effect.
They\'ve been educated at an investigator meeting. There\'s a lot of
stuff that goes on.

What I worry about is what happens in Sioux Falls, South Dakota when a
patient kind of goes in a rural office where it\'s a much less protected
environment. Because once you let a drug out of a clinical trial
environment, you\'re less protected.

Given the fact that this is a pretty serious side effect, my worry is
that patients won\'t make it in time or won\'t be recognized in time
because they\'re not going to be as protected as they would be in a
clinical trial. I\'d appreciate any insight about what kind of a risk
that represents here.

DR. LEVY: Maybe I can just make a comment on it. It\'s an excellent
question. One of the reasons why we did a 25,000-patient trial at 3,300
sites in 12 countries was to provide as much information as possible
about how the drug would be used and what the results would be in
real-life practice. Of course, there were many clinics in places like
Sioux Falls, South Dakota, very remote locations in Russia, all over the
world.

It\'s also worth pointing out that by and large, when patients
experienced angioedema, they sought medical attention at a facility
other than the investigator\'s office. So, the question is whether those
facilities in a small town can provide epinephrine and, if necessary, in
the rare cases mechanical airway protection.

DR. NISSEN: I guess the final comment ‑‑ and perhaps it\'s a rhetorical
one ‑‑ is on page 114 of your document, you say that treatment of
life-threatening angioedema does not require specialized training.
Angioedema associated with omapatrilat is managed in the same fashion as
angioedema due to any other cause. Treatment of serious allergic
reactions is a core skill for physicians and nurses, and airway
protection is a routine procedure for emergency personnel, et cetera.

Well, one of the things that was most troubling, in reading the case
narratives, is that 3 of the 6 patients required cricothyroidotomy.
Other than my friend here, Blase Carabello, who does everything well, I
would doubt if any of us on this panel with a Bic pen ‑‑ I mean, I\'m
glad to hear that Dr. Temple is skilled in this.

(Laughter.)

DR. NISSEN: But I\'m standing in the shoes of being somewhere and giving
the drug and having a patient get laryngeal edema. And those 3 patients
could not be intubated. So, somebody that was skilled enough to take a
scalpel and pierce the cricothyroid membrane was necessary to save the
life of the patient. So, to say that this is a core skill I think is to
trivialize the problem. I guess I would like your comment, but 3 of the
6 serious cases had to have a cricothyroidotomy in order to protect
their airway.

DR. LEVY: Perhaps one of the clinicians on the panel would care to speak
to that.

DR. NISSEN: Mike Weber, do you do these cricothyroidotomies?

(Laughter.)

DR. WEBER: Well, I have done them in rabbits.

(Laughter.)

DR. WEBER: I\'m working my way up to humans.

But no, this clearly is an issue. I think the most important thing I can
say about it is what Dr. Kaplan and Elliott have also pointed out, that
fortunately these cases do not suddenly announce themselves as sudden
respiratory embarrassment. There is a fairly long prodrome. So, as long
as the patient knows that they ought to be going to an emergency room,
hopefully that will allow us to deal with those patients. But if you can
ask for some sort of a guarantee that there would be a 100 percent
system to get absolutely everyone taking an ACE inhibitor who\'s going
to have angioedema, I guess we can\'t guarantee that. But luckily, we do
seem to have those several hours for the patient, as long as they know
that they ought be doing it, to get to the emergency room.

DR. NISSEN: I\'m going to, Jeff, hold further questions. I did have some
further questions on the risk management program, but I thought it would
be better not to do those now because, obviously, there\'s an issue
about how do you manage the risk here.

DR. PACKER: Jeff, I just wanted to comment one thing about the need for
a cricothyroidotomy. I actually have done a couple, having trained in a
city hospital, but it has been a while.

I just wanted to emphasize that the core message, I think, which needs
to be conveyed to physicians is the importance of epinephrine because
epinephrine is the most effective treatment to prevent progression of
this disease. Antihistamines don\'t work and steroids work but they work
too late to have an impact on progression. And what is striking is the
fact that in so many cases the use of epinephrine was delayed. In all
the cases you\'re talking about, epi wasn\'t even given or epinephrine
was delayed. I think part of the educational program is to remind
physicians as to what really is the appropriate treatment for a serious
and potentially life-threatening angioedema.

DR. BORER: I think that\'s a very important point. The only problem is,
as Dr. Kaplan pointed out, if the drug is actually given to the people
that you\'re targeting, there\'s going to have to be more known than
that you give epinephrine. There\'s going to have to be something known
about how you deal with the problems that may develop when you give
epinephrine to that target population. So, it\'s a somewhat more
complicated problem.

DR. PACKER: But we\'re talking about what might be called a risk-benefit
relationship. You\'re not giving epi to everybody. You\'re only giving
epi to people in whom the risk-benefit relationship is favorable.
Someone who is going to die from angioedema ‑‑ the risk-to-benefit
relationship is extremely favorable.

DR. BORER: Right. I\'m not suggesting you wouldn\'t give epinephrine.
I\'m suggesting that you have to know how to do more than give
epinephrine. You have to be able to deal with the consequences of it.

DR. NISSEN: It\'s a little more complicated also. Let me just tell you
that you have an educational program. You educate people like me that
treat hypertension on the importance of epinephrine. But the patient
goes to an emergency department somewhere where there\'s not been any
omapatrilat education given, and that doctor there has to know that the
first thing you\'ve got to do is give epi to the patient, not steroids
or something else. I question. Because so many of these patients were
treated elsewhere for their angioedema, the ability to educate people
about this is challenging.

DR. PACKER: See, the patient and the patient\'s family play such an
important role here because they can have a card that says I\'m at risk
of angioedema or whatever. This is the appropriate treatment.

DR. BORER: Paul.

DR. ARMSTRONG: I have a couple of questions for Dr. Levy and perhaps for
Dr. Kaplan.

Dr. Levy, I may have missed it, but if you look at the 95 percent
confidence limits on the estimates of angioedema in the 10 milligram
versus the higher dose, do they overlap? You showed that there was a
difference in the frequency, but I didn\'t see the confidence estimates
around those.

DR. LEVY: Again, we\'ve not directly compared the incidence. We didn\'t
intend to. We provided two estimates of risk.

DR. ARMSTRONG: The second question is that you reminded us that this was
a trial of international scope and very large. As someone who\'s had the
experience of doing some of these trials, one of the things that one
finds amongst events that are of fairly low frequency is that there\'s
sometimes a difference in the surveillance detection when it\'s left to
physicians who are participating. We\'ve been finding, for example, that
things like bleeding detected in Russia are less frequent with the same
exposure and have hypothesized that that might lead to a better
understanding of how different countries survey these phenomenon. So,
with that background, what is the difference in the frequency of
angioedema across the countries which participated in this
25,000-patient trial?

DR. LEVY: We looked at the incidence of angioedema by region comparing
North America with Europe, which is where almost all the other patients
were treated. And the incidence of angioedema was a little bit lower in
Europe than in North America, as you\'d expect, since there are
essentially no patients of African descent in Europe.

DR. ARMSTRONG: And in Russia?

DR. LEVY: We didn\'t look at it by country.

DR. ARMSTRONG: Perhaps you or Dr. Kaplan can help me then. You\'ve
identified that Afro-Americans have a higher frequency. Do other ethnic
groups also have a higher frequency of angioedema if one looks at
Southeast Asians or Chinese or Japanese? What do we know from the ACE
inhibitor data and other data vis-a-vis ethnicity and angioedema?

DR. LEVY: We\'re not aware of any other described ethnic associations,
and there aren\'t sufficient data in OCTAVE to look at that question.

DR. ARMSTRONG: Dr. Kaplan, when you inject bradykinin subcutaneously to
other ethnic groups, what do you find? You commented on that being a
detection ‑‑

DR. KAPLAN: Yes, but it hasn\'t been done. That study was strictly
Afro-Americans versus whites. I think the answer to your question, like
people in Southeast Asia or Japanese or so on, has not really been
looked at. There are just no data on that in terms of the incidence of
angioedema. I know of nothing to suggest that it\'s accentuated in some
way, but there\'s basically no data on it.

I\'d like to make a comment with regard to when angioedema occurs
because we mentioned that there was no way we could predict. There\'s no
test. There\'s no way you could tell who was at risk. I\'m going to make
a statement that\'s really just theoretical, but just think about it a
little bit because part of it has a certain randomness to it. It would
be logical that if you take more, that you might see more angioedema,
but that doesn\'t necessarily hold uniformly.

I have seen patients on ACE inhibitors who had a few multiple episodes,
say, of facial angioedema and it was not recognized that it was due to
their ACE inhibitor. And they come to me, now taking it for 3 months
more, and they haven\'t had a swelling. When they come in, once I see
that there\'s no other available cause, I immediately stop the drug. So,
there\'s something that we truly don\'t understand about when the
angioedema occurs.

I\'ll tell you what I think is going on, but it\'s right out of my head,
and that is obviously it\'s got to relate in some way to bradykinin
levels, which has to do with the rate of formation versus the rate of
degradation. If you\'re taking a drug and you\'ve reached a reasonable
steady state, there\'s no question on an ACE inhibitor that you get some
elevation of the kinin level. But if you\'re measure blood levels,
they\'re a little bit up but you\'re not struck that it\'s tremendously
high. I\'m suspicious that when the angioedema occurs, something that is
not yet identified is occurring to the person that produces bradykinin.
They have a cold. They have an infection. They fell. They bumped their
hip against the corner of their table, something of that sort. Then it
doesn\'t take much to have levels soar sky-high.

And let me emphasize the lability of it. If I measure a blood
bradykinin, just put a tourniquet on, stick the needle in, versus do the
same procedure, get the needle in, remove the tourniquet, take 10 mls of
blood and throw it in the garbage, and measure the bradykinin in the
11th ml, the difference between those two is 50-fold in bradykinin
level, just from the needle stick and a little pressure. So, it\'s
exquisitely labile.

So, I have a hunch that there are unknowns here that relate to when the
actual attack of angioedema occurs, and that\'s why it has such a random
feel.

DR. ARMSTRONG: If I may, Mr. Chairman, with Dr. Kaplan, I\'m sure one of
the easiest places to develop consensus today will be what\'s not known.
But as we pursue this, can you just again help me with the epidemiology
of angioedema that\'s not drug-related, that\'s spontaneous as it
relates to age? With several hundreds of thousands of patients treated
with ACE inhibitors, is the distribution by age any different with
patients on ACE inhibitors than it is spontaneously, sir?

And when you explore co-factors or factors that you believe produce
bradykinin and then engender an episode of angioedema, do you reckon
that those co-factors are any different in patients on ACE inhibitors as
opposed to other agents and, by inference, with the drug that we\'re
discussing today?

DR. KAPLAN: To my knowledge, the angioedema that one would see with an
ACE inhibitor is not going to vary particularly, let\'s say, between the
ages of 20 and 80. I don\'t think anyone has looked at it in terms of
age groups but I don\'t think it would be dramatically different. The
most common form of angioedema that we see, regardless of etiology, is
that autoimmune one that I mentioned to you. It persists for a long
time. It\'s recurrent. It\'s like there all the time, and it\'s often
associated with hives. First of all, it\'s two-thirds women and
one-third men. So, it\'s skewed by sex. And the peak is between 20 and
40, and it\'s at both tails. As you get older and in youngsters, it\'s
quite a bit less. I\'m positive that although I don\'t know the details,
that the ACE inhibitor situation would not parallel that. My best
estimate is that it would be fairly level among age groups.

DR. BORER: We have a question from Mike and then a comment from Doug.

DR. ARTMAN: This may be more theoretical and perhaps Dr. Kaplan might be
the one best to address it, but I\'m just wondering if these risk
factors for angioedema are additive. In other words, if you\'re a black
female, smoker with renal disease and seasonal allergies, is your
relative risk up to 10 to something?

DR. LEVY: No. The answer is no. The two major risk factors identified
were black race and current smoking. You put them together and the
incidence of angioedema is identical to that you see in blacks. It\'s
5.6 percent.

DR. THROCKMORTON: And yet, Elliott, the timing of those angioedema
events for those two particular populations was quite different, as I
recall. Could you show those two curves? The time to angioedema events
for blacks and for smokers.

DR. LEVY: Yes.

DR. THROCKMORTON: Because those seemed very different. Again, going to
the question of are all risk factors equal and are we talking about a
single angioedema thing or are there different kinds of angioedema.

DR. LEVY: They\'re certainly not additive. There is a difference in the
time to onset of angioedema amongst blacks and current smokers. In
current smokers, the risk is greatest at the initiation of therapy.
There were 45 cases in smokers on the first day of therapy, and then the
rate declined fairly dramatically to a level that was near that seen in
other patients.

In blacks, on the other hand, the risk was not dramatically greater on
the first day of therapy than it was in whites, but it remained at a
higher level for a longer time and the risk decayed more slowly.

So, there is a difference in the time course of angioedema in patients
with each of those risk factors.

DR. CUNNINGHAM: Yes. You got me to wondering. What are the risk factors
for angioedema in the group that was on enalapril. Are they the same?

DR. LEVY: The risk factors were quite similar with the exception of
current smoking which did not appear to be a risk factor for enalapril
associated angioedema.

DR. CUNNINGHAM: Because one of our questions is whether or not the two
are the same, and if they have different risk factors, that makes you
wonder.

DR. LEVY: It\'s a little hard to look at the enalapril group because of
the relatively small number of events. The profile is quite similar with
that one exception.

DR. BORER: Tom and then Steve.

DR. PICKERING: Yes. I\'d like to pursue the question of the definition
of black a little further. In this country it usually refers to African
American, but I practice in northern Manhattan and a lot of patients
look black to me but define themselves as Latino or Hispanic. And the
distribution of risk factors is not necessarily the same as in African
Americans. Can you tell us what the definition was and also how many of
the blacks were U.S. African Americans as opposed to some other
dark-skinned group?

DR. LEVY: Well, they\'re almost all U.S. The investigators were provided
with one of four categories and simply asked the subjects to identify
which of the four they belonged to. They were white, black, Asian
Pacific, and other. So, it\'s not possible to tell you where the black
subjects came from, whether they were Afro-Caribbean or of Spanish
descent.

DR. BORER: Steve.

DR. NISSEN: None of us has asked you about cough, and obviously cough is
an ACE inhibitor side effect that I think we believe is bradykinin
related. Was there a difference in incidence of cough across all your
trials in ACE inhibitors and omapatrilat?

DR. LEVY: No. They\'re pretty much spot-on, identical.

DR. NISSEN: Can anybody give me an explanation for that? It seems
surprising.

DR. KAPLAN: The data on cough are not as good as the data on angioedema
in terms of relating a kinin level to the actual event. Most people
think that it is related to bradykinin, however.

DR. PACKER: I think that from the understanding that I have, there may
be multiple mediators of cough. Bradykinin may be one. Substance P, a
whole host of other factors have been implicated. So, I think it\'s
probably much more multifactorial, which is why we\'re not seeing a
signal here.

DR. THROCKMORTON: Steve, if you\'re interested, the incidence of cough
was looked at by Dr. Pelayo in the original safety review, and that\'s
on page 23 of his tab, which I guess is tab 4. As they said, the numbers
are fairly small, but there does seem to be an ordering where the
majority of the events were in the omapatrilat group and not placebo.

DR. NISSEN: Statistically speaking, there\'s no difference?

DR. THROCKMORTON: It\'s 2.1 percent versus 0.3 percent. It was a safety
analysis. So, we wouldn\'t have normally don\'t statistical.

DR. NISSEN: I see, okay.

DR. LEVY: I\'m sorry. I couldn\'t hear that data. Could you repeat that?

DR. THROCKMORTON: It\'s page 23 of Dr. Pelayo\'s. This is comparing
against placebo. Is that what you were interested in, Steve?

DR. NISSEN: No.

DR. THROCKMORTON: You were interested in enalapril.

DR. NISSEN: Yes. Again, tolerability compared to enalapril. It sounds
like it\'s a wash.

DR. LEVY: Well, you can see there\'s ‑‑

DR. NISSEN: No difference.

DR. LEVY: ‑‑ no difference.

DR. NISSEN: Very good. That\'s helpful.

Let me just ask one more final question for me, and then I\'ll pass this
along. Part of your risk management program is to try to keep patients
in physicians\' offices for a couple of hours after they get that first
dose. I assume that that\'s going to be a recommendation. Am I correct?

DR. LEVY: It\'s a consideration. The program is under development now.

DR. NISSEN: But I guess one of the things that I know about physicians
and their levels of patience is ‑‑ I\'ll ask you a question and see if
the clinicians agree with this. When you do something like that and you
have an event that\'s relatively rare, like angioedema, physicians may
start out keeping patients for a couple of hours. They won\'t see an
event and they will start to get a little complacent, and they\'ll start
letting people go sooner. And I guess I\'m worried that in a big program
that goes on for a while, because the events themselves are rare, any
individual physician is not likely to see one. And there\'s going to be
a tendency to get increasingly complacent until something catastrophic
happens. It\'s a just a question of behavior and it\'s something that
worries me. Any thoughts that any of the clinicians have about whether
this is a real concern or not a real concern I\'d be interested in.

DR. BLACK: I haven\'t even done trachs in rabbits, so I\'m not sure I\'m
really qualified to talk about it. But I\'ve had angioedema that, in
fact, had to do with something else in Charlotte Hungerford Hospital in
Torrington, Connecticut, which is near Russia actually.

(Laughter.)

DR. BLACK: My own feeling just in general is every emergency room, in
fact, can do this procedure. The care that I got was exactly what you
heard. It was shotgun. I got the right stuff and it got better. But I
think, in fact, this program will really improve the care and awareness
of angioedema whatever the cost. And we know there are cases from ACE
inhibitors also. So, I think it\'s going to really help out. The people
who are going to do most of the care are going to be people in ERs.
It\'s not going to be in the first few hours in the doctor\'s office.
So, I\'m not as concerned.

I think a program that asks you to stay there for a while is probably
going to be, as you say, not in fact ‑‑ and it probably wouldn\'t make
too much difference. The anaphylactic case was the only one, and those
are clearly by chance.

DR. LEVY: I think it might be useful for the committee just to know a
little bit more about the risk management program at this point, if
you\'d be interested, because the topic has come up a few times.

DR. BORER: If we can hold that just a little bit because that ultimately
will be part of our discussion in terms of risk-benefit and we will want
to hear a little bit about it. You know, we got a lot in our handouts
and materials about what you submitted.

Why don\'t we just go through this OVERTURE data quickly and then we can
come back and clean up.

DR. FLEMING: Jeff.

DR. BORER: Oh, I\'m sorry. Tom.

DR. FLEMING: I had two or three questions on safety. I\'d like to pursue
a little bit more what Steve and I think Paul were getting at earlier
about what is the evidence that there is, in fact, a relationship here
and a safety risk with starting dose.

Can you put up slide 36? As Steve was alluding to, in slide 36 there
appears to be evidence that there may be a two- or three-fold lower risk
of angioedema when you\'re starting below a 20 milligram dose. In fact,
in this experience, there were no cases of airway obstruction, airway
compromise, in the less than 20 dose. So, in a certain sense, the OCTAVE
study is a disappointment when you look at the fact that the 10
milligram starting dose gave a higher overall occurrence rate of 2.17
percent.

Yet, as you point out, that readily could be under-detection in this
setting here. One piece of evidence of that is when you look at the rate
of airway compromise, it turns out that in OCTAVE it\'s 1.6 per 10,000.
Here, if you look at the greater than 20 milligram group, it\'s almost
10-fold larger. It\'s 15 per 10,000. So, there really is evidence when
you look at airway compromise that there really is a relationship with
dose.

To try to get a better sense about this, beyond just relying on the
airway compromise rates, we know that in OCTAVE there were these two
cases, but there were overall 19 cases that were hospitalized. Can you
give us for these two columns here, the below 20 and the greater than or
equal to 20, how these cases break out relative to hospitalization?
Because that may give us further reinforcement to the airway compromise
data that there really is a dose-response relationship.

DR. LEVY: Let me just see if I understand. You want to know from these
data in this program what proportion of patients required mechanical
airway protection, what proportion were hospitalized.

DR. FLEMING: Yes. We know it\'s 0 and 4 for airway compromise. So, in
these two columns, of the 18 cases in the less than 20 milligram
setting, how many of them were hospitalized, and of those 66 in the
greater than 20 milligram, how many were hospitalized?

In essence, what I\'m getting at is if there\'s under-detection, as I\'m
almost certain there is here, it\'s less likely to be under-detected in
the most serious cases. Airway compromise I\'m assuming you\'re going to
see. Hospitalization I would think you would be more likely to see. So,
we\'ll get a better clue, along with the airway compromise, that there
really is a dose response.

DR. LEVY: In those who were started at 20 milligrams or more, there were
4 patients who were hospitalized for angioedema without requiring airway
compromise. I\'ll ask my team to verify it for me. My recollection is
that in those less than 20 milligrams, it was 1 patient hospitalized,
but I\'ll ask them to check for me.

DR. FLEMING: Okay, and they can give that to us later after they check.

Let me go on to a second question.

DR. KAPLAN: Could I make a comment on the 19 hospitalized patients? In
looking those over, I read all of them to see what was the criteria for
hospitalization. If you look at it carefully, you will see that about 8
or 9 out of the 19, upon arrival to the emergency room, were almost
asymptomatic, had either a little bit of lip swelling that was left or
had nothing, but gave a history of having had tongue swelling or
pharyngeal swelling or drooling or something that had happened hours
before and they were then hospitalized for observation. That\'s a safe
thing to do and it\'s exactly what you might consider doing if it were
anaphylaxis.

But the fact is, if you read them individually, of course, they were all
hospitalized overnight. Nothing happens. They\'re discharged the next
morning. And the fact that about 8 or 9 of them, by our criteria I think
and by my judgment as an allergist, ought not to have been hospitalized
because if you understand what happens with an ACE inhibitor, you get
the swelling, it crescendos. That time may vary depending upon the
person and severity, and then it finally abates, and it does not recur.
So, it doesn\'t rebound, which is the reason why steroids are of no
value actually in treating them in contrast to anaphylaxis.

So, I think that those who have respiratory embarrassment on arrival are
the obvious. But I think hospitalization may not be the best criteria as
we look at this study for the actual incidence of the \"severity\"
because a substantial proportion of those patients resolved
spontaneously and really didn\'t need hospitalization.

DR. FLEMING: Let me go on to the second question and that\'s slide 39.
Having seen in the prior experience before OCTAVE no cases of the airway
obstruction and evidence of lower rates, the intention here was to see
if we could show that the rate was below 2. So, the null hypothesis was
a rate of 2. The alternative was something discernibly less than 2.
Ultimately what we see here in the bottom confidence interval is that we
cannot only not rule out that the rate is less than 2. We can\'t even
rule out the rate is less than 4, and the data suggests that the rate is
actually 3.2.

I see Jim Neaton here. I don\'t know if it\'s because he was on a DSMB
for this study. I\'m just guessing.

How was the DSMB monitoring this phenomenon as the study was ongoing?
Because it appeared your null hypothesis was 2 and the alternative, I\'m
assuming, was 1 or 1.5 or something like that. And you\'re entirely way
inconsistent with that with these data. How was this being factored in
during the monitoring of the trial?

DR. LEVY: Let me comment on that. Jim was actually not on the DSMB.

But the DSMB was provided with these data, as well as safety data. In
their view, it was very important to weigh both potential harm and
potential benefit in assessing whether this study was to continue or
not, and they didn\'t apply a simple stopping rule based on whether or
not the prespecified hypothesis for angioedema was reached. In their
view, there was clear evidence not only of increased risk of angioedema,
but also of greater blood pressure reductions.

DR. FLEMING: So, the protocol simply said the null hypothesis is 2,
alternative is less, and there was no stopping guideline specified in
the protocol.

DR. LEVY: There was no prespecified stopping rule.

DR. FLEMING: The last question. When we look at angioedema by severity,
you\'ve given us that data in the aggregate. The add-on group with 4,751
patients is an important subgroup here. In this subgroup, do you have
the breakdown of the cases of angioedema by grade?

DR. LEVY: Yes, we do, but let me just make a point and that\'s that in
that group and all other groups, there\'s a remarkable consistency
across this database. What you\'ll see is that the incidence of
angioedema in group 3 is similar to that seen overall, and that 60
percent of the cases received no treatment or antihistamines only as
they did overall. So, we\'ll be happy to show you those data, but
they\'re quite consistent with the overall data.

DR. FLEMING: Okay, and please do so, though. At some point bring those
back to us.

DR. BORER: If there are no other questions of fact here, maybe we can go
on here about OVERTURE, and then we\'ll come back to some of the other
safety issues.

DR. PACKER: Before I begin, I just want to note that in light of my
status as an SGE but also in light of my role as principal investigator
of the OVERTURE study, the Advisors and Consultants Staff of the FDA has
consented to my participation and presentation in today\'s meeting.

I also wanted to correct Steve\'s comment, and I think this is
particularly sensitive to both Jeff\'s and Tom\'s views. I think those
who live in Manhattan neither characterize it as a State or a country. I
think they characterize it as a universe.

(Laughter.)

DR. PACKER: With that in mind, at yesterday\'s meeting on candesartan,
the advisory committee indicated it was comfortable believing that an
incremental decrease in blood pressure would be translated into a
reduction in cardiovascular events if it could be reassured that the
experimental drug did not exert an adverse effect independent of its
antihypertensive action that could increase the risk of a cardiovascular
event. Therefore, the committee implied it would feel comfortable,
assuming that a decrease in blood pressure would produce a predictable
reduction in cardiovascular risk, if the drugs being compared were in
the same class, but they might not feel such comfort if the drugs were
in different classes. And I think Steve in particular made this point.

DR. FLEMING: Some of us, though, might not have been as comfortable with
such a broad generalization as you have stated.

DR. PACKER: Even in the same class. Right.

So, I\'d like to consider the present situation which is that both
omapatrilat and enalapril are both ACE inhibitors and that\'s in part
reassuring, but omapatrilat differs from enalapril in also being a NEP
inhibitor. So, the question is, how comfortable can the committee be
that NEP inhibition does not produce adverse cardiovascular effects that
could negate the cardiovascular benefits expected from its incremental
ability to lower blood pressure?

This table shows the cardiovascular events that were observed during the
6 months\' treatment with omapatrilat and enalapril in the OCTAVE study.
Now, although this was a prespecified analysis, the study was not
designed to compare the two drugs on the risk of cardiovascular events.
So, I think these data need to be interpreted very cautiously. Having
said that, there were 105 cardiovascular events in the omapatrilat group
and 121 in the enalapril group.

This slide shows the Kaplan-Meier plots for these events. The hazard
ratio of omapatrilat to enalapril is 0.87, with an upper bound of the 95
percent confidence interval of 1.13, I think in and of itself suggesting
that NEP inhibition is unlikely to exert a meaningful adverse effect
that might detract from the expected clinical benefits of the drug.

Now, although these data might be considered to be reassuring, my own
view is that these data need to be interpreted very carefully since the
duration of follow-up in the study is only 6 months.

I also think that it is likely that Tom might ask for an analysis of
these data according to the characteristics that the sponsor is
proposing. It might form the basis of use of the drug. And I just want
to let you know we are working on that as we speak, including trying to
address the issue of the blood pressure lowering effects in all of those
individual subgroups at high risk.

Well, in light of the limitations of these data, I think it\'s important
to consider the results of OVERTURE. Preliminary results of this trial
were presented at the ACC in March. Final results will appear in
Circulation online in about a week from now, and before reviewing the
results, I want to emphasize that although these data have been
presented to the FDA, they have not been reviewed by the FDA. Therefore,
they are being presented with the proviso that if they have any
influence on your judgments, they will need to be confirmed by the
agency.

The OVERTURE trial evaluated 5,770 patients with class II, III, or IV
heart failure. All patients had an ejection fraction less than or equal
to 30 percent. All were hospitalized for the treatment of heart failure
within the past year. All patients were receiving excellent background
therapy for heart failure, including beta blockers in 50 to 60 percent
of patients and spironolactone in over 40 percent.

Importantly, about 1,300 patients, or about 20-25 percent of the
population, were hypertensive. I just want to mention that hypertension
is a particularly important problem in patients with heart failure since
it is so critical to lower blood pressure in these individuals. Yet,
there is a sizeable risk for frequency of hypertension in people with
heart failure. It\'s 20-25 percent in moderate to severe heart failure.
It\'s over 40 percent in milder degrees of heart failure. And these
patients are already receiving diuretics, ACE inhibitors, beta blockers,
and they can\'t take calcium channel blockers. So, I think that an
analysis of that subgroup would, in part, address Tom\'s request for
additional data, including outcomes data, in high-risk individuals.

Now, eligible patients for this trial had any prior with an ACE
inhibitor discontinued and were randomized in a 1-to-1 fashion to either
omapatrilat or enalapril. The target dose of omapatrilat was 40
milligrams once daily, which had shown promising results in earlier
heart failure trials, and the target dose of enalapril was 10 milligrams
b.i.d., which was the target dose used in the SOLVD Treatment trial. I
think this remains the most definitive study showing a favorable effect
of ACE inhibitors on morbidity and mortality.

What I\'d like to do is to make two points about these doses. First, the
target doses of both drugs was half the target dosage used in the OCTAVE
trial, and second, because this was a heart failure trial, enalapril was
given twice a day, whereas the drug is conventionally given only once a
day in the treatment of hypertension and, as Steve has mentioned, the
use of a b.i.d. regimen arguably provided a tougher test for
omapatrilat.

Now, the primary endpoint in this study was the combined risk of
all-cause mortality or hospitalization for heart failure. This endpoint
was used prospectively in the original protocol to test two hypotheses,
a non-inferiority hypothesis and a superiority hypothesis. According to
the original protocol, omapatrilat would be considered non-inferior to
enalapril if the upper bound of the 97.5 percent one-sided confidence
interval was less than 1.09, and if this were achieved, we would have
been able to conclude that omapatrilat would have retained at least 80
percent of the effect of enalapril seen in the SOLVD Treatment trial,
which was the protocol-specified reference standard, greater than 80
percent. Of course, if the upper bound of the one-sided 97.5 percent
one-sided confidence interval was less than 1, then we would have
concluded that omapatrilat was superior to enalapril.

Now, here are the results on the primary endpoint. There were 973
patients who died or were hospitalized for heart failure in the
enalapril, 914 such patients in the omapatrilat group. It translates
into a 6 percent lower risk of the primary endpoint in the omapatrilat
group. The upper bound is 1.03, which is greater than 1 but less than
1.09. Therefore, we could not conclude omapatrilat was superior to
enalapril, but we could conclude that omapatrilat was not inferior to
enalapril.

Now, this slide shows the effect of omapatrilat and enalapril on the
combined risk of cardiovascular death or cardiovascular hospitalization.
This was a prespecified secondary endpoint in the study, and it
represented the most comprehensive cardiovascular endpoint specified in
the original protocol. For this endpoint, omapatrilat had a 9 percent
lower risk of a cardiovascular event which was nominally significant.

Now, as I said at the beginning, over 1,300 patients in OVERTURE were
hypertensive in that they had a systolic blood pressure that was greater
than 140.

Now, this slide shows the influence of baseline systolic blood pressure
on the magnitude of the difference between omapatrilat and enalapril on
the primary endpoint of death or hospitalization for heart failure, and
on the secondary endpoint of cardiovascular death and cardiovascular
hospitalization. And as can be seen, the higher the systolic blood
pressure, the greater difference in favor of omapatrilat, and this was
true for both endpoints. The difference in favor of omapatrilat in
patients with a systolic blood pressure greater than 140 was a 16
percent lower risk of death or hospitalization, and a 21 percent lower
risk of cardiovascular death or cardiovascular hospitalization.

I guess, Tom, these are probably the best estimates we now have with
respect to outcomes data in hypertensive patients, albeit it in
hypertensive patients with heart failure.

I would like to close with a brief note about safety. This slide lists
selected adverse events that were seen in the OVERTURE trial. As can be
seen, omapatrilat had more reports of hypotension and dizziness, but
fewer reports of heart failure and fewer reports of impaired renal
function. Angioedema was seen in 14 enalapril patients, 24 omapatrilat
patients, and of these, 3 patients were hospitalized, 2 in the enalapril
group and 1 in the omapatrilat group, and none had airways compromised.

Now, in summary, I think the results of OVERTURE are at least suggestive
and certainly I think consistent with the hypothesis that in patients
with hypertension and heart failure, omapatrilat might reduce
cardiovascular events when compared with enalapril even when enalapril
is given twice daily.

But I want to emphasize a much more important point, and that is, I
think these data provide considerable reassurance that NEP inhibition
does not detract from the cardiovascular benefits one can expect from
the incremental antihypertensive effects of omapatrilat.

With that, I\'d be delighted to answer any questions the committee might
have.

DR. BORER: How were heart failure events defined in the protocol,
Milton?

DR. PACKER: Heart failure was defined by the investigator, which in most
heart failure protocols, heart failure is defined by the clinician. The
qualifications for heart failure are based relatively on the severity of
the disease. So, they had to have class II, III, and IV symptoms limited
by dyspnea and/or fatigue.

DR. BORER: No, no. I\'m sorry. That\'s not what I\'m asking.

DR. PACKER: Oh, I\'m sorry.

DR. BORER: These are adverse events. Everybody in the trial had heart
failure.

DR. PACKER: Oh, I understand. I think, as you may appreciate, in a trial
where the ‑‑ and we see this all the time in heart failure trials.
Investigators are asked to report all AEs. There is no guidance given to
investigators as to how they should report AEs or not. In general, heart
failure as an AE is by far the most frequent AE reported in heart
failure trials. In general, in drugs that work in heart failure, the
reports of AEs in heart failure tend to be lower in the active treatment
than in the placebo. But there is no quality control here. There is no
guidance as to how heart failure as an AE should be defined. It\'s
really up to the judgment of the investigator.

DR. BORER: And similarly I assume for hypotension.

DR. PACKER: Similar for hypotension. All the AEs are reported at the
discretion of the investigator in a spontaneous manner without any
specific instructions as to what they should or should not report or how
to define specific terms.

DR. BORER: Can you tell us what doses of the two drugs actually were
achieved? I see the design, but what was actually achieved?

DR. PACKER: I know the estimates, and Jeff, we can give you the actual
numbers, but it\'s in the range of about 80 to 82 percent in both
treatment groups received target dose. We will check on whether that\'s
‑‑ that\'s correct? It\'s 82.7 percent and ‑‑ we\'ll get you the data,
but that\'s the range.

DR. BORER: Steve, do you have any questions?

DR. NISSEN: I just wanted to come back to the blood pressure issue since
what\'s on the table here is the application for approval of this drug
for hypertension. I want to hear again your thoughts, Milton, on why
there was no blood pressure difference between omapatrilat and enalapril
in the hypertensive heart failure patients because, again, this does
shed some light on whether b.i.d. enalapril might be as good as
omapatrilat.

DR. PACKER: I just want to, again, emphasize the points, but let me
supplement them as well since you\'re asking me to do that.

First of all, again this wasn\'t a hypertension study. This was a heart
failure trial, and heart failure investigators in general view blood
pressure as a range as opposed to a number. I don\'t know another way of
saying that. There\'s a complete difference in the quality of the blood
pressure data in the context of a hypertension trial than in the context
of a trial done for another indication.

Having said that, I think that the most important point is the trough
blood pressures were similar, but there is evidence from other trials in
heart failure, not from OVERTURE, that during most of the day the blood
pressure is considerably lower in the omapatrilat group than in the ACE
inhibitor group. And the difference, by the way, in previous heart
failure trials has been in the realm of about 7 to 8 millimeters of
mercury greater in omapatrilat than, for example, in the previous trial
with lisinopril.

In that trial, Steve ‑‑ and the trial I\'m referring to IMPRESS.
Lisinopril is a once-a-day drug. The blood pressures came down and were
very similar at trough in that trial, but during the day the blood
pressures were dramatically different in the two treatment groups. I
think that reinforces the point that the committee made yesterday, which
is it isn\'t just trough blood pressure that affects cardiovascular
events, it\'s the delta blood pressure throughout the day.

DR. NISSEN: I\'m not sure I get the argument. What you\'re sort of
saying is blood pressure isn\'t measured as well by heart failure docs
as it is hypertension docs. But that variability would occur in both
arms of the trial. By most blood pressure standards, it\'s a pretty big
trial. The number of patients with hypertension. OVERTURE is 5,700
patients and of that, what, 1,500 of them are hypertensive. That\'s a
pretty big sample. So, when you see spot-on same trough effects ‑‑ I
recognize there might have been differences in peak effects, but the
most important metric that\'s used in hypertension evaluation is that
trough blood pressure. When given b.i.d., these two drugs had an
indistinguishable effect on trough blood pressure. So, it\'s troubling
me.

DR. PACKER: Obviously, there are other hypotheses, but the other
hypothesis, at least suggested by the data, is that NEP inhibition has
cardiovascular benefits independent of blood pressure lowering.
Obviously, we can\'t say that from the data. Both of those hypotheses
are possible.

I actually feel more comfortable with the delta blood pressure during
the day than I am suggesting to you that NEP inhibition has an
incremental effect on the biology of this disease that is independent of
blood pressure.

DR. BORER: From the AEs, at some point during the day, 8 percent more on
omapatrilat are having a lower blood pressure. They were hypotensive.

DR. PACKER: Steve, the blood pressures had to be lower at peak because
hypotension and dizziness was much more frequent in the omapatrilat
group than in the enalapril group. I know we didn\'t measure it, but it
had to be that way.

DR. NISSEN: I agree although, again, conceivably there is a very early
effect. It doesn\'t last very long. The patients get kind of dizzy and
syncopal for an hour or two, but then the levels track together. Without
having ambulatory blood pressure data, we really don\'t know. But again,
at least at trough, which is what you measured, there really wasn\'t
much difference.

DR. BORER: Are there any other questions? Tom.

DR. FLEMING: Milt, could you put your last slide 13 up again?

You seem to be saying that we\'re looking at two mechanisms that
omapatrilat would have. One is through NEP inhibition and the other is
through whatever mechanisms that lead to the incremental
antihypertensive effects, and that somehow this study is telling us that
the favorable benefits on cardiovascular endpoints mediated through that
second mechanism aren\'t in some way offset or compromised by NEP
inhibition. And where does that come from ‑‑

DR. PACKER: Oh, no, no, no.

DR. FLEMING: That\'s what the technical wording seems to say.

DR. PACKER: This addresses specifically the concern that you raised
yesterday, which is if you compare an ACE inhibitor and ACE inhibitor ‑‑
and let\'s assume for a moment that one reflected the committee\'s view
that they would feel comfortable doing that. That may not precisely
reflect your view, but ACE inhibitor and ACE inhibitor ‑‑ then if the
one ACE inhibitor or an angiotensin II antagonist lowered blood pressure
and another one lowered blood pressure more, that the delta that one
observed in blood pressure would be translated into a cardiovascular
benefit is because there was no other mechanisms that these drugs had
that had been identified that might detract or modify the relationship
between delta blood pressure and delta events. That\'s a hypothesis, but
that\'s the concept that I think was promulgated yesterday.

If you go across classes, you\'re less certain. What I wanted to
emphasize here is that there is an overlap between the mechanism of
omapatrilat and an ACE inhibitor. Everyone is comfortable with what an
ACE inhibitor might do. So, I want to put forward the OVERTURE data as
reassurance that the incremental action of omapatrilat ‑‑ there is no
evidence that that would have an unfavorable effect on cardiovascular
events especially if you think that blood pressures were the same.
Therefore, whatever you see in hypertension, that you could translate
the delta in blood pressure to the delta in events without being
concerned that there\'s some other action of the drug that might be
adversely affecting cardiovascular events.

DR. FLEMING: Milt, it would seem, to follow through on this argument,
you would have to be saying you know somehow that if you take away NEP
inhibition, that the remaining mechanisms that omapatrilat would have
would yield overall better antihypertensive effects than an ACE
inhibitor alone.

DR. PACKER: No. I\'m actually suggesting that if this drug were not a
NEP inhibitor, it would look like an ACE inhibitor.

DR. FLEMING: The argument that we were saying yesterday is if you\'re
comparing two agents that yield different antihypertensive effects and
we want to infer from that difference a difference in cardiovascular
benefits, that is a perfectly acceptable inference so long as there
aren\'t any other mechanisms out there that would offset that.

So, therefore, for the logic to carry over to here, what you\'re having
to conclude here is that omapatrilat has mechanisms relative to
enalapril that yield a better antihypertensive effect and NEP inhibition
is not in any way compromising the corresponding beneficial effects you
would expect to see on the endpoints.

Let\'s move on, though, to maybe an even more fundamental question. This
is sort of a negative in a certain sense. Basically when I\'m looking at
omapatrilat against enalapril, another way of interpreting this is to
say, well, at least with omapatrilat we didn\'t make things worse, or
we\'re not less effective than enalapril. And there\'s a little bit of
that even in your hypothesis of non-inferiority. Yes, we\'re trying to
maintain at least 80 percent of the benefit.

I\'m always troubled in a non-inferiority argument, though, when the
experimental arm is not anticipated to be more favorable in some way. I
believe strongly in non-inferiority when I have an experimental
intervention that has a safety profile or a convenience or a cost
profile that would make it more favorable in that domain such that if
efficacy is the same, then I come out ahead. And as a result, because of
that, I\'m willing to potentially give up a little bit of efficacy.

So, bottom line here is for this trial to be interpreted as positive,
it\'s positive only in the sense that we can say we\'re ruling out that
omapatrilat is meaningfully worse, and hence that\'s a win as long as in
the safety domain we\'re all convinced omapatrilat is better than
enalapril. But I think what this whole discussion is about today is that
that\'s not where we are. So, shouldn\'t you have expected to be
required to show at least superiority here for it to be win?

DR. PACKER: Could I have my backup slides, please, on the SOLVD
Treatment definition and the slide that follows that?

DR. BORER: As you go through this, I think it\'s important to remember
you did a heart failure trial, and we\'re not evaluating this drug for
its efficacy for heart failure. We\'re trying to evaluate it for its
efficacy as a treatment for people with high blood pressure. So, I think
that\'s really Tom\'s point.

DR. PACKER: I think what Tom is saying ‑‑ and we have certainly learned
this lesson many, many times in heart failure trials ‑‑ is that in spite
of the prior hypothesis of non-inferiority, one would be a lot more
comfortable if this trial had met its primary endpoint. In light of the
fact that it didn\'t meet its primary endpoint, one has to be
particularly cautious of subgroup analyses on either primary or
secondary endpoints.

In light of that, I just want to mention one aspect of OVERTURE which is
new. This was not presented at the ACC, but it does appear in our
publication in Circulation.

Let me emphasize that the primary endpoint was death or hospitalization
for heart failure. This was the definition of hospitalization used in
the OVERTURE trial. It included all hospitalizations attributable to
heart failure as adjudicated by the endpoint committee which required IV
treatment and had a duration of more than 24 hours. This was exactly
what was said in the protocol.

The reference standard for this trial was SOLVD Treatment. This was the
reference standard for non-inferiority. We recognized only after the
trial was over that the definition for hospitalization for heart failure
in SOLVD Treatment was different than for OVERTURE. In SOLVD Treatment,
the hospitalization for heart failure was all hospitalizations
attributed to heart failure by the investigator regardless of treatment
or duration. And there was no adjudication process in the SOLVD
Treatment trial.

So, I just want to, for purposes of curiosity, show you what the data
would look like if one had used the reference standard definition.

DR. FLEMING: If this is in interest of answering my question, just
because time is short, I don\'t know that we have to go into this
because I don\'t think this is getting at that separate issue that I was
asking.

DR. PACKER: Jeff, I\'ll be done in one second.

This is the results you\'ve already seen, a 6 percent lower risk with a
p value. This is the primary endpoint using the SOLVD definition, 11
percent lower. This is obviously a post hoc analysis. But I offer it
only to suggest the fact that had we been wise enough or whatever, if we
had used the same definition used in our reference standard, maybe
things would have worked out better. I don\'t want to put too much
emphasis in it. I only provide it for whatever reassurance it would give
you.

DR. BORER: Bob, did you have a comment?

DR. TEMPLE: Only that, I guess while Milton is suggesting there might be
something really good going on here, the main purpose I think was to
make the case that at least nothing bad happened other than the
angioedema, so you don\'t have to worry. And that point would be fairly
strong I think.

DR. BORER: Yes. I think that the issue that we\'re trying to focus in on
here is that we\'re considering this drug as an antihypertensive. We
want to be sure that the safety is acceptable for the intended use. It
certainly is nice to know that it might turn out to be a real good drug
for people with heart failure where the benefit-risk issues are very
much different. But in the hypertensive population, what are we going to
see?

And what we saw was that, for whatever reason, the measure that was used
showed no difference in the efficacy of the drug for the hypertensive
population here and perhaps no additional cardiovascular risk. So,
we\'re still talking about the angioedema as being our primary concern.
And that\'s reassuring to know. I mean, that\'s useful.

DR. FLEMING: Just in a single sentence, Bob, in view of the angioedema,
all I\'m saying is it\'s not enough to convince me that nothing bad is
happening. I want to see something good happening.

DR. TEMPLE: Right, and I don\'t think it\'s being alleged, although
perhaps it\'s being suggested, that there was any finding like that. All
it does is give you some assurance that it doesn\'t do anything bad.

DR. BORER: That there\'s no new problem.

DR. TEMPLE: Given the choice of primary endpoint, you really can\'t say
much more than that probably.

DR. PACKER: I\'d like to introduce Dr. Black for the next presentation,
if that\'s all right.

DR. BORER: Henry, just tell me approximately how long do you think
you\'ll be taking?

DR. BLACK: Well, if I use my Manhattan speed, it will be 5 minutes. I do
want to bring us back to blood pressure and I think this is a good way
to do it.

DR. BORER: Okay. Why don\'t you go ahead.

DR. BLACK: Thanks. I do appreciate it. I realize how late it is and how
tired everybody is, but I do think it would be useful to talk a little
bit about where we are on high blood pressure now and to answer one
question in particular, which is whether omapatrilat\'s greater efficacy
does add to the value of current agents. I\'m not going to talk about
safety at this point.

In order to do this, I want to review what we did in the Joint National
Committee to try to improve hypertension care. You heard yesterday from
Dr. Kannel that overall we were controlling 27 percent of hypertensives
in America. This is actually considerably better than any of the rest of
the world, and this is only people from 18 to 74. The data for older
people are considerably worse.

In order to educate physicians and also patients about how we would do
this, we borrowed somewhat from ATP II and we talked about goals rather
than control, understanding this was dichotomous and you could be a
millimeter above or beyond or not and be at goal. But that\'s what we
thought was easier for people, in fact, to operate with.

The goal for most hypertensives was less than 140 and less than 90. For
high-risk individuals like diabetics or people with heart failure or
chronic renal failure, we set that goal lower, even though at that point
in time, with the possible exception of SHEP, there was no trial that
confirmed that more aggressive therapy was beneficial in diabetics in
particular. Syst-Eur, UKPDS, HOT, and other studies as well, LIFE, have
really suggested this was a good call even though it wasn\'t at that
time evidence-based. And for those with proteinuria, it was even lower
still. This goal was not dependent on age, gender, or other forms of
comorbidity.

What I want to do is show you, with that in mind, three clinical trials
and my own clinical experience as to whether we can achieve that goal
and why we can\'t.

I\'ll begin with LIFE, which was completed this year. This was a
comparison of two regimens, one beginning with an ARB losartan, one
beginning with a beta blocker atenolol, and only about 11 or 12 percent
of individuals took only those drugs. It was a large trial. It was a
long trial. And the goals here are shown, as you see it.

Overall, those who reached diastolic goal of less than 90 for both arms
was quite impressive, almost 90 percent. However, for those who reached
the systolic goal ‑‑ and as you heard yesterday, again it\'s systolic
pressure, especially in older people, that\'s a better predictor of
outcomes ‑‑ it was under 50 percent. And those who reached both goals,
it was also about 45 to 48 percent.

In the diabetics, the highest risk group, you had quite similar data or
you didn\'t do quite as well, 85 and 82 percent for losartan and
atenolol, respectively, but under 40 percent for both arms to get
systolic pressure under 140. That\'s not the 130 goal that we\'re
talking about.

Two other studies, one of which is published and one of which is not yet
published, I also want to show you. This is the ALLHAT trial, which was
just completed. It\'s 42,000 high-risk hypertensives. Everybody enrolled
was over 55 and had another risk factor. There were 15,000 diabetics in
ALLHAT. There were about 15,000 African Americans in ALLHAT. And
everybody had to have something else.

What I want to call your attention to is not the outcomes, because those
aren\'t available yet, but how we did with respect to blood pressure. In
this study, 90 percent of people were on treatment when they started and
only 27 percent of that 90 percent overall were at the JNC VI goals, not
even again using the diabetic goals. What happened here was you got
switched to one of the treatment regimens which was a diuretic or
lisinopril or amlodipine or doxazosin. And there was very, very careful
nagging of our clinicians to titrate to a goal, and the goal was less
than 140 over 90.

We accomplished a lot. In one year, we got 86 percent to diastolic goal,
58 to systolic goal, and this was maintained throughout. Now, this
suffers from patients we can no longer follow and not having blood
pressures, from people with events not being followed, people who died
not being followed, but it\'s a good look at what happens.

However, for systolic blood pressure, which began at 31 percent under
140, we got only up to 70 percent. So, there\'s still a large number of
high risk older people whose systolic blood pressure we could not get to
below 140 in spite of these efforts, and overall, 69 percent at 6 years
reached both. These numbers approximate 30,000 hypertensives.

In the CONVINCE trial, which we just presented in May, we see very
similar data. Here we were comparing a non-dihydropyridine verapamil to
diuretics or beta blockers as the comparators. 16,000 individuals, 13
countries. Began with 20 percent at the JNC VI goals of less than 140
over 90. Once again, no problem getting diastolic under control in this
older high-risk group, but a lot of difficulty getting equally good
results for systolic pressure. Started with 20, got to 67 percent.
That\'s quite good. That\'s as good really as any study so far, but
there\'s a large group of people untreated.

Now, what we did ‑‑ and you don\'t have this slide in your book. We
added it after some of the earlier discussion ‑‑ is to show how we did
it. At the end of titration, almost by definition, people were on one
drug. Step 1 is monotherapy. But with time, the number of people who
could reach and maintain that goal has slipped. So, by 30 months, which
is the last data we have, only about 24 percent were on single agents,
44 percent were on one or two agents, many were on third agents or open
label. Our physicians could use just about anything they wanted. We
nagged them unmercifully to get there, and this was the best we could
achieve.

Well, that\'s fine. Let\'s look at how we do in a specialist clinic.
These are clinical trial patients at one end of a spectrum. They\'re
watched closely. What about people who are refractory? And that\'s what
we see mostly in our clinic.

We used HEDIS criteria here to see if they were reasonable, and then we
had to follow everybody for at least a year. We just looked at that
visit to see how well we were doing. This is 437 consecutive patients
and we saw how often we achieved the goal of less than 140 and less than
90. This is where we started.

These are people sent to us because their doctors couldn\'t control
them, and I would want to parenthetically say that main reason in two
studies we\'ve done of refractory hypertension why that doesn\'t happen
is that people do not in practice use the right drugs in the right
doses. That\'s simply a reality. Those are two studies separated by 10
years with exactly the same findings.

So, we started with 35 percent at systolic goal, 51 percent at diastolic
goal, and that\'s same interesting 28 percent at both. When we got done
‑‑ and we think we\'re pretty good at doing this ‑‑ we came very close
to the clinical trial results. 86 percent were under 90, 63 percent were
under 140, and 60 percent were at both. But that\'s still as good as we
can do.

If you look at the diabetics, it\'s a little more interesting. HEDIS
goals at that point are less than 140 over 90, just the way the trials
were. This is how we did. 87 of those 437 had diabetes. 52 percent at
both goals, but if you look at JNC VI now, which was less than 130 over
85, we were only controlling 22 percent. And the biggest gap was, of
course, in systolic pressure. Diastolic, we weren\'t doing too badly.

If you look at ADA or NKF, it\'s considerably worse. Now we can only get
15 percent of this high-risk subset at the goals set by expert
committees.

And how did we do this? We weren\'t afraid to use drugs. Most of our
patients were on three or four or two. Occasionally we could use
non-drug therapy, but very rarely. So, of the diabetics, 50 percent were
on three or more and 30 percent were on two drugs at least. And we used
everything. We didn\'t have the restrictions you have in a trial of not
having availability of a class. We used diuretics. We used calcium
antagonists. We used ACE inhibitors in about 60 percent, ARBs in about
20 percent. So, we\'re practicing according to guidelines. That was nice
to see. We looked at the few people who weren\'t on one of those and
there was a good reason in almost every one. And we used minoxidil,
central acting agents, beta blockers, alpha blockers without any
particular bias.

So, I think right now we can conclude ‑‑ and I don\'t know if I\'ve
quite made my 5 minutes ‑‑ that we\'ve failed to reach systolic goals in
a substantial number of patients despite what we currently have to do
and despite expertise and despite what happens in a trial. So, I think
regimens that include omapatrilat will greatly improve our ability to
achieve goals, especially systolics.

Thanks.

DR. BORER: Thank you, Henry. I didn\'t mean to suggest that you had to
hurry. It was just that we have to take a break at some point so people
can check out of the hotel and then come back.

DR. BLACK: I do understand.

DR. BORER: Why don\'t we take just a few minutes to ask you questions.
Then we\'ll break for lunch.

DR. BLACK: Sure.

DR. BORER: Steve.

DR. NISSEN: Actually, Jeff, I had questions that are probably more
complex than we can do in a few minutes. I think I would prefer
everybody take a break. I think what Henry raises is the issue of
benefit to risk. You\'ve now given us the benefit side and I want to
explore that, but I don\'t think I can do that quickly.

DR. BORER: Why don\'t we then break now and we\'ll come back here at
12:50.

(Whereupon, at 12:00 p.m., the committee was recessed, to reconvene at
12:50 p.m., this same day.)

AFTERNOON SESSION

(12:55 p.m.)

DR. BORER: We\'ll begin again.

It occurs to me, Dr. Waclawski, perhaps you want to make your concluding
statements and then we\'ll get into the issues that we want to get into
in terms of the questioning about safety and risk-benefit, to the extent
that we have questions about these things.

DR. WACLAWSKI: If you would just let me clarify one thing. Did you
intend to have questions specifically with respect to Dr. Black\'s
presentation?

DR. BORER: Yes.

DR. WACLAWSKI: And you\'d do that after the concluding statements.

DR. BORER: Yes. We\'ll wait for you to finish.

DR. WACLAWSKI: Very good.

Good afternoon again. I\'m Anthony Waclawski. We\'d first like to thank
the committee and FDA for their kind attention and the chance to present
these data to you.

As you continue your discussion today and you consider the target
population, we would welcome the committee to consider our proposal for
a target population. But we fully realize that there may be other
subsets of this population where the committee considers the
benefit-to-risk ratio for omapatrilat to be favorable. We\'re looking
forward to your continued deliberations on these points.

That concludes our formal presentations for the day. Thank you again.

DR. BORER: Thank you.

DR. WACLAWSKI: Elliott Levy can now return to the podium.

DR. BORER: Let me ask you, because I think we want to be absolutely fair
in hearing everything you think is important. You presented us or we
were presented with extensive documentation of the risk management plan.
Is there something that\'s changed since the document that was submitted
to us? Because if not, I don\'t think we need an extensive presentation
here. If it has changed in some substantial way and you think that\'s
important, then you should be able to tell us about it.

DR. WACLAWSKI: I think we\'ll agree that what you\'ve seen we\'ve
sufficiently clarified through our presentations and made the points
that we felt we needed to make, mainly about the objectives of the plan
and why we think that an education-based program is one that could have
some success, and that we\'re confident with working with the agency
going forward.

DR. BORER: With that having been said, let\'s get into the questions of
the committee, the remaining questions regarding safety and the
risk-benefit issues. We\'ll start with the committee reviewer. Steve.

DR. NISSEN: Thanks, Jeff.

Again, we left with Henry up there and we didn\'t get a chance to
interact with you, Henry, and I really would like to. I\'m going to make
a couple of statements and then ask you some questions.

I assume you would agree with me that the long-term effects of
vasopeptid ACE inhibitors on morbidity and mortality are not known.

DR. BLACK: Yes, I would agree.

DR. NISSEN: And that we\'ve seen demonstration of very perhaps superior
blood pressure reduction with omapatrilat in these studies. So, what
I\'m grappling with is how or whether we can translate the blood
pressure differences for this new class of drugs into estimates for
event reduction. And I want to ask you a hypothetical question because
in my mind what we\'re all balancing here is benefit versus risk, which
you were obviously addressing in your presentation. So, here\'s my
question.

If we had a diuretic that reduced 24-hour ambulatory blood pressure by
12 millimeters of mercury and an ACE inhibitor that decreased ambulatory
blood pressure by 10 millimeters of mercury, would we be confident that
the diuretic arm would result in reduced events? So, you have a diuretic
that decreases by 12 and you\'ve got an ACE inhibitor that reduces by
10, using the most elegant 24-hour measures available.

DR. BLACK: This is if compared to each other?

DR. NISSEN: Yes, compared to each other.

DR. BLACK: I think in general I can\'t answer that specific question
without having some real data to back it up.

I do think ‑‑ and I think this point was talked about a lot yesterday ‑‑
that incremental drops in blood pressure, even small ones, seem to
result in considerable reduction in outcome events.

DR. NISSEN: I guess what I\'m trying to get at is whether, in fact, one
can predict that a drug that has a modestly greater blood pressure
reduction will result in a greater reduction in events. Because isn\'t
that what we\'re being asked to assume here in terms of the benefit of
this agent?

DR. BLACK: Yes, I understand. There have been some attempts to do this.
Some have used epidemiological estimates. I think you saw some of that
yesterday from Dr. Kannel. Dr. Stamler has used similar things to
predict reductions in mortality, of small reductions in systolic
pressure leading to fairly large reductions in mortality. And there\'s
been a large meta-regression done by Jahn Staessen suggesting that small
differences in systolic pressure could result in 20 to 25 percent
reductions in cardiovascular mortality. Now, those studies are always up
for some interpretation, but there\'s a consistency about them based on
31 clinical trials that have been done so far.

DR. NISSEN: Mike Weber, do you want to offer us some advice here?
Because there are some calculations that appear in here about this
relationship between how many events are prevented versus the risks.

DR. WEBER: Yes, but underlying that, Steve, is exactly the conversation
you had yesterday morning and that the difference in blood pressure has
its greatest meaning when you\'re comparing the same kinds of
pharmacology. So, if you had one ACE inhibitor that was minus 10 and the
other was minus 12, then I\'m going to favor the one that\'s minus 12.
But you gave us a diuretic at minus 12 and an ACE inhibitor at minus 10,
and that\'s a very difficult situation because they clearly have very
different profiles, and I suspect there are some patients who are going
to do a lot better with one than with the other. But I think what we\'re
talking about here, of course, is within the ACE inhibitor family.

DR. NISSEN: Well, see, it was a deliberately difficult question because
for me to make a judgment here, I have to believe that vasopeptide ACE
inhibitors fundamentally will act on events in the same way that the ACE
inhibitors act on events. Yet, we\'re talking about the first drug in a
new class that does different things. So, I\'m asking you guys ‑‑ I
respect both of you. You\'ve done tremendous work over the years in
hypertension ‑‑ whether you can justify that sort of assumption, and if
so, how you can justify that assumption.

DR. WEBER: Well, I think we would both depend quite heavily actually on
what Milton showed us just before lunch because a concern you would
always have is that what it is that is different about omapatrilat
didn\'t just mean more blood pressure reduction but everything else
stays the same, but whether there is something about adding in this NEP
inhibition that\'s going to cause something that\'s unexpected or
adverse.

I think the two things that Milt showed us, first of all, the major
cardiovascular endpoints in OCTAVE were certainly moving in the right
direction, for whatever that\'s worth, but certainly not moving in an
adverse direction, and secondly, in the OVERTURE study, the heart
failure trial, where again you could have a pretty strong level of
confidence, particularly in the hypertensive patients, that if anything,
things were favoring omapatrilat, for whatever that\'s worth. But I
think we can at least lay to rest the concerns that Tom Fleming was
expressing yesterday about comparing different classes.

DR. NISSEN: Well, I guess the problem we see with using the OVERTURE
data isn\'t the problem that that\'s not the population that this drug
is being proposed to treat. It\'s not being proposed for heart failure.
It\'s being proposed for hypertension. So, the reassurance is obviously
going to be limited, is it not, by the fact that it was studied in a
different population than is being proposed to be used here?

DR. WEBER: That\'s right, albeit a high risk population with
hypertension, but I acknowledge that.

Dr. Hennekens, I wondered, would you have a comment?

DR. HENNEKENS: Well, on this point, Steve, I\'m a recent addition to
this advisory group because of work I had done at Harvard on
hypertension, some of which included collaboration with the Oxford
Group. We looked at 14 randomized trials, including over 30,000 subjects
that were treated for 2 to 3 years with blood pressure lowering agents.
We predicted going in that the 3 to 5 millimeter reductions would be
associated with about a 40 percent lowered risk of stroke and a 30
percent lowered risk of CHD and about a 20 percent lowered risk of
cardiovascular mortality.

What we found is that 2 to 3 years of blood pressure lowering led to the
predicted 42 percent lower risk of stroke, about a 16 percent reduction
in heart disease, and about a 21 percent reduction in vascular
mortality, so that the stroke and the vascular mortality reductions,
over 2 to 3 years with this amount of blood pressure lowering, were very
similar to the epidemiology. Where there was the shortfall was in CHD.

We speculated that chance in the trials might explain it. We speculated
that there might be a more immediate and direct effect on the brain, a
more delayed and indirect effect on the heart via atherogenesis. We also
speculated that the first-line drugs, the diuretics and beta blockers,
which have a 5 percent adverse effect on LDL, might be increasing the
risk of coronary heart disease events.

The issue here becomes complicated in terms of the application of those
data to the risk-benefit ratio on this drug, and I think that\'s why the
sponsors have correctly tried to define a target population, all of whom
have a 10-year risk of about 20 percent or greater, and if we add
uncontrolled hypertension to that risk, it\'s probably closer to a 40
percent 10-year risk of adverse cardiovascular outcomes. And it\'s in
these patients where I think the claim is that the benefits will
outweigh the risk, but that does presume a 2- to 3-year sustained
difference in blood pressure of that amount.

DR. NISSEN: I\'ve looked at these data very carefully as the primary
reviewer here, and as I think we all at this table know, there is no
long-term exposure data to omapatrilat available. So, we don\'t know
what happens down the road.

DR. HENNEKENS: No, but what we do know, though ‑‑ and I will yield to
Dr. Levy in just a second ‑‑ is that you see a sustained advantage over
24 weeks in 25,000 subjects, and that\'s not the same as a 2- to 3-year
reduction, but it\'s at least heading down the right path.

DR. BORER: Bob, did you have a comment about this?

DR. TEMPLE: Slightly different.

DR. LEVY: May I just respond? A point of clarification. We do actually
have quite a bit of long-term experience with omapatrilat. We have
patients treated for up to 5 years. Patients have been treated in
controlled trials for up to a year, and the antihypertensive effects are
sustained and they\'re superior to comparator. Over 5 years, there\'s no
indication that the antihypertensive effect is lost. In fact, we did a
withdrawal study in which patients who were maintained on the drug for
over a year and had stable blood pressures were withdrawn from therapy
to demonstrate that it retained its antihypertensive effect.

DR. NISSEN: But let me just make sure I understand what you know. The
differential effect against, say, enalapril is sustained in those
longer-term trials?

DR. LEVY: We have comparative data versus losartan not enalapril in a
trial that lasted a year, and the difference between the two drug
regimens is sustained.

Our longer-term experience is in primarily open-label, uncontrolled
trials.

So, of course, we can\'t speculate what would happen if patients were to
be followed for 5 or 10 years. On the other hand, in the patient
population we\'ve identified who don\'t seem to be able to get to target
with existing meds, it seems highly likely that there would be some
lasting benefit if they can stay on this one.

DR. NISSEN: But there\'s no hard data on differential effects beyond 12
months.

DR. LEVY: Yes, that\'s right.

DR. NISSEN: Now, the second question ‑‑

DR. BORER: But just before you go on to that, Steve, Bob.

DR. TEMPLE: I have an observation about this. Steve is obviously asking
the fundamental surrogate question. You always, when you rely on blood
pressure, are making some assumptions, and they\'re not always right.
I\'m absolutely positive you get better blood pressure control with 100
milligrams of chlorthalidone than you do with 25 milligrams of
hydrochlorothiazide, and there are even well-controlled studies that
show improved survival or improved stroke anyway in those people. But it
turns out you pay a price for the better control in the form of
arrhythmias and other things. So, it turned out there was an additional
effect in addition to the one that you were relying on that was a worry.

Nonetheless, for what\'s it worth, we do act ‑‑ and the whole community
acts ‑‑ as if lowering blood pressure to goal is a desirable thing
however you do it, with whatever drugs you do it, even though they
can\'t prove that. ALLHAT is supposed to get you some further insight on
that question, is lowering blood pressure equivalent, to the same extent
the same, no matter how you do it?

DR. NISSEN: I guess the spirit of my question relates to trials like
LIFE where a similar blood pressure reduction has different effects on
events. So, what I said yesterday I\'m kind of repeating today, which is
when you cross classes, there may be class-specific effects that are
unknown, uncertain, and it\'s particularly germane when it\'s the first
drug in the class were we don\'t really know, over a period of time,
what the effect of morbidity and mortality are, let alone know what it
is relative to some other agent.

DR. TEMPLE: Yes. But of course, every time you approve a new drug,
especially of a new class, you don\'t know that. Some people would tell
us we should make people know that and do an ALLHAT each time, but we
have not adopted that policy.

DR. NISSEN: Well, Bob, again, the difference here is that there\'s risk.
If the drug had a similar risk profile, we wouldn\'t have this
conversation.

DR. TEMPLE: That\'s fair.

The other observation I guess ‑‑ I\'ve written this, so I want to say it
‑‑ is it doesn\'t seem out of the question about you can learn about
some unexpected bad news from studies in different populations. So,
I\'ve always felt some of the concerns about calcium channel blockers in
hypertension were, to some extent, resolved by the post-infarction
studies, a fragile group, and it didn\'t seem to do anything bad in
those, other than cause heart failure. And I believe that\'s the
argument they\'re making about OVERTURE, that it should reassure you
that nothing unexpectedly awful is happening even though it\'s a
different population.

DR. NISSEN: So, for me the most powerful evidence would be obviously
direct evidence on morbidity and mortality, but there is less powerful
evidence that might be germane here, and I wanted to give you an
opportunity to give us your perspective on it, and that is the issue of
target organ protection. So, I wanted to know if there is any evidence
here of superior target organ protection for omapatrilat in comparison
to other available agents.

So, this would obviously be another kind of surrogate, but it would be
one that we probably ought to weigh in our deliberations. So, I\'d be
interested in anything you can provide that might help us there.

DR. LEVY: Some of this information was cited briefly in the briefing
documents. Let me just review that.

DR. NISSEN: But we haven\'t discussed them. That\'s what I want to
discuss now.

DR. LEVY: Yes. There\'s a presentation on this issue.

We conducted a number of studies designed to examine the effect of
omapatrilat on target organ damage. Three of them were cited in your
briefing document.

DR. NISSEN: Now, keep in mind now we\'re talking about in comparison to
other agent, not just against placebo.

DR. LEVY: Yes. I\'m going to show you the findings from three studies
and briefly cite a fourth.

In your briefing document, the first is a trial that was conducted in
patients with chronic stable angina. We had noted in preclinical studies
that omapatrilat had an anti-anginal effect that wasn\'t shared by ACE
inhibitors. And we conducted a trial ‑‑ it was a placebo-controlled
trial ‑‑ in which omapatrilat was shown to improve exercise tolerance.
That was this study.

And if I could go to the next slide. We demonstrated significant
improvements in various measures of ischemia, including maximal exercise
duration, time to onset of angina, and time to ST segment depression.
So, not an active-controlled trial, but a novel finding that hasn\'t
been described with ACE inhibitors.

DR. NISSEN: Unfortunately, it wasn\'t germane to what I was asking
because I\'m looking for evidence that there is some target organ
protection here not afforded by an active control agent. In other words,
is there anything that says that omapatrilat improves angina in
comparison to enalapril or lisinopril or amlodipine or anything like
that?

DR. LEVY: Right. Well, again, this hasn\'t been described with the ACE
inhibitors, so we thought it was worthwhile.

DR. NISSEN: Also, certainly with amlodipine it\'s been described.

DR. LEVY: If I could have the next slide. We conducted a study to
examine the effects of the drug on proteinuria. This was actually a
study conducted early in the clinical development program. We used
amlodipine as the comparator because of its potent effects on blood
pressure and its apparently neutral effects on proteinuria. We found in
this trial, if I could have the next slide, that omapatrilat produced
significant reductions in urine albumin excretion rate that in magnitude
were about comparable to that seen with the ACE inhibitors.

DR. NISSEN: Were there any direct comparisons made between omapatrilat
and, say, ARBs, which I guess are about to be labeled for this
indication, or ACE inhibitors?

DR. LEVY: Not for this purpose.

Now, the next study we have a comparison with losartan in patients with
left ventricular hypertrophy. The primary endpoint here was change in
echocardiographically determined LV mass after 24 weeks of therapy with
omapatrilat or losartan, and then patients remained on therapy for up to
a year. At the primary time point, at week 24, both drugs reduced left
ventricular mass to a significant degree with a trend towards greater
reduction with omapatrilat.

DR. BORER: What were the blood pressure responses to the two drugs?

DR. LEVY: Can I see the tracing, summarized blood pressure changes over
the full duration of the study?

These are the blood pressure changes over the full 52 weeks of the
trial. In the first 24 weeks, patients remained primarily on
monotherapy, and then they went on to add adjunctive therapy. About 34
percent of those treated with omapatrilat received another agent; about
60 percent of those treated with losartan. And there\'s a difference in
systolic blood pressure of about 4 millimeters of mercury that\'s pretty
well sustained from week 24 in the trial on.

You had asked me before about what evidence we had that there\'s a
long-term superiority. This is an interesting trial, much smaller than
OCTAVE, but one in which, despite a much greater discrepancy in the rate
of adjunctive therapy use, you still see a preserved difference of about
4 millimeters of mercury in systolic blood pressure.

DR. NISSEN: But I guess I was looking more for evidence. I guess what
I\'m trying to understand is it would help me if there were evidence
that in comparison to ACE inhibitors or calcium channel blockers or
diuretics, that some organ system was protected in some way.

DR. LEVY: Let me show you one more study, if I could just have the
primary finding from the CHOIR study. These are data that were not
included in the NDA, and so the FDA hasn\'t reviewed them. If there of
interest to you, I\'d certainly like them to review the study.

But this was a study that we conducted in patients with systolic
hypertension, randomized to treatment with omapatrilat or enalapril, in
which we assessed the effect of the drug essentially on conduit vessel
stiffness, which is a major finding in older patients with primarily
systolic hypertension and is thought to have a pathogenic role. Now, in
animal studies the natriuretic peptides were shown to have a favorable
effect on the large arteries.

In this study ‑‑ can I just have the primary results?

DR. NISSEN: I\'m not sure I would call that an end organ, though.

DR. LEVY: Well, there\'s a degenerative change in these vessels over
time that seems to be associated with poor outcomes.

Anyway, the drug produced a reduction in central pulse pressure that\'s
not seen with enalapril, and it indicates that there\'s a distinct
effect on the pathologic change in these conduit vessels.

So, we certainly have a variety of information about target organ
damage. At the very least, the drug appears to share the beneficial
effects of existing drugs. It may be superior in some areas.

DR. NISSEN: Yes, I would agree with that conclusion, from what I\'ve
seen in the documents, that it does appear to share those properties.
But again, looking for superiority as a way to justify the increased
risk, that was what I was really probing for.

That\'s all I have.

DR. WEBER: I just wanted to remind Steve that, in fact, that in previous
trial with losartan, the differential effects on left ventricular
hypertrophy were really quite clear. And that\'s interesting because in
the LIFE study, if you remember, losartan was clearly superior to the
beta blocker in regressing LVH. So, this is, if you like, one good
example of a target organ difference to the favor of omapatrilat against
a standard comparator.

DR. NISSEN: Well, Mike, the differences were highly significant compared
to placebo, but there was not a significant difference compared to
losartan. The p value was nonsignificant. So, again, it was a
demonstration of equivalence, not necessarily of superiority.

DR. WEBER: I think it was 7 versus 4.

DR. NISSEN: Well, but the p value was greater than .1.

DR. LEVY: You\'re correct. There was a trend towards greater reduction
with omapatrilat.

I have data on some of the subgroup analyses that were requested before
the break.

DR. BORER: Why don\'t you go ahead and then we\'ll get on to some other
questions.

DR. LEVY: Dr. Fleming had asked about efficacy and safety in the
proposed target population. If I can have the first slide there. This is
the proposed target population. These patient populations are identified
based on review of the clinical guidelines to determine patient
populations that would increase CV risk and therefore might stand to
gain the most from incremental reductions in blood pressure. Of course,
the second criteria, hypertension difficult to control with existing
agents, patients who can\'t benefit elsewhere.

We presented these data by subgroup because they\'re post hoc analyses,
and it\'s very important to be able to examine each of the subgroups for
consistency.

Can I have the next slide? I showed you these results earlier. I call
your attention to the right-hand panel. There\'s a very consistent
reduction in blood pressure in all these high-risk groups, ranging from
3 to 5 millimeters of mercury more with omapatrilat than with enalapril.

But for the sake of clarity, we\'ve prepared a pooled analysis in which
we put together these populations. This is what a population looks like.
Again, the two largest risk groups that were represented in OCTAVE were
diabetes and atherosclerotic disease with 3,300 and 2,300 patients
respectively, and then smaller numbers with renal disease and heart
failure. So, there are about 6,000 patients represented in this
analysis. They tend to be a little bit older than the overall study
population, but otherwise they\'re not remarkable in terms of
demographic characteristics.

DR. FLEMING: And do all of these patients also satisfy the criterion of
having had a difficulty to control hypertension?

DR. LEVY: This is all subjects. I wanted to show you the largest group
possible. We\'ve also done these analyses for those who entered the
study uncontrolled on medication and the results are very similar.

DR. FLEMING: If you have it, because time is short, it would be adequate
just to drill down to that target group rather than including this
bigger group that includes a number of people who wouldn\'t be in your
target, if you have it.

DR. LEVY: I\'ll call it up, but there really are only two slides to show
and one is that, as you\'d expect, when you see groups that are
consistent, you see a consistent difference in efficacy of about 4
millimeters of mercury in the target population at week 24. As I showed
you earlier, the rate of angioedema in the study was lower in those with
diabetes or atherosclerotic disease than in others. So, the risk of
angioedema in the target population is also lower. The two events that
are subject to that airway compromise were not in the target population
and the number of patients hospitalized was also quite small.

DR. FLEMING: So, it\'s just not been possible at this point still to
produce the actual target population subgroup? I\'m presuming that the
target population subgroup would only be half that size or two-thirds.

DR. LEVY: I\'m sorry. If we were to focus on those patients who entered
the trial uncontrolled on therapy with the same comorbid
characteristics, there are about 2,000 subjects in the analysis. Again,
the reduction in blood pressure is 3.6 millimeters of mercury more with
omapatrilat than with enalapril.

DR. FLEMING: And do you happen to know what the distribution is for the
clinical events and also for the safety events?

DR. LEVY: Yes. As you know, there were 226 clinical events in the trial.
In this group there were 102, 58 in subjects randomized to enalapril and
54 in subjects randomized to omapatrilat. So, the hazard ratio is .91.
It\'s very consistent with what we saw overall.

DR. FLEMING: And the angioedema? Did you have that data?

DR. LEVY: Well, this is the angioedema.

DR. FLEMING: That\'s still a bigger group. Right? That doesn\'t focus or
drill down on only those people that were difficult to control
hypertension at baseline.

DR. LEVY: In those who had these comorbid characteristics and who
entered the study on medication uncontrolled, there were 18 angioedema
events out of 1,140 subjects on omapatrilat, an incidence of 1.58
percent, and 8 events out of 1,053 subjects on enalapril, .76 percent.
In both cases, most of the events were severity class I.

DR. FLEMING: Do you have how many were at III-IV?

DR. LEVY: I\'m sorry?

DR. FLEMING: Severity class III-IV.

DR. LEVY: Well, as you can see here, in the larger group, there were 2
patients who were hospitalized, neither with airway compromise, and
there were no patients who required mechanical airway protection. In the
smaller group, there were also 2 subjects hospitalized without airway
compromise.

Does that answer your question?

DR. BORER: Not quite. Just so it\'s on the record here, people who
entered the trial uncontrolled are not actually the group that Tom is
focusing on. I\'m sure you don\'t have these data, and nobody expects
you to put them together in 2 minutes. But it\'s the people who
couldn\'t be controlled, not the people who weren\'t controlled.

Henry Black showed us that there are people in his own clinic ‑‑ and
he\'s an expert ‑‑ on maximal therapy who aren\'t controlled. So, they
exist but those aren\'t the people who came in uncontrolled into this
clinical practice population for a study.

The question we would really have to define the risk-benefit ratio we
want most precisely would be the people who, on maximal medical therapy
under optimal care, could not be controlled without omapatrilat and now
could be controlled with omapatrilat. What\'s their risk?

I don\'t think you have that group, but it\'s different from your group
3 in the OCTAVE trial. Again, you may have those data. I don\'t know.

DR. LEVY: We\'ve showed you data from a variety of groups that are
relatively difficult to control. I think what you can conclude is that
the efficacy advantage is preserved, no matter how difficult the patient
is to control, and we got some very difficult-to-control patients
represents in OCTAVE. In patient populations where there\'s a higher
risk of diabetes or atherosclerotic disease, there\'s less angioedema.

DR. BORER: All the data you\'ve shown us are consistent with what
you\'re suggesting.

One of the reasons that I\'m sort of not fully satisfied ‑‑ and it may
be impossible without some additional trial to provide that satisfaction
‑‑ is that the argument that routine clinical practice does it this way
and they don\'t make it just isn\'t really a very good argument to me,
as I suggested earlier.

One of the reasons that I\'m concerned about this and the underuse of
appropriate medications and whatever are the data that Ray Lipicky
presented I think the first time two years ago, although maybe he put
them together earlier than that, about the dose-response curve of
antihypertensive drugs showing that, by and large, probably everybody
underdoses most antihypertensive drugs, and if you just push the dose a
little bit more, you\'d get the blood pressure down with conventional
agents that have already been approved.

So, to assuage my concern about that, the most convincing thing I\'ve
heard and seen was the slide that Henry showed earlier from his own
clinic where there are people who are really expert at this who have ‑‑

DR. BLACK: I can perhaps try to give you some idea. I don\'t think it\'s
possible with what you saw here to make that guess. But in our diabetic
group, which is not large, where we are very aggressive using the real
guidelines for diabetics ‑‑ and diabetics are one of the groups that
this is being recommended to use ‑‑ we could only achieve goal in about
20 percent of people with what we currently have. And we use large
doses. We use four or five or six drugs if necessary. So, there\'s a big
gap in that group alone.

DR. LEVY: If I could show one slide just to clarify a point. If I could
have the slide from the 73 study.

We\'re proposing that the drug be used in the patients that Henry Black
is talking about, the patients who can\'t be brought to control despite
very honest attempts to get them there. In the right-hand panel here,
you\'ve got patients who were on very high dose ACE inhibitor therapy
plus one or two or three other medications. They remain far from target
with systolic pressures at baseline in the 150s. The substitution of
omapatrilat for their prior ACE inhibitor therapy produced further
reduction in blood pressure of around 10 millimeters of mercury. There
are few alternatives for these patients.

The question was raised before about whether one could achieve the same
results with b.i.d. enalapril or with the addition of a thiazide. In
patients who can reach those with those manipulations, this is not the
role of the drug. But there is a very substantial incremental blood
pressure reduction which may be of value in patients who are very
difficult to control with existing drugs.

DR. BORER: You don\'t really believe that if the drug were approved and
marketed, that it would only be used in the group that Henry Black
couldn\'t control with six other drugs.

DR. LEVY: I think Henry has shown data that there are 30 to 40 percent
of patients who can\'t be controlled.

DR. BORER: I understand, but I\'m asking you do you really believe that
that\'s the way the drug would be used if it were marketed. It\'s a
rhetorical question.

(Laughter.)

DR. CARABELLO: But it\'s a question I\'d like to go into a little bit
further. I see this drug perhaps as somewhat akin to amiodarone where
you have the nettlesome problem of atrial fibrillation, very few drugs
to control it, and we have a very toxic, not particularly safe drug, but
its risk is mitigated by the fact that it\'s only prescribed by a few
people, those people who have a special knowledge of the drug and of
arrhythmias. My question would be is, could we limit the drug in terms
of who prescribes for what, where, and when? And would that not be yet a
strategy we haven\'t talked about for mitigating risk?

DR. WACLAWSKI: Excuse me, Dr. Borer. Could I just add to your rhetorical
question perhaps? It\'s certainly something we have been discussing on
the risk management side within the company for some time, and it
certainly is one of our concerns as well, which is that if and when the
drug were to be approved with a target population, it would be necessary
to show that we could limit the use to those patients where the
benefit-to-risk is clearly favorable.

And that\'s important to us not only for the good of the patients, but
also because even if the benefit-risk was to be expanded beyond that
later, it\'s important to focus on a group that has the highest
benefit-to-risk initially for the initial marketing of the product. We
recognize that as a risk and we\'ve worked internally try to work
through that. And there may be some tools, some ways to build the risk
management plan around that, and that\'s something certainly we would
welcome input on. But your concern is well taken.

DR. BORER: 15 years ago ‑‑ and I guess it\'s 17 years ago now ‑‑ this
same discussion revolved around amiodarone, and the consultants who were
speaking for the drug insisted that it should be approved only for use
by experts who were the six of them sitting in the front row ‑‑

(Laughter.)

DR. BORER: ‑‑ and shouldn\'t be used by anyone else. I don\'t think we
achieved that, but perhaps that\'s okay.

Bob.

DR. TEMPLE: I have a slightly different question. Let\'s say we were
willing to assume that it really was good for outcome to be able to
lower blood pressure 3 millimeters of mercury more than you otherwise
could. That\'s sort of what Henry is saying in some ways.

There are two sets of data. One is moderately convincing evidence I
think that this works a little better than other ACE inhibitors. At
least with lisinopril, how many times a day you give it probably
doesn\'t matter, and they seem to have some data there. So, that\'s one
thing.

What I hear Henry saying is, look, if this is as well as you can do with
available therapy without omapatrilat, you\'re going to do 3 millimeters
of mercury better when you substitute this for your other ACE inhibitor.
So, that\'s one line of argument.

The other line of argument is that OCTAVE actually showed that you could
get 3 millimeters of mercury better with this than without it, but I
have some questions about that. These are all points raised by Dr.
Stockbridge in his review.

It\'s quite striking that even though people were allowed to increase
the dose of enalapril to gain control, only about 40 percent of people
got on the maximum dose, and just to save Steve from having to say it,
they didn\'t get an opportunity to have it twice a day. So, you don\'t
really know what would have happened if they had gone to the right dose.
Maybe that 3 over 2 would be 1 over .5.

In addition, the fairly simple expedient of adding another drug was only
used in a very small fraction of patients. So, I recognize the idea that
is implicit in what Henry said, which is, well, it works better, so
you\'ve got to end up better. And I guess I raise the question, don\'t
you have to know in practice how different these resistant patients will
be when you actually do it as opposed to sort of the theoretical
advantage which is, well, how can it not, which is I think what Henry\'s
argument is.

So, I\'d be interested in some response to why, given the opportunity to
use the proper dose or the maximum dose, if you like, of enalapril and
given the opportunity to add therapies which they could have, nobody
really did it. So, do we really know how much better this is than
conventional therapy in an actual \"I can\'t control this patient\"
setting?

I take your point. A lot of people can\'t be controlled, but if this
were available, do we actually know in a hands-on way and a demonstrated
way how much difference it would make? That\'s really what Norm was
asking in this review.

DR. BLACK: Bob, if I could, I\'d try to give you two impressions. We\'ve
done two assessments of our clinic when I was in New Haven and again in
Chicago about 10 years later to look at our patients who were resistant
and see what the reasons were and what we could about it. The most
common reason both times was that the patients that we got were not
properly dosed, did not get the right drugs in the right order, didn\'t
have them long enough, exactly the practice gaps we see.

We were able with our manipulations to get control in about 60 percent,
very similar to what you saw here, both times. In 1990, it was using
diuretics when people didn\'t know how to use them, and there are newer
things now. That wasn\'t quite the problem. So, I think that\'s going to
be an issue. I don\'t think you can address exactly what would happen if
omapatrilat were around, but I think that\'s the pattern of practice.

In our trials, where we do lay out a protocol, we reward people for
getting control and punish them when they don\'t and let them use
whatever they want. We still can\'t do any better than, in fact, what
we\'re seeing.

DR. TEMPLE: But I\'d still like to hear a little bit about ‑‑ I mean,
you had a difference of 3 over 2, or thereabouts, with people on
inadequate doses of enalapril. You\'ve got to imagine that if the dose
had gone up or if it had been b.i.d., the difference would be less than
that, and you certainly have to imagine if they\'d added a drug, which
in many cases they did not, the difference would have to be reduced.
Now, Norm had an estimate based on what happened when you did add a
drug, that it wouldn\'t be very hard to get control by adding another
drug, and yet they didn\'t.

Obviously, the question is, okay, on the one hand, I can get away
without this other drug. On the other hand, I have the angioedema. So,
you sort of have to know how you do with another drug. Or maybe you
don\'t think you do. So, what do you think about that?

DR. FLEMING: Henry, just for my understanding of your response to Bob\'s
question just now, you\'ve made the strong point that we have to do
better in being able to get a larger fraction of patients to target and
that it\'s hard. A lot of the existing agents in a lot of patients are
unsuccessful. Yet, it seemed in this trial that there was a large
fraction of patients in which there wasn\'t even the attempt made or the
additional ‑‑ in the population here in table 5 in the FDA briefing
document, it looks like there are approximately 20 percent that received
adjunctive treatment in weeks 9 to 14 and large fractions in the first 8
weeks didn\'t get to maximal dosing.

So, that seems to be perplexing. It seems like in the majority of cases
we\'re not taking advantage of what there already is available to us to
achieve what you\'re saying we need to achieve. It\'s not a matter of
they\'re trying it and it\'s not getting there.

DR. BLACK: I think that worked in both arms of the study. You didn\'t
get to 90 or 100 percent control rates in the omapatrilat arm either.

DR. FLEMING: In both arms.

DR. BLACK: In either arm. And that\'s only 6 months. Ours is a year. The
trials are 4 and 5 years. So, there are several different ways to look
at that.

I don\'t think that\'s how people practice. We have an education message
for that as well, but I\'m not sure we can manage even with what we do
in trials or what happened here to get people to practice as we would
like them to do it. I think a couple of extra millimeters for each one
of our steps is going to get us much further along the road. We\'ve got
a lot of education to do beyond what you see here to get people to use
what we have right and to have a more powerful tool to use that right.

The NHANES IV data is kind of almost done. NHANES III is where the 27
percent comes from. There\'s been a big national campaign to improve
control rates, and it\'s been, at best, only modestly successful. We\'ve
improved control rates in men to about 30 percent, which is about what
women get, but nowhere near what we ought to. So, there\'s a lot to
still be done. I think we need better agents. Even with the optimal
circumstances of a trial or of a specialist clinic, we\'re still not
where we want to go.

DR. TEMPLE: That\'s what I understood your argument to be. You\'re
basically saying how can we not do better if we have a drug that works a
little better than the thing it\'s going to substitute for. And maybe
that\'s sufficient. I\'m not trying to prejudge this, but that\'s not
the same as saying in a population where we couldn\'t get control,
here\'s what we know about substituting versus, say, adding another
drug. It\'s a question of whether you need data on that point or have
data on that point as opposed to making some not necessarily
unreasonable assumptions.

DR. LEVY: Let me just make two points. We freely concede that in
patients who can readily be brought to target with the addition of a
thiazide or up-titration of an existing drug or a switch to b.i.d., that
this drug is not needed. The drug is being proposed for use in patients
in whom the option of adding another drug or adding another drug and
reaching target isn\'t available.

Now, physicians in this trial, as you pointed out, didn\'t invariably
add adjunctive therapy when it was available to them. They did so about
40 percent of the time, and they were much more likely to do so in
patients whose blood pressures were well above target on monotherapy
than in those who were closer to target, just as physicians in practice
would. But there\'s a wide variety of practice represented in the trial.

What we did here was just to classify the investigative sites according
to the aggressiveness of the physician, how frequently did they add
adjunctive therapy at a visit where a patient\'s blood pressure was
above target? These are 20 percent of sites, the quintile, where the
rate of adjunct use was highest, and these physicians I think were very
diligent adding adjunctive therapy at least two-thirds of individual
visits where patients remained uncontrolled, up to 100 percent at some
sites. And even at these sites, you see the same difference in blood
pressure reduction between omapatrilat and enalapril that you see
overall. You see the same difference in control rate.

This speaks to Henry Black\'s point. In the difficult to treat patient,
if the physician decides to become more aggressive, add therapy,
up-titrate, they\'re going to do that whether the patient is on
omapatrilat or enalapril, and the results will be better with
omapatrilat.

DR. FLEMING: But that\'s not in your targeted subgroup. That\'s all
patients at the sites that had the highest adjunct use?

DR. LEVY: These are roughly 2,000 patients at the 20 percent of sites
where the physicians were most aggressive.

DR. FLEMING: So, what were the results at those sites that had the
highest adjunct use that were in your target population? What were the
results?

DR. LEVY: Well, we haven\'t done that analysis. You\'ve seen the results
were extremely consistent across this database.

DR. BORER: Tom and then Steve.

DR. PACKER: Jeff, if I could, I just want to address directly Bob\'s
question. You\'ve seen the data that Dr. Levy just showed you, but this
shouldn\'t be too surprising and I wouldn\'t be surprised if it were
shown in the patient population that was being proposed. The concept I
think is that if you have a patient who has easy-to-control blood
pressure and you can get people to target, then I think it would be a
very easy assumption to say that the difference between omapatrilat and
an ACE inhibitor could be made up by adding a diuretic. No big deal.

But if patients are very far away from target, then a diligent
physician, a really good physician, would then add incremental therapy
or give b.i.d. or however you want to do it to both groups. The
difference in blood pressure only disappears if there\'s a differential
use of adjunctive therapy or intensive therapy. But that differential
use would never occur if you\'re not to target. You would expect a
patient who is resistant to therapy to ‑‑ the physician would add
adjunctive therapy or optimize dose or would do whatever you would want
them to do to both groups. As long as they\'re far from target, the
difference in favor of omapatrilat would always persist.

DR. TEMPLE: So, that\'s an argument of logic, although it\'s not
necessarily an argument of data, although that last thing was
interesting.

DR. PACKER: Yes. But if you think about it as the fact that in order for
the difference to disappear, there has to be a differential use of
adjunctive therapy, which cannot ‑‑ and by the way, to a substantial
degree, the calculations that Norm Stockbridge made was 50 percent
difference in differential use. Regardless of what the number is, the
number isn\'t important. As long as you\'re far away from target, that
differential use won\'t happen, especially if you\'re requiring people
already to be on multiple drugs at the beginning.

DR. TEMPLE: It\'s still a question of whether that makes sense, which I
wouldn\'t say it doesn\'t, and whether there\'s actual data so you can
see actual numbers about how much better you do.

DR. PACKER: I think what I\'m addressing is not whether what I\'m saying
absolutely has to be true, but I think you were struggling with how it
could be true. What I\'m proposing is that\'s the explanation for why it
would be true.

DR. BORER: Why don\'t we move on to another issue. Tom.

DR. FLEMING: Can I have one last comment?

DR. PICKERING: It is actually a related issue. Starting with the
possibility that if OCTAVE had been continued longer, the difference
might have diminished, my reading of the protocol was that there were
only two clinic visits at which it was possible to add additional drugs,
which in my opinion is not very long.

Henry, you mentioned the ALLHAT trial. I don\'t know if we could see
your number 6 slide which shows that using conventional therapy in not
perhaps quite as high a risk population but certainly in an enhanced
risk population, you can in fact do extremely well, going from 27
percent to 69 percent control at 6 years. I guess it\'s a question of
whether you see the glass is half full or half empty, but I would say
that\'s a huge increment just with the use of conventional therapy.

DR. BLACK: I would agree. I think we did make a lot of progress, but I
think there\'s still a lot more progress to be made especially in what
we don\'t have the tools for. These people are seen every 4 months.

One thing too, when you begin to add third and fourth and fifth drugs,
you get into less well-tolerated drugs, drugs with their own inherent
problems too. It\'s not just adding drugs that are free of side effects
when you get to that, and patients don\'t comply well with that. So, we
begin to run out of well-tolerated options a little earlier than maybe
has been implied.

But we\'re not doing badly here, nor did we in CONVINCE, but we\'re not
doing nearly as well for systolic as I would like to do. That\'s where
the problem is I think.

DR. BORER: Bob.

DR. TEMPLE: Well, Henry, if I remember ALLHAT, the additional therapy
was sort of peculiar. For example, if you were in the diuretic group ‑‑
you tell me ‑‑ you couldn\'t use an ACE inhibitor because that was
another group and that would have confounded. So, you were limited in
the number of specific additional drugs you could use.

DR. BLACK: The trial protocol ‑‑ the artificiality of any active
comparator where you can\'t use what you would ordinarily use ‑‑

DR. TEMPLE: No, I\'m not blaming the trial. But it means that may not be
as good as ‑‑

DR. BLACK: What you could do, though, if you felt you needed it, was add
an agent of the blinded class at half the initial dose, drop down your
drugs. So, you could do it. I don\'t have the drug use in ALLHAT yet as
to how many people got on open-label, how many people crossed over, but
it was in fact substantive. It wasn\'t just that you couldn\'t do it.
People did use their own drugs.

DR. BORER: Steve.

DR. NISSEN: I feel compelled to point out for Bob and for others, which
I know everybody here knows, but we don\'t know whether that extra 3
over 2 millimeters for this drug actually lowers events. So, this is all
hypothetical, what if we did this and what if we did that. The reality
is if there were a very large difference between the arms, I think one
could be more confident, but these are small differences. Therefore,
without knowledge of the relationship for this class of drugs on the
amount of blood pressure control versus morbidity and mortality, we\'re
really speculating about what the ultimate impact is going to be.

DR. BORER: Are there any other questions, issues the committee wants to
raise? Because if not ‑‑ Tom.

DR. PICKERING: I\'d like to return to the issue of adherence. I think
we\'re all agreed that omapatrilat is a more effective antihypertensive
than the other existing drugs. One of my concerns is what the adherence
will be with this medication, given all the warnings and education about
potential risks. It could be that the potential benefits in its potency
might be offset by decreased compliance.

On that note, I think it\'s just worth mentioning that patients\'
self-report about compliance with antihypertensives is generally thought
to be next to worthless. Pill counts are maybe a little better, but a
lot of the pills end up in the parking lot of the hospital of people in
studies. So, I think it is a real issue, and I would be concerned about
this.

DR. BORER: We\'ll structure the remainder of our discussion around these
questions. I want to frame them before we begin. I think, although the
questions are reasonably straightforward, there are some key issues
about which we need to make judgments.

First ‑‑ and Tom just mentioned this ‑‑ is are we convinced that
omapatrilat is more effective within the labeled range than other
available antihypertensive agents so that one might expect that it could
add something. And a subset of that is does it add to other drugs that
might be given at the same time.

Second, is there a population that could be controlled by omapatrilat
that cannot be controlled with all the other conventional therapies and
approved therapies that we have?

Third, if there is such a population, can we define it?

Fourth, if there is and we can and we do give the drug and it does lower
blood pressure by some amount, is there a clinical benefit associated
with that, something what we really have never required anybody to show
and maybe we can take on faith. But the issue still remains as Steve has
said several times.

Finally, assuming that lowering blood pressure is equivalent to a
clinical benefit, what are the risks associated with gaining this
benefit in the specific group that we have defined that couldn\'t be
controlled in any other way than by adding omapatrilat? That\'s really
the sequence of issues that we have to face and we\'re going to face
them in different ways in these questions.

Bob.

DR. TEMPLE: If you got to that point, you would also really need to
address the risk management program and whether you think that will do
it. We have people here who reviewed the risk management program who
could comment further than what they\'ve already written, if that were
helpful.

DR. BORER: Ultimately, presumably that mitigates to some extent or may
mitigate to some extent the total risk, and if you believe there are FDA
comments about that, then perhaps when we get to that question, we\'ll
ask for the comments.

DR. TEMPLE: Well, you\'ve seen some of them.

DR. BORER: Yes.

DR. TEMPLE: There\'s a fair amount of skepticism probably noted.

DR. THROCKMORTON: It\'s important for us to hear some comment around
that I believe not perhaps specifics that this one thing you think works
or whatever it is, but what you said, Jeff, was perhaps it reduces the
risk or changes the risk somehow. We need to understand whether there\'s
sort of a belief that that is possible or is not. Again, not necessarily
that you know the exact right answer but that you are optimistic about
those things as possible would be something we need some help on.

DR. BORER: You\'ll hear it.

Why don\'t we then begin. What I\'d like to do, I\'ll read the preamble
here, and then as we go through these questions, I\'d like to hear
Tom\'s response first, Tom Pickering because he is a nonvoting member,
and then we\'ll go to Steve who\'s our committee reviewer and then to
Tom Fleming and then the rest of us.

The committee is asked to provide an opinion on the approvability of
omapatrilat for hypertension. Omapatrilat is an inhibitor of
angiotensin-converting enzyme and neutral endopeptidase. Reviews of
chemistry, pharmacology, toxicology, and biopharmaceutics present no
apparent barriers to approval. Omapatrilat clearly lowers blood
pressure.

During its initial development, an increased risk of life-threatening
angioedema was noted for patients taking omapatrilat compared with other
antihypertensives, including ACE inhibitors.

To characterize this safety finding and to gain additional information
on the relative antihypertensive efficacy of omapatrilat, the sponsor
conducted the OCTAVE trial.

OCTAVE was a randomized, double-blind study in which 25,302 subjects
with hypertension were randomized to once-daily enalapril or omapatrilat
and followed for 24 weeks. During the first 8 weeks, subjects were
titrated to a maximum dose of 40 milligrams enalapril or 80 milligrams
of omapatrilat as needed, after which subjects who did not achieve the
blood pressure goal could have additional antihypertensive agents added
through week 24. At 8 weeks, 41 percent of subjects in the enalapril
group and 33 percent in the omapatrilat group were on the highest
recommended doses. Between weeks 8 and 24, 19 to 36 percent of the
enalapril subjects and 13 to 26 percent of the omapatrilat subjects
added antihypertensive therapies. At 8 and 24 weeks, omapatrilat had a
significantly greater effect to lower trough blood pressure compared
with enalapril, but angioedema, including serious angioedema, was
significantly more common in subjects taking omapatrilat. And we have a
table outlining those data.

With these results and the data from the other trials of omapatrilat,
the committee is being asked to characterize the risks of omapatrilat,
to identify and characterize the benefit to which this risk needs to be
compared, and to discuss whether omapatrilat\'s benefits outweigh its
risks.

So, we\'ll begin. How should one best characterize the risk of
angioedema with omapatrilat? 1.1. Are the clinical features of
angioedema associated with omapatrilat similar to those associated with
approved ACE inhibitors? Tom.

DR. PICKERING: Well, I think we\'ve heard quite convincingly that the
clinical features are generally similar, although with omapatrilat, the
extent of the angioedema is more likely to be severe.

DR. BORER: Is it not true that the angioedema tends to occur earlier
also with omapatrilat than with the ACE inhibitor?

DR. PICKERING: Yes, since most of the episodes did occur during the
first day.

DR. BORER: Are there any other comments about the characterization?
Steve.

DR. NISSEN: I want to emphasize that there\'s a pretty steep gradient
here compared to enalapril in terms of the risk ratio for mild,
moderate, and severe. So, it really looks like there\'s a significant
shift from the more mild forms to the more severe forms. So, it\'s not
just a quantitative measure. It\'s really also I think a qualitative
measure which I think you were saying also, Tom, that there is
disproportionately more severe angioedema with omapatrilat.

DR. BORER: Any other opinions?

(No response.)

DR. BORER: Then let\'s go to 1.2. In the original development program,
about twice as many subjects were exposed to omapatrilat 20 milligrams
than to 10 milligrams as an initial dose, and the rate of any angioedema
was about three-fold higher in subjects initially receiving 20
milligrams. OCTAVE\'s primary safety hypothesis was that starting
omapatrilat at a low dose and titrating up would reduce the risk of
angioedema of any severity to no more than twice that of enalapril. Was
this hypothesis supported by the study?

I don\'t think this needs much discussion. It wasn\'t. Is there any
dissent from that?

(No response.)

DR. BORER: No.

1.3. In OCTAVE, there were two cases of life-threatening angioedema
among 12,000 subjects treated for about 6 months. In the original
development program, there four such cases in a population about
one-third as large. Estimate the risk of life-threatening angioedema to
expect post-marketing and estimate the upper confidence limit for that
risk.

I think in fairness maybe we better begin with Tom Fleming for that one,
and then go back to Steve and Tom.

DR. FLEMING: Well, let me respond to this and add a little bit of
response that relates to question number 1.2.

The sponsor has provided us the estimate with these two cases that the
upper limit of the confidence interval is 5.7 per 10,000.

Let me just add to this answer to question 1.2 that as the question
indicated, there certainly was evidence before OCTAVE that those
patients at 10 would have had a lower rate of angioedema than 20.
Roughly, it appears 1.1 percent as opposed to the 2.4 percent. So, hence
the design of the trial to rule out that the rate could be as high as 2
percent, hoping it\'s around that 1.1 percent, and obviously,
disappointingly the rate was at 3.2 percent. So, as you said, Jeff, the
answer to 1.2 in that sense is no, although I\'d go on and say when one
looks at these life-threatening cases, the rate appears to be by
estimate 10-fold higher in those in the historical experience who had
received 20 as a starting dose.

So, the bottom line is, as I see it, the rates that had been hopefully
reduced to levels below the 2 certainly were not. The rate was 3, but it
might have that there was systematic under-detection in the previous
experience. My own read of this is that there probably is a dose
response, and again the best measure of that would be looking at the
fact that we see approximately an estimate of 2 with an upper limit of
5.7 per 100,000 life-threatening cases in the OCTAVE trial in contrast
to a 10‑fold higher rate than that in the previous experience at 20.

DR. BORER: How about the 1.3? I\'m sorry.

DR. FLEMING: I started off by saying the estimate that I accept that was
given by the sponsor that the upper limit of the 95 percent confidence
interval is 5.7 or about 5 to 6 cases per 10,000.

DR. BORER: Steve.

DR. NISSEN: Well, I think that, of course, Tom is right statistically,
but I think there are other factors that we have to think about here.
Let me see if I can make this very clear.

I\'m concerned that when the drug is administered in the community
outside of a setting of a clinical trial, the rigor, the discipline of
giving 10 and waiting 2 hours, and then waiting 2 weeks before
up-titrating, that we may lose some of that discipline in
administration. So, I would tend to raise that estimate somewhat because
I\'m not convinced that in general use you achieve the discipline that
you do in a clinical trial. So, I think I\'ve got to make some upward
revision of that estimate based upon the fact that in clinical use
recognition may be a little bit less because people may be further from
tertiary care centers, and therefore the risk of a life-threatening
event, which is what you\'re asking us, Bob and Doug, I think could be a
lot higher because I don\'t believe that this plan can be as tight as it
was in the clinical trial.

DR. BORER: Blase.

DR. CARABELLO: I see the potential actually for the opposite of that,
that in post-marketing that we don\'t release this to general use. I
agree with Steve. I think that\'s looking for trouble. The risk of an
angioplasty is not predicated so much upon the equipment or the
atherosclerotic lesion, but rather the judgment of the angioplaster. If
you have an experienced person with a lot of judgment, his or her
complications are usually less than someone who doesn\'t do it very
well. I think if you limit the use of this to people who have, because
of the kind of practice they\'re engaged in, extraordinary judgment, the
complication rate actually could be less.

DR. BORER: Yes. The problem is making that limitation. But let me ask a
question and you can comment on that and whatever else, Doug.
Dofetalide. In order to use dofetalide, it\'s necessary to go through an
educational program and then be approved for use. So, I guess the
precedent exists. I assume we could do that.

DR. THROCKMORTON: Yes. That\'s probably not a precedent, unfortunately,
that we\'ve had a broad amount of success with. We understand there has
been movement towards other pharmaceuticals perhaps in some areas
because people have been reluctant to use that.

DR. TEMPLE: But that is because there\'s an alternative. You can get
sotalol without it, unfortunately, for the same use.

DR. THROCKMORTON: Right.

DR. TEMPLE: But here that might not be true.

DR. CARABELLO: But going back to amiodarone or adriamycin, we have
plenty of drugs that, even if the agency doesn\'t restrict them, people
restrict their own use because they\'re scared as hell to use the drugs.
A generalist is not going to prescribe adriamycin to the next person who
walks into his clinic.

DR. THROCKMORTON: Right, and we of course don\'t restrict that at all.

And there is precedent for restricted distribution, which is I gather
what you\'re sort of talking about. Normally it\'s drugs that have
extraordinary toxicities that the Office of Drug Safety people are
convinced can be managed using those kinds of restricted distributions.
But it\'s very hard. And for an antihypertensive where we have several
dozens of alternatives, it seems like you\'d need to be able to make a
clear case for doing that. That would be a hard thing, maybe not an
impossible thing, but not straightforward.

DR. NISSEN: Just a comment, though. The analogy here of, say, the
angioplasty population, Blase, is not in my view a good one, and I\'ll
tell you why. Somebody doing an angioplasty looks at the lesion and all
kinds of characteristics and can kind of profile the patient. The
problem is other than skin color, I can\'t look at a patient and know
who\'s going to have it and who\'s not. So, I could be the world\'s
greatest expert in hypertension, but I\'m not sure that I can pick the
patient out who\'s going to have this side effect. So, it\'s not quite
the same as deciding who you\'re going to put a stint into.

DR. CARABELLO: Yes, but you can, as an expert in hypertension, pick out
the group of patients for whom the benefit is the most, at least alter
the risk-benefit ratio that way and say, okay, yes, you may get
angioedema, but in your case my judgment is you\'re the patient who\'s
likely to benefit from this drug. People like Dr. Black and others might
well want to have this drug in their armamentarium when the other stuff
doesn\'t work.

DR. TEMPLE: We\'re developing numerous models for risk management.
You\'re familiar with one of them, bosentan, Tracleer, where there\'s a
central distribution system, and it is shipped directly to the patient
from a single place, which allows you to assure that people get the
information which could include a video or a lot of different things.
That\'s relatively extreme, manageable with a relatively small
population, somewhat intrusive, but in that case we thought it was worth
it. And there is a wide range of others. Anne or Julie could probably
tell you some of the details.

One that might be considered highly relevant would be what we did with
Lotrinex, which has risks of somewhat the same order of magnitude and
severity, but we thought it was appropriate for a well-described
population of people who were made miserable by their irritable bowel
syndrome. That\'s no so different from people who are put at very high
risk because their blood pressure is uncontrollable. So, perhaps a
description of that.

But in fact, we\'d like to hear what you suggest. Obviously, shipping
directly from a central pharmacy is burdensome in one sense but worth it
if the risk is bad enough and if you really want to be sure all of the
people involved get educated. As an example, if you wanted to be
absolutely sure that patients knew what angioedema was like, well, the
only way to make really sure is to tell them, enable them to ask
questions, show some pictures of it, or something like that. So, I\'m
skeptical of whether your local pharmacist will be able to do this in a
reliable way, but there might be other people who could do that.

So, there\'s a very wide range of possibilities. We\'re happy to hear
any suggestions you have, and if that was considered sufficient to make
this available, we would work with our own staff and them to figure out
what that is. They\'ve ranged from giving good advice, having a patient
insert, putting a black boxed warning, all the way to specialized
distribution systems.

DR. BORER: Well, that\'s exactly the point we\'re up to here, 1.4. I\'m
sorry. Tom.

DR. FLEMING: I was just going to briefly say, as we\'re leaving 1.3, I
accept Steve\'s comments as amending my response. My response is based
on what this trial shows, and I understand clearly your concern and
endorse that concern that this, in fact, in clinical practice could be
worse. Blase makes the relevant point that we may well have a
differential benefit-to-risk, but other than blacks and smokers we
don\'t know how to prevent this. So, I accept your point, Steve.

DR. BORER: 1.4 requests some opinion about the risk management plan. The
sponsor has proposed a risk management plan focusing on patient
education by pharmacists. To what extent can a risk management program
based on patient education be expected to reduce the risk of death from
angioedema?

Why don\'t we begin this time with Steve, and then we\'ll go to Tom.

DR. NISSEN: Well, I think it\'s a start and I think it certainly does
help. The question is how large a magnitude of reduction in risk will we
get. It\'s not going to prevent angioedema. What it might do is get
people to seek treatment earlier, and I\'m convinced by the arguments
from Dr. Kaplan that that could make a difference.

I actually think to really reduce risk, a much more comprehensive
program of risk management will be required. I was a little surprised
there wasn\'t much more here for physician education because, in fact, I
must tell you that I didn\'t understand the subtleties of differences in
what drugs work and what drugs don\'t work and so on. So, in my view we
would have to get information to most emergency department physicians.
We\'d have to make sure they understood about omapatrilat, they knew
what to do, how to do it, and so on. I didn\'t see that in here. So, I
think the effect here of this is likely to be modest rather than more
than that.

DR. BORER: Tom.

DR. PICKERING: Yes, I generally agree. I think it\'s a great idea, but
my impression is that brief pharmacy education programs are not in
general terribly effective. Again, I guess I would be concerned about
what happens in a sort of busy pharmacy in Harlem where there\'s a long
line of patients waiting for their prescriptions, how much time there
would actually be to do this. I think it\'s an untested possibility.

DR. BORER: Mike, do you have any thoughts about the education program,
the risk management program?

DR. ARTMAN: Yes, I agree with what Tom just said. I think, in a
practical sense, it\'s impossible to say that this is going to be useful
or not. It\'s interesting talking about where the trials were done. I
assume if this is going to be used overseas, we heard from Dr. Black how
he had an experience in a remote emergency room in Connecticut and
everything came out of fine, which he said was like being in Russia. But
I wonder what it\'s really like in Russia. So, I have little confidence
that this risk management plan is going to do anything.

Now, that said, the sponsor also sort of made the case that it really
doesn\'t matter because these are obvious signs and symptoms. The
patients recognize them. They come on slowly. So, it\'s six of one, half
a dozen of the other. I don\'t know which side of the fence they\'re
sitting on.

DR. WACLAWSKI: Dr. Borer?

DR. BORER: One second. Once we start this part of the session, we don\'t
really want input unless we ask for it.

Susanna.

DR. CUNNINGHAM: Is there any evidence that actually a pharmacist-based
program can do risk reduction? It\'s a very theoretical thing and I
think, really, we\'ve already heard how it probably is quite
impractical. So, I would be interested if somebody has evidence that it
would work.

DR. BORER: Is there any experience that we can refer to?

DR. TEMPLE: Julie or Anne may want to comment, but I\'m sure they\'ll
tell you the answer is probably not. But come on. Don\'t let me speak
for you.

DR. TRONTELLE: I\'m Anne Trontelle from the Division of Surveillance
Research and Communication Support in the CDER Office of Drug Safety.

We do have some evidence. It\'s mostly known at this point to be
published by Duke Center for Education and Research in Therapeutics on
the dofetalide program which involves not only education of pharmacists,
but also of practitioners and specially staged introduction of that
drug. I think there\'s some suggestion of improved efficacy over
comparable drugs, but that\'s again a highly specialized program and one
that has probably resulted in substantial voluntary restriction on use
of the product perhaps because that program has been perceived to be
burdensome. We really are lacking data from any of the other programs at
this point.

DR. TEMPLE: But a crucial distinction. You start dofetalide in the
hospital or some ambulatory equivalent.

DR. TRONTELLE: That\'s correct.

DR. TEMPLE: So, it\'s not your local CVS pharmacist who\'s responsible
for this. It\'s the hospital pharmacist. Well, no. That was no offense.
It\'s not your local pharmacist. It\'s a highly specialized group of
people and there\'s a lot of exchange of information. But do we believe
that a complicated information system will be handled by local
pharmacies? I\'m not aware of any information, and as a profound user of
many drugs, I think that\'s very unlikely.

(Laughter.)

DR. TRONTELLE: I think it\'s hoped for but we don\'t have data at this
point.

DR. TEMPLE: Actually we know that patient package inserts are not well
handed out by local pharmacies. That\'s a not a very hard thing to do.
But we even know that. That seems unlikely.

DR. ARMSTRONG: Maybe I\'ll speak to that point and also give an opinion
on this issue on the table.

There is data in western Canada on pharmacists and cholesterol lowering
and adherence to medication which engages pharmacists and actually
demonstrates enhanced adherence to the guidelines. So, there is some
data.

On the point about the education program on the table, notwithstanding
the great intentions and efforts of the sponsor, my worry would be that
the infrequency of the event, even with the best efforts of educating
the physicians and the patients would lead to desensitization, and I use
that term advisedly in relationship to recognition of the event as time
elapses.

DR. NISSEN: Would the pharmacist be reimbursed for this activity, or
would this be sort of gratis?

DR. THROCKMORTON: Yes. It\'s important to note and we may want to ask
the sponsor to comment on it. The program they\'ve proposed, the outline
of the program ‑‑ again, remember, the specifics would be worked out
were you to give us some level of comfort that it was possible. The
program that they\'ve outlined involves a central pharmacist who would
interact with the patients initially and I wouldn\'t want to guess how
that person would make their living. The sponsor might want to comment a
little. Is that enough, Elliott, that there\'s a central pharmacist and
then a follow-up with the dispensing pharmacist?

DR. LEVY: Well, there\'s no intention to make the local pharmacist the
focus for patient education. We would use pharmacists in a program that
would require that every patient receive counseling before they went to
the local pharmacy and got the drug. That, of course, is in addition to
physician counseling and to a host of messages that are provided them
through the packaging and educational materials.

DR. CARABELLO: I personally don\'t think we\'ll have too much success in
mitigating risk, although patient education to let them know what
angioedema is would clearly be valuable. Going back to my original plan,
I think our best bet is trying to improve the risk-benefit ratio by
focusing on the prescriber so that whatever the risk is it\'s only
matched by the higher benefit by prescribing this to some specific
patients.

Finally, I\'d like to distance myself from any group that would compare
both South Dakota and Connecticut to Russia. I think that\'s a very
dangerous thing to do.

DR. BORER: Because you have asked for a lot of opinions about this, I
want to say a couple of things here in addition to what\'s already been
said.

My perception of the risk has been modified in an important way by Dr.
Kaplan\'s comments and the fact that there are perhaps several hours off
usually before major sequelae of angioedema might be expected to occur.
On the other hand, that means you have to be within a couple of hours of
help and you have to be aware that you need help.

I share the concern that has been raised by a couple of people on the
committee that a patient education program just isn\'t going to cut it,
or by itself it won\'t. It\'s an important component if one could do
this at all, but the physician education is crucial. I don\'t know how
one could achieve adequate physician education without limited
distribution, which is a tall order, as we\'ve heard. So, I have real
concern that a practical program could be developed.

But I do not believe that a risk management plan focusing on the
patients and the pharmacists would be sufficient to deal with the risk
if we perceived the risk to be an important risk relative to the benefit
and if ‑‑ on and on and on. Again, I think we still have to discuss what
the risk is in view of the information we received today, but I don\'t
think this kind of a plan would do it.

Was there another comment?

DR. THROCKMORTON: Susanna, do you have a comment at all?

DR. CUNNINGHAM: No.

DR. BORER: Tom, I\'m sorry. I didn\'t ask you specifically for a comment
about this.

The sponsor has shown the results of OVERTURE ‑‑

DR. TEMPLE: Jeffrey, before we leave that, could we hear other people\'s
views of that last point? I mean, that\'s not unimportant, after all.
You are skeptical that anything but a limited distribution system which
allows you to interact clearly with the physician ‑‑ I assume that\'s
the point ‑‑

DR. BORER: That\'s right.

DR. TEMPLE: ‑‑ is likely to do anything. Is that everybody\'s view?
That\'s potentially very critical depending on your answer to the rest
of it.

DR. BORER: Well, let\'s hear.

DR. NISSEN: I also concur.

DR. CARABELLO: I think I made my own point clear.

DR. CUNNINGHAM: I agree.

DR. ARTMAN: Well, I agree but yet even that ‑‑ there are two issues. One
is controlling the use of the drug and restricting its use, and the
other is managing this adverse event and that we can\'t really predict
who\'s going to get that. There are some that are at little bit higher
risk than others, but anybody who\'s on this drug for any given time at
any dosage may develop significant angioedema. So, yes, I agree with
that that you can maybe minimize it by minimizing the number of people
you expose, but I think it\'s a whole different issue to say that
that\'s going to reduce the risk. I don\'t think it will.

DR. TEMPLE: The theory I think ‑‑ Blase has said this several times ‑‑
is that you make the risk acceptable because the benefit is particularly
good. That\'s certainly the theory of Lotrinex. If you only give it to
people who are willing to accept and understand all the various risks,
then the benefits might outweigh the risk for that portion of the
population, whereas if you just gave it to everybody with IBS, you
wouldn\'t feel that.

DR. ARTMAN: Well, let\'s extend that logic that Blase used to amiodarone
and angioplasty. There are knuckleheads out there using amiodarone and
angioplasty. And some of these things started out being sort of
restricted. So, once the cat is out of the bag, all bets are off.

DR. NISSEN: There\'s one other part of the equation again I think
that\'s very important to understand, and that is that the suggestion
here is that we can optimize risk-to-benefit ratio by selecting patients
that are most likely to benefit. Tom Fleming tried to drill down very
hard to find that group that\'s most likely to benefit and to see
whether or not there\'s very good evidence here that lets us identify
such a group and then to estimate the magnitude of benefit.

The problem I have is I\'m not quite sure how to drill down to that
group that\'s most likely to benefit, and I\'m certainly not sure how to
estimate the magnitude of benefit of a 3 over 2 millimeter blood
pressure difference in a new class of drugs. So, this is all predicated
on the assumption that we know that and therefore, by picking these high
risk individuals, we can somehow optimize overall benefit, and I just
don\'t think the data gives us that information.

DR. BORER: Let\'s go on to question 2. The sponsor has shown the results
of OVERTURE, a comparison of omapatrilat and enalapril in the treatment
of chronic heart failure. If the results of this study are as presented,
how relevant are these data to the approval of omapatrilat for
hypertension?

Tom and then Steve.

DR. PICKERING: Well, I certainly think the results are relevant because
I guess we were hoping there was some evidence of additional benefit on
outcomes from omapatrilat above those of enalapril. But my own
interpretation is that the study was negative. In terms of the blood
pressure reduction, there doesn\'t seem to be any convincing evidence
that there was a difference using the b.i.d. dose. On the other hand, I
guess you could argue that the doses weren\'t necessarily the maximal
that are used for blood pressure control, and it wasn\'t designed as a
blood pressure study. So, the bottom line is I don\'t think it adds a
whole lot of support for the case.

DR. BORER: Go on to 2.2. How reassuring are these data with respect to
the use of omapatrilat in a hypertensive population? I think you\'ve
just answered that, but do you want to elaborate a little bit? I think
you\'ve answered it.

DR. PICKERING: Yes.

DR. BORER: Steve.

DR. NISSEN: I guess I think the OVERTURE data are minimally relevant.
I\'m glad we have them, and I agree with Milt Packer\'s suggestion that
it does tend to make us believe that there\'s not being harm done by
this drug with respect to that particular group of patients. But because
it is a different group of patients, it\'s hard to interpret it.

I think I\'m convinced that probably there was a blood pressure
difference in OVERTURE, particularly given the greater incidence of
hypotension. But I think the amount of weight I would put on OVERTURE in
our decision is very, very small, and I wouldn\'t urge us to consider it
very much in our overall decision making.

DR. TEMPLE: Let me ask a specific question. You\'ve raised the issue
several times now that you don\'t know what a new drug that hasn\'t got
outcome data does. You don\'t know whether the expected benefit of a 3
millimeter of mercury systolic pressure difference ‑‑ okay.

Well, there are a number of possible reasons for that, but one of them
is maybe it\'s like a high-dose diuretic and it kills you in some way.

One might have argued ‑‑ I\'m not trying to put words, but we need to
understand this because, without understanding, we might go off and say
the wrong thing. One might think that OVERTURE is somewhat reassuring on
that point. You have a fragile population susceptible to getting MI,
sudden death, all those things, and that didn\'t happen to them. So, why
doesn\'t that, to some extent, contribute to your answer on that?

DR. BORER: Let me respond to that. It does for me. I don\'t think that
the OVERTURE data are the panacea to respond to our concerns, but it\'s
hard not to begin to develop the belief that there isn\'t a smoking gun
in terms of other cardiovascular toxicity out there. When you look at
the OVERTURE data, as Tom said, it\'s not an antihypertensive study and
the doses were half the maximal doses that were given in OCTAVE and half
the maximal doses that would be used in clinical practice, though they
were relevant for a heart failure study. But remember, of the people
with heart failure, more than half had coronary disease as the basis,
and we didn\'t see a jump in myocardial infarction, sudden death, and
whatever.

So, I think these are useful data. They\'re not dispositive, but I think
they\'re useful data in making us focus in on the safety concern that we
have to balance against the benefits, specifically the angioedema. It
wipes away some of the potential peripheral noise.

DR. NISSEN: Bob, I wanted to also respond directly. Let me see if I can
be clear about this.

I agree with Jeffrey and I agree with Milton that it does, in fact, help
us in the belief that there is no harm being done by the drug. But I was
speaking to the question of what inference can we place on that 3 over 2
millimeter blood pressure decrease upon the likelihood that that will
produce an incremental benefit on events, and I can\'t tease that out of
OVERTURE. I still don\'t know yet whether the better blood pressure
reduction that we get with omapatrilat will, in fact, ultimately
translate into a reduction of events.

DR. TEMPLE: You obviously have no direct information on that. And Henry
may be invited to talk to this too. The people who do meta-analyses and
look at various drugs generally reached the conclusion that, if you
like, it\'s the blood pressure, stupid, and that a fallen blood
pressure, unless it\'s balanced by something toxic or some failure to
treat a component, maybe like doxazocin, will have the expected effect.
That\'s not proof, but I\'m curious to know where your skepticism comes
from. Do you doubt that or where does it come from?

DR. NISSEN: I do doubt it, and I doubt it because of some studies. I
doubt it because LIFE is a study where similar blood pressure reductions
produced different effects on events. Looking at all the different
events, I\'m pretty well convinced, for example, that the same amount of
blood pressure lowering with a calcium channel blocker may lower stroke
to a greater extent than, say, ACE inhibitors, whereas lowering with ACE
inhibitors may do a better job of preventing heart failure. I think
there are lots of clinical trial data that suggest it is not just the
blood pressure, stupid.

I think that given that fact and given the fact that we\'ve got an
entirely new drug in a new class, I cannot estimate ‑‑ and OVERTURE
doesn\'t allow me to estimate ‑‑ the magnitude of benefit of a 3 over 2
blood pressure increase on the long-term morbidity and mortality in this
population. It was even a different population from OVERTURE.

DR. BORER: Are there any other comments from the committee about
OVERTURE? Susanna. I\'m sorry. Tom.

DR. FLEMING: I find OVERTURE very relevant to the setting in which it
was conducted. In this chronic heart failure setting, we see a 6 percent
reduction in these primary endpoints, and in my sense, a nonsignificant
modest difference here is not an adequate difference when you\'re
looking at angioedema risks as part of the overall spectrum of side
effects.

To get to the question, though, how relevant is this to the
antihypertensive setting? As I understand it, in essence the way it\'s
supposed to be relevant is we ‑‑ and I\'m going to oversimplify the
world probably, but omapatrilat, let\'s say, is an inhibitor of ACE and
NEP, and let\'s say that it\'s the inhibition of NEP that\'s the causal
mechanism by which we\'re achieving a higher level of blood pressure
control. So, what I really want to do is be able to be reassured that
the only effect that that inhibition of NEP has is mediated through this
blood pressure control. That\'s essentially, I assume, the reassurance
I\'m supposed to get out of this study. And yet, I don\'t see the
magnitude of blood pressure difference in this setting that I have in
the antihypertensive setting.

I struggle to see the logic behind how I\'m going to be able to then use
this as a way to conclude that in the antihypertensive setting, that
these data provide me compelling evidence or reliable or even useful
insights that I\'m not going to have unintended effects on clinical
endpoints which, in fact, wouldn\'t have to occur in the magnitude that
they would occur in a chronic heart failure setting to be important on
relative risk. Events are much more rare in an antihypertensive setting.
So, if something doesn\'t show up in a setting where events are
frequent, it doesn\'t mean that there isn\'t a signal there that\'s
being lost in the background of a lot of other naturally occurring
events that in the antihypertensive setting would be important. So, I
don\'t see how this is informative for our setting.

DR. BORER: May I just ask you to elaborate a little further, Tom? I
wonder whether the data from OVERTURE have to be understood in context
of the data from OCTAVE about cardiovascular events. There was no
significant reduction in cardiovascular events, but they went in the
right direction and we didn\'t see a problem with excessive
cardiovascular events in this very high risk population of OVERTURE.
Taken together, do they or do they not give you some confidence that we
don\'t have to be overly concerned?

DR. FLEMING: There\'s not nearly enough known to draw that conclusion.
One could argue ‑‑ and maybe it\'s entirely wrong ‑‑ that what small
trends that are there are, in fact, due to the intended mechanism that
is the added blood pressure control.

What I want to be reassured about is the point Steve has articulated on
several occasions, and that is if we now have a new agent that not only
is an inhibitor of ACE but NEP and it may be through that mechanism that
we get this additional 3 millimeter blood pressure control, that I can
now conclude I\'m going to achieve the full benefit in reduction of
clinical events, and there won\'t be any other unintended effects on
cardiovascular events. I can\'t glean that from the OVERTURE data.

DR. TEMPLE: But, Jeff, this is really critical. If the committee as a
whole doesn\'t believe that lowering the blood pressure more, even if
that were well documented, is of any value, then we can stop now.

DR. BORER: But I\'m not sure we\'re at that point.

DR. FLEMING: We\'re not at that point.

DR. BORER: We\'ll answer that question.

Blase.

DR. CARABELLO: Just to make the point that in OVERTURE, I think it is
somewhat reassuring that in what is surely a very sick group of
patients, we didn\'t see increased cardiovascular events.

But the other point I was going to make is that in some respects this is
comparing apples with freight trains. Remember, cardiologists only have
to remember two things at once. In this case it\'s total peripheral
resistance and cardiac output. And the two things supporting blood
pressure and heart failure are so vastly different with every system
known to man revved up and screaming at one another. Whatever the
difference between that is and in essential hypertension I don\'t know,
but I suspect that we\'re talking about two very different
pathophysiologic settings.

DR. BORER: Paul.

DR. ARMSTRONG: Just to respond to Bob\'s point, I\'m not sure that the
prevention of the degradation of AMP, adrenomedullin, and bradykinin
long term aren\'t harmful. So, I\'m not prepared to accept blood
pressure lowering with this agent as a likely mechanism for the
prevention of long-term cardiovascular morbidity and mortality.

DR. BORER: Bob, has pointed out that we do have to deal with this issue
as to whether we accept blood pressure lowering as a surrogate. I think
that what\'s developing from this discussion may not be that everybody
wants to tell the FDA to junk the surrogate ‑‑ or maybe they do and
we\'ll ask specifically ‑‑ but that when the surrogate is achieved by
the use of a new agent that acts by a different mechanism, are the risks
associated with the use of that new agent sufficiently modest so that
even though there may be mechanism-specific differences in the magnitude
of benefit from a given degree of blood pressure lowering, we can assume
that the blood pressure lowering causes a benefit sufficient to overcome
those risks that we don\'t understand so well. That\'s sort of a
complicated statement, but I think you get the idea.

DR. TEMPLE: But it is fundamentally untestable. You can\'t use this in a
10,000-patient study because it wouldn\'t be even ethical to even give
those people the drug.

DR. BORER: Right.

DR. TEMPLE: Just remember.

DR. BORER: Just to answer your question, is there anyone here at the
table who wants to tell the FDA today that we just cannot accept the
blood pressure lowering as a surrogate anymore?

DR. THROCKMORTON: In this case, you must say ‑‑ since yesterday you said
you could do that for drugs within the same class. Specifically you must
now be saying comparing drugs not within the same class.

DR. FLEMING: Jeff, we don\'t really want to make a blanket statement.
Right? I mean, I think as has been articulated by many people, it
depends on the circumstance. There are an awful lot of surrogates that I
wouldn\'t put much stock in at all. This one is one that stands out
among the few that really has some considerable credibility, and yet you
don\'t blanketly apply it. And there are certain settings, for example,
within drugs within the same class where there are no detected concerns
in safety where you\'re going to be more confident in relying upon it
than in other settings where you have different drugs in different
classes or, in particular, as is in this case ‑‑ I\'m not saying you
wouldn\'t give it some credence, but there is a higher bar that you have
to hit when you have to overcome an important significant side effect.

DR. BORER: I think that that statement probably stands for the committee
here. The committee isn\'t suggesting that the surrogate has to be
scrapped. We don\'t have the database to be able to suggest such a
thing. But with this particular agent, there is information that
indicates a risk that\'s higher than we might have expected for some new
antihypertensive drug, and now we have to explore whether the risk or
other risks that we haven\'t quite fully fathomed yet outweigh the
putative benefits of the blood pressure lowering. And that\'s what
we\'re sort of grappling with here.

DR. TEMPLE: I think I\'m hearing that you think under these
circumstances, it\'s sufficiently uncertain as to whether there is a
benefit, that there cannot be anything that outweighs the well-known
risk. The risk is documented. That can\'t go away. You can manage it,
but you can\'t make it go away. But in this case, you can\'t know with
enough certainty that there\'s a benefit of a 3 millimeter of mercury
difference, so that there is really no presumed benefit from that
outcome.

DR. BORER: I don\'t think that\'s the consensus here yet.

DR. TEMPLE: I\'m being provocative. I want to hear what you do think.

DR. NISSEN: I know you are and I really want to try to directly answer
that a little bit.

The reason that I think Tom Fleming said that it depends is because it
depends on the magnitude of the difference in blood pressure and the
magnitude of the risk. So, if you give me a drug that has no defined
risks above that of comparators and has a fairly robust and substantial
blood pressure advantage over a 24-hour period of time, we\'re going to
probably be just fine. And we did that yesterday. We took a few hundred
patient trials, a couple of trials, and we said a drug in the same class
with no special risks that has a couple of millimeters better blood
pressure reduction is superior.

So, if this drug could produce an 8 or 10 millimeter increase, very,
very robust differences, that would shift the equation a little bit. And
if the risks here were a bit smaller, if it were only a twofold increase
in the risk of angioedema, not a threefold, and there weren\'t these
racial issues.

And so, the reason it\'s context that makes a difference here is we have
to as clinicians and you have to as an agency balance the magnitude of
the benefit with the magnitude of the risk. What I think we\'re saying
is that for a 3 millimeter over 2 millimeter blood pressure difference,
we know that there are interclass differences in effect on events, and
those could potentially overwhelm that 3 over 2 benefit, particularly in
the context where safety is a problem.

DR. TEMPLE: I just want to ask one other thing. To my best knowledge, no
placebo-controlled trial of any class of drugs, which includes calcium
channel blockers, reserpine, hydralazine, even high-dose diuretics which
are lethal, has failed to show a favorable effect on stroke in other
matters. That doesn\'t mean there can\'t be differences between the
classes. There can.

But I would have said the general observation of lowering blood
pressure, barring some bizarre thing like causing arrhythmias, is always
good for you was fairly well established. You\'re absolutely right. That
doesn\'t mean there can\'t be interclass differences. But you don\'t
think that\'s necessarily good enough because you can\'t really quantify
it.

DR. NISSEN: Well, it\'s true, true, and unrelated. I mean, the fact that
drug X is better than placebo, because it lowers blood pressure, isn\'t
the same as saying that drug X is better than drug Y because it lowers
blood pressure by a little bit more. I think that\'s the problem. The
problem is we have shown interclass differences. So, it\'s true that
every drug that lowers blood pressure has been better than placebo. I
think that\'s right.

DR. TEMPLE: So, across class, even something that was a little bit
better at lowering blood pressure might not be better because of other
factors.

DR. NISSEN: And that\'s what ALLHAT is testing in an enormous
population. If ALLHAT is a wash, then okay. But I would make you a
prediction that different endpoints in ALLHAT may go in different
directions based upon which agent you use independent of blood pressure.

DR. BORER: Today, however, we have to make our judgment based on what we
know. Of course, ALLHAT isn\'t available yet.

And I want to hear Tom\'s comment about this, but I think to put it in a
slightly different context, I\'m willing to accept that 3 over 2 is
good. If omapatrilat is what it takes to get there, that\'s a good
thing. The issue is do the benefits outweigh the putative risks. At the
end of the day, we\'re going to have to come to a qualitative judgment
of that because there is absolutely no way we can quantify these things.
And we\'re going to get there, I promise. I don\'t know what that
judgment will be, but that\'s what we\'re going to have to do and
that\'s what we\'re sort of moving towards.

Tom.

DR. PICKERING: Yes. I\'m one of those who says that a 3 over 2 reduction
in blood pressure is extremely important clinically for the reduction of
risk.

I\'d like to sort of clarify what we\'re talking about in terms of risk
here. Maybe angioedema is one that\'s clearly defined, but I think I\'m
sort of hearing insinuations that there may be other risks that we
really don\'t know about, and if so, I think that\'s unfair to the
sponsors. What we should be judging is the blood pressure and the known
risks at this stage.

DR. BORER: Yes, I agree with that statement to the extent that we have
looked at the adverse event profile for this 25,000-patient study plus
the OVERTURE data for a different population. That\'s true. If anything,
it would tend to reassure one that bad things aren\'t happening. I think
Tom\'s point, which is absolutely right, is it also doesn\'t tell you
you\'re clearly benefiting in terms of event reduction from the blood
pressure lowering. On the other hand, that\'s not what the trial was
designed to do, but it does make a pretty reasonable case that there\'s
not a smoking gun out there that some horrible thing is going to happen
besides the angioedema, the relative importance of which we\'re going to
have to judge at the end of the day.

Why don\'t we try. Unless anybody has anything else to say about 2,
we\'ll move on to 3, which is fairly specific. Consider the
antihypertensive effects of omapatrilat relative to other drugs. 3.1. Is
omapatrilat superior to enalapril? What results support this?

Tom, can you give us an opinion about that?

DR. PICKERING: Yes. I would say the answer is yes and I accept that
these studies against twice-daily enalapril might have reduced the
superiority a little, but I would expect it would still be there.

As I said earlier, I\'m sort of disappointed that there aren\'t
head-to-head studies between omapatrilat and enalapril or lisinopril
plus a diuretic. I would very much like to see what those data would
show. I know there\'s an additive effect when you add omapatrilat to a
diuretic, but I think the head-to-head studies would have still been
helpful.

DR. BORER: Steve, what do you think about omapatrilat versus enalapril?

DR. NISSEN: I\'m convinced. If you show it in a 25,000-patient trial of
this strength, the evidence is just overwhelming that it is superior at
lowering blood pressure to enalapril. Not controversial.

DR. BORER: Tom, do you have any concerns about that? No. Anybody else?

(No response.)

DR. BORER: So, we\'re willing to accept the answer to 3.1 as being yes.

How about 3.2? Steve, why don\'t you start.

DR. NISSEN: Two adequately controlled trials against lisinopril in
reviewing Dr. Throckmorton\'s material ‑‑ and I think they were well
done, and there\'s also ambulatory blood pressure data. So, I think that
in fact there is adequate evidence of superiority to lisinopril.

DR. BORER: Tom.

DR. PICKERING: I agree.

DR. FLEMING: Well, I just have a comment, additional thought that will
apply to 3.2, 3.3, and 3.4, and that is I certainly agree the data are
there to establish a superior antihypertensive effect. All of these
studies, though, that will be relevant for 3.2, 3.3, and 3.4 had
starting doses of 20. So, these superior antihypertensive effects were
established in settings where, from a point estimate perspective, the
angioedema rates were maybe an order of magnitude higher than what we
see in OCTAVE, although I suppose it could reasonably be presumed that
had these studies also been done with the lower starting dose, that they
still would have yielded comparable improvements in antihypertensive
control or effects.

DR. BORER: So, you\'ve extended now to 3.3 and 3.4 and accepted
omapatrilat as superior to the other drugs as well.

Tom Pickering, would you agree with that?

DR. PICKERING: Yes.

DR. BORER: And Steve?

DR. NISSEN: I do not. I reviewed this pretty carefully. Let\'s take 3.3
first. There were two trials against amlodipine, one of which was
positive with a delta of minus 2.1, and one of which showed a delta of
minus .3 and a p value of .6. So, if you say it takes two trials, the
two trial rule was not achieved against amlodipine. Now, both trials
were adequately done, but I don\'t think there are two positive trials.
Doug, correct me if I\'m wrong, but when I read your review here, the
study CV137-032, your review said, failed to detect a significant
difference between omapatrilat and amlodipine, and the delta was minus
0.3, p equals .617. So, I would say not proven.

And for 3.4, I don\'t think there\'s adequate data against losartan. I
think the two trial rule requiring well-performed trials simply isn\'t
there. But correct me if I\'m wrong, Doug. You\'ve reviewed this.

DR. THROCKMORTON: Review the losartan data, maybe.

DR. NISSEN: You\'ll have to point me to the ‑‑

DR. BORER: While you\'re looking for ‑‑

DR. NISSEN: I think the only trial I saw was the LVH study, but maybe
there\'s something I don\'t know about. I don\'t think that was
adequate.

DR. BORER: While you\'re looking for them, though, remember that the
replicability of effect principle is really an approvability principle.
We\'re talking here about whether we have data that would convince us
rather that for approval purposes for moving forward with an opinion
about whether this drug adds something that the drug actually was more
effective than losartan or amlodipine, in which case it might be
reasonable. I\'m not suggesting you should do it, but it might be
reasonable to add the data together and look at the average. Both trials
went the same way, for example. I\'m not suggesting that that should be
the opinion, but one might look at it that way.

DR. NISSEN: Let me tell you why it\'s relevant.

DR. THROCKMORTON: Let\'s ask the sponsor to just briefly review the
losartan.

But just to comment, the general notion here was, is there any
superiority that you discerned for any comparative antihypertensives?
Where you define none, then we\'re done.

DR. LEVY: Just two points. First of all, in addition to the 38 study,
there were two adequate and well-controlled trials versus losartan, one
of which is shown here and the second of which is shown on the next
slide, which was an ambulatory blood pressure comparison shown on the
right.

I\'d just like to briefly comment on the -32 study. Dr. Throckmorton\'s
comment on the office trough diastolic blood pressure results are
correct. This was an ambulatory blood pressure study, powered for
ambulatory blood pressure. Primary outcome measure, ambulatory mean
blood pressure, which was positive, as were ambulatory systolic,
diastolic, and office systolic pressures. The sole outcome measure in
the entire program that I described to you that was not positive was the
office diastolic blood pressure in this study which was not even a
primary outcome variable.

DR. NISSEN: That\'s helpful I think. That might have been pruned, Doug,
from your packet because in the material we got, the losartan studies
were not in here. So, I didn\'t get a chance to review them.

DR. THROCKMORTON: No. That\'s correct. They were not part of my original
review.

DR. NISSEN: So, when I said there wasn\'t adequate evidence, it was
based upon what I was given to review. So, I stand corrected. It sounds
like you\'ve done the two adequate trials against losartan. So, I think
the answer to that is yes.

DR. THROCKMORTON: Jeff, we\'ve heard what we need, I believe, on this
question. You\'ve identified agents where superiority is adequately
demonstrated. That allows you to go the next step I think.

DR. BORER: Which we will now do. Question number 4. And here we\'re
going to need a vote. With what potential benefit should the risk of
angioedema be balanced? We may need a little clarification here from the
FDA, but let me read through the question. The sense of it is reasonably
clear, but we may need some specific clarification so we answer you
correctly.

With what potential benefit should the risk of angioedema be balanced?
OCTAVE allowed the addition of no new antihypertensive drugs during the
first 8 weeks, at which time the blood pressure was about 3 over 2
millimeters of mercury lower on omapatrilat. During the following 16
weeks, other drugs were to be added to meet blood pressure goals, but at
the end of 24 weeks, the blood pressure difference was still 3 over 2
millimeters of mercury. What explains the persistence of the
differential effect at 24 weeks?

4.1. Is a regimen including omapatrilat able to lower blood pressure to
an extent that combinations of enalapril and other drugs cannot? Which
is one of our key issues here. If so, is the risk-benefit comparison
between the risk of angioedema and the expected reduction in
cardiovascular events attributable to this blood pressure difference?

DR. TEMPLE: I think the question is should the risk-benefit comparison
be based on that difference. That\'s sort of the question that Norm
emphasized in his review and that I raised before. What if they had
added another drug or gone up in dose, which didn\'t happen? So, that\'s
the question.

DR. FLEMING: Which the second part of the question does more get at.

DR. THROCKMORTON: That is the second option. The first option, to phrase
it another way, is that omapatrilat has a property that allows a regimen
using it to lower blood pressure 3 millimeters of mercury more than any
regimen containing enalapril by some means. Even if you add additional
medications, you can\'t obtain those additional 3. If so and you
concluded that 3 millimeters of mercury matter, then it seems that what
you want to know is the potential benefits of those extra 3 millimeters
of mercury compared versus the risks of angioedema.

If, on the other hand, you\'re not convinced or on the other side, that
you believe that perhaps just adding one more drug in the OCTAVE trial
would have sufficed to bring the enalapril group to the same blood
pressure control as the omapatrilat group, then perhaps ‑‑ and that\'s
what we need to have some discussion about ‑‑ the comparison is the risk
of adding that additional approved medication compared with the risk of
the angioedema.

Does that help to clarify things?

DR. TEMPLE: But also, you don\'t know what would have happened had they
done that because it didn\'t happen.

DR. THROCKMORTON: They may be convinced that they do.

DR. TEMPLE: Yes, okay.

DR. BORER: I\'ll tell you what let\'s do here because you said you
wanted a specific vote on the components of this and we\'ll restructure
it so you get one. Let me start by asking Tom for his opinion because he
can\'t vote, and then we\'ll move on from there.

DR. PICKERING: My problem with this question is that I don\'t think this
was a question that OCTAVE was really designed to answer. It was
designed to look at the relative incidence of angioedema. The word is
\"cannot.\" I\'m not convinced that if the study had continued longer
and additional drugs had been added to the enalapril group that the
difference might have become smaller. I don\'t think I know. It may have
persisted, but as I say, it wasn\'t really designed to get at this
question.

DR. BORER: Steve.

DR. NISSEN: My sense here is that this was an artifact of the trial
design, and let me see if I can be clear. There were only two
opportunities for dose titration in the trial, in a relatively
short-term trial. If you think about patients and physicians and how
they care for them, there\'s a little bit of inertia here, and if you
see a patient over time and your blood pressure is not falling,
eventually you come around to adding another agent. Now, should we be
quicker on the draw? Maybe. Are we a little lackadaisical? I think Henry
and others have taught us that we are.

But my guess is that the reason there was such a small amount of
additional drug use in the enalapril arm related to that artifact of
only having two opportunities to do so, and if you had carried this
trial out for a year and had five or six or seven attempts, or
opportunities rather, to add additional drugs, that eventually you would
have seen some upward creep in the additional drug use in the enalapril
arm and that would have equalized. We don\'t know that. I\'m just trying
to help explain why that difference persisted.

DR. TEMPLE: Some trials, of course, insist that you titrate and insist
that you add if a criterion isn\'t met. This didn\'t do that.

DR. NISSEN: That\'s right.

DR. TEMPLE: The question is how important it is.

DR. NISSEN: Yes, and I guess what I\'m saying is I think this was a
design issue, not an efficacy advantage because I\'m convinced that if
those physicians had been instructed to do so and given time to do so,
they would have closed the gap between the two regimens. Or they might
have.

DR. CARABELLO: But, Steve, why wouldn\'t it work with the other arm as
well?

DR. NISSEN: I\'m not sure I understand your question.

DR. CARABELLO: Well, why wouldn\'t the ability to titrate omapatrilat
more aggressively continue to maintain the gap? Why would they only
titer to one of the arms?

DR. NISSEN: Well, because there was a differential. So, the group
that\'s in the differential with the higher blood pressures is going to
naturally get more adjunctive therapy. I think that there\'s a tendency.
If you\'re treating to target and you give the same target to both arms
and one arm has omapatrilat, then the group that doesn\'t have
omapatrilat is going to end up getting more adjunctive therapy and is
going to tend to close that gap. So, I\'m going to guess that a 1-year
trial with five or six opportunities to titrate would have ‑‑ now,
whether it would have closed it completely or not, nobody knows because
it wasn\'t done. But I think that\'s the explanation for the difference.

DR. BORER: Yes, I think an important issue here is that, for better or
for worse, we treat to goal and once you achieve the goal, perhaps
inappropriately there really isn\'t an aggressive attempt to lower
further. If you weren\'t able to achieve the goal in either arm,
presumably you\'d give more and more and more drug until you did, and
then we would have known the true impact of omapatrilat.

Susanna, do you want to talk about 4.1 and 4.2?

DR. CUNNINGHAM: Well, I don\'t think I know for sure what would have
happened, just as Steve has just outlined. So, I think it\'s
unfortunate.

DR. BORER: Do you have any other comment?

DR. CARABELLO: No.

DR. BORER: Mike, Tom.

DR. FLEMING: Should we be answering both questions?

DR. BORER: Yes.

DR. FLEMING: Actually there are two parts, as I see it, to 4.1. The
first is relating to the answer that Steve was just giving about whether
omapatrilat is able to achieve better blood pressure lowering than other
combinations would be able to do. I support Steve\'s answer and I would
ask one other scenario that could justify why more aggressive dosing
might have closed the gap is that if a lot of patients at baseline that
we\'ve had reported to us had been on ACE inhibitors and had not, in
fact, achieved adequate response, if I\'m going to randomize those
people to something else to achieve a better result, omapatrilat is a
very logical option as something that provides a more aggressive
approach. If I\'m going to randomize in control to enalapril, one of the
ways that you could have gotten better response there would have been a
b.i.d. or more aggressive dosing in that as a control arm.

What I don\'t know ‑‑ and I\'ve already said I won\'t put too much stock
in the OVERTURE trial, but maybe the OVERTURE didn\'t show as much
difference in blood pressure dosing because of that reason. It\'s
uncertain, and I would agree with Tom\'s original answer. I think the
trial was not designed in a way to truly address this question. It may
not be true and it may be true that more aggressive dosing with
enalapril and then with other adjunctive therapies might, in fact, have
closed the gap.

The second part, as I understand the rewording of question 4.1 in the
second part, it\'s ‑‑ and I\'m going to read it as I understand the
rewording ‑‑ what is the risk-benefit comparison between the risk of
angioedema and the expected reduction in cardiovascular events? At least
I\'m going to answer the question as I\'ve just worded it.

The risk of angioedema at the most serious level, as has been
approximated here, the upper limit of the confidence interval is around
5.7 per 10,000, although it could be considerably larger if one, in
fact, starts with a dose of 20.

What is in fact the benefit? And there are two ways of getting at the
benefit. One way is through the surrogate and extrapolating from a 3
millimeter reduction in blood pressure and essentially using estimates
from HOPE and other sources that would say we would expect per 1,000
person-years 30 clinical events of cardiovascular death, MI, heart
failure, stroke, and using the HOPE trial with the 3 millimeter
reduction, maybe a 15 to 20 percent relative risk reduction, that would
translate to something on the order of 40 to 80 events per 10,000
person-years.

We actually observed much less than that. Granted, the data are limited,
but we still had 170 events, and these are from the very trial on which
we\'re trying to make our assessment. The actual event rate was maybe
half what was expected, and in turn, the actual relative reduction was
half of what was expected. So, we ended up with maybe a quarter of the
number of reduced events. The data of 89 versus 82 cardiovascular
deaths, MI, heart failure, stroke at 6 months translates into roughly 10
to 15 events prevented per 10,000 person-years.

So, I stand back and basically make the assessment of what\'s prevented
based on two sources of information, one, what the data actually said,
and that\'s 10 to 15 percent, against what you might extrapolate if you
truly believed in the surrogate. And it\'s probably twice that size. So,
that\'s what we achieve in the context of what we are seeing as serious
events of life-threatening events of angioedema which are roughly 5.7.

What it indicates to me is that there is a favorable benefit to risk in
those analyses, although the serious events of angioedema are not
trivial in the context of what we\'re trying to achieve, hence the
concern that can we achieve what we\'re trying to achieve in ways
without raising those events.

DR. BORER: Paul.

DR. ARMSTRONG: I would say that based on the doses of amlodipine and
diuretic we heard were used in the adjunctive therapy, that there was
additional opportunity for enhanced blood pressure control in the
comparator arm.

I would say in relationship to 4.2 that the obvious blood pressure
lowering superiority of the new agent may translate into a long-term
benefit, and if the risk of angioedema was not a player, I would be
comfortable in that proposition.

But given that there are three separate neurohumors that are affected by
this agent and at least one and perhaps others that we don\'t know about
is modulating the angioedema, and that the risk of angioedema is not
likely to diminish over the lifetime of a hypertensive patient once the
early first or 2 days is obviated, I have meaningful and real concerns.

DR. BORER: Bob and then Doug.

DR. TEMPLE: I just want to be sure we separate the two things out. The
first part of the question is about do you believe this difference would
persist if people had titrated or added other drugs, and what I heard
from a number of people is the study wasn\'t designed to tell that,
therefore you can\'t know in a hands-on way. You might suspect, but you
can\'t know.

And the second was Tom\'s observation that even though there was a
better control of blood pressure, you didn\'t the events. But I have a
question for you on that. This was a relatively short-term study. Is
that a question that could be answered in a study of this duration, or
does it really take a little longer before you even have a shot at
showing a benefit from that change? So, that\'s a question of how
negative the failing to find that difference is.

DR. FLEMING: If what you\'re saying is we can estimate a relative risk
reduction in these clinical events, but recognizing this is a small
study, how wide is the confidence interval?

DR. TEMPLE: No. I\'m saying it\'s short. It\'s true the benefits of
antihypertensive therapy are observed relatively quickly, but I don\'t
think they\'re usually seen in 6 months or a year very prominently. So,
I\'m not sure what the expected benefit would be even if it had the
usual effect. So, I\'m really asking how negative should one feel about
the failure to see the reduction in actual risk in that study.
Obviously, my implication is I\'m not sure you would have expected it in
a study of that duration.

DR. BORER: I\'d like to provide a response. Everybody else has responded
to this. I look at it just a little bit differently than some of the
other commenters. And I\'m going to divide it into parts here if I can.

Is a regimen including omapatrilat able to lower blood pressure to an
extent that combinations of enalapril and other drugs cannot? I believe
that it can, and the reason I do is not that there are direct data.
There are not direct data of the kind that I would have liked to see to
come to a firm conclusion. But in every comparison that we saw, regimens
containing omapatrilat were better than the comparators. So, I believe
that a regimen containing omapatrilat would be able to lower blood
pressure to an extent that combinations of enalapril and other drugs
cannot.

However, I\'m not sure what group of patients that\'s referable to
because that study wasn\'t done. The truly refractory patients weren\'t
identified here. So, if you asked me to write a label, I would be
hard-put to do it because I\'m not entirely sure what group we\'re
talking about, and I\'d like a little bit more evidence that in such a
group, this drug actually does provide a benefit of the magnitude we\'re
talking about, though I believe it probably does.

But having said that, I believe that the judgment should be based on the
risk-benefit comparison to angioedema because I haven\'t seen evidence
that there is any other meaningful risk that we ought to be worried
about. There don\'t seem to be other problems coming up with this drug.

Having said that, if I accept the 3 over 2 millimeter fall in blood
pressure, additional reduction in blood pressure, if I accept that, in a
truly refractory group that I didn\'t really look at here, but if I
accept that for the moment as the benefit, or the surrogate for the
benefit, and I compare the angioedema risk, I would come to the same
conclusion that I think Tom did, that the benefit outweighs the risk.

Why do I say that? It\'s not just on a basis of event rate, but the fact
that the risk of angioedema is not immediate closure of the airway and
sudden death, but that in most cases the problem is not so severe as
that, that there\'s some time to respond, and on and on and on. So, the
really meaningful mortal risk is I think relatively low although we
probably underestimated it here because of the fact that this was a
study constructed as it was.

But my real sticking point here is figuring out who these people are
that the drug would be used for, how you would define that. I\'m saying
it\'s people who were refractory, but I\'m not sure exactly how I would
define that.

Then the issue of the persistence of the blood pressure difference at 24
weeks. Is it a consequence of trial design goal, the blood pressure goal
or the goal blood pressure, inadequate use of additional drugs? I think
it\'s all of the above.

DR. THROCKMORTON: But you just said that you believed in your heart of
hearts that despite difficulties in interpreting the 24-week data, that
there was some population there for which omapatrilat alone had a
greater blood pressure lowering effect than combinations of enalapril
and other agents?

DR. BORER: No, no. That a regimen including omapatrilat would achieve
better blood pressure control than a regimen of multiple drugs that
didn\'t include omapatrilat.

DR. THROCKMORTON: I think we\'re saying the same thing, that you
couldn\'t get to the place that you could get with a regimen containing
omapatrilat with a regimen ‑‑

DR. BORER: Without it.

DR. THROCKMORTON: ‑‑ without. Then your trouble is you\'re not sure you
can identify the population, but that the data from that trial are
sufficient for you to believe that.

DR. BORER: Well, no. I said the data really are not sufficient. I\'m
making an inference. I\'m making a leap of faith here.

DR. THROCKMORTON: I want to understand that leap.

DR. BORER: I\'m looking at the data here and I\'m saying in every
comparison that was made, omapatrilat was superior to the comparator.
Within the OCTAVE trial, there were, I believe, undoubtedly people who
would be within the population for whom the sponsor is suggesting the
drug should be used, people who were on multiple drugs probably at
reasonable doses who just didn\'t respond and who were given omapatrilat
instead of enalapril as part of the regimen and who did better.

It\'s just that I haven\'t seen precisely those data. The sponsor may be
able to tease them out. I don\'t know if the documentation is sufficient
to do that, but certainly one could look at the subpopulation that was
on multiple drugs at at least such and such a dose of each of the
components and omapatrilat rather than enalapril and could show that
that group had a greater blood pressure reduction than the comparator. I
mean, you could do that. You could ask them to do that.

DR. TEMPLE: Well, they actually did do that in some sense. What\'s
missing I think is what would happen if they added guanfacine or
something like that. That you don\'t see.

DR. BORER: Well, that\'s true. We don\'t know what range of drugs they
gave, but we didn\'t see how much of each component they gave. So, we
really don\'t know whether the maximum appropriate dose or the maximum
labeled dose of all the components was given. We don\'t know that.

That\'s a tough row to hoe, and I\'d like to see those data. I think it
would be useful for the company to go back and tease them out because
that would allow us to begin to answer one of the key questions that Tom
raised. But if you asked me, do I believe we would find it? Yes, I do
believe we would find it. And if we did, and if the blood pressure
dropped 3 over 2 or greater, then I would say the risk-benefit
relationship would favor the use of the drug for the reasons that I
stated about risk. It\'s just that I\'m having a hard time identifying
the population.

DR. TEMPLE: I won\'t ask it now but I might later. Obviously, there\'s
not complete agreement on that 3 over 2 because I don\'t think Steve
would say the same thing, but that\'s what makes horse racing.

One possibility I guess if you did believe that a bona fide advantage of
that amount was meaningful is that there could be another study in
people who are refractory in some well-defined way in which people were
randomized to two different approaches, including adding another drug,
and you got to see if there was a persistent difference. So, maybe it\'s
available in those data, but if it were not, I take it, that\'s another
possibility.

DR. BORER: That would be an alternative solution to the problem.

DR. NISSEN: You kind of took the words right out of my mouth. I was
going to suggest that ‑‑ I mean, this would be a very useful piece of
information for us ‑‑ to take patients and to do everything you can to
get them to goal using conventional agents, used aggressively with
multiple opportunities for titration, and then randomize either to have
them switched to omapatrilat or to continue on the ACE inhibitor that
would be part of their regimen and see whether or not, in fact, you
could do better.

DR. TEMPLE: But that only works if you believe that lowering blood
pressure more with this drug is good. I just want to remind you.

DR. NISSEN: I understand. I\'m not disagreeing with you, Bob, that
lowering blood pressure is a very good thing. I\'m not disagreeing at
all. But I\'m trying to say that in the context of a drug with very
significant risks associated with it, we just can\'t accept that as
being sufficient.

DR. FLEMING: If I could add to the comments you were just making. You
had noted, as I had stated, that I believe there is a favorable
benefit-to-risk in terms of cardiovascular events prevented against
life-threatening cases of angioedema, which I do believe. I don\'t
believe that the data are as strong as the sponsor said a couple of
times when they said there\'s an order of magnitude difference in
frequencies of those events. I would have put it more as a twofold
larger number of cardiovascular events, and if you truly believe in the
blood pressure lowering surrogate, maybe it\'s two- to five-fold. But
then we have the uncertainties we\'ve been discussing about the full
validity of the surrogate in this setting and about the durability of
maintaining that 3 millimeter difference.

All of this would be adequate from my perspective; i.e., I would
consider those uncertainties of not sufficient magnitude to cause
concern to me if it weren\'t for the life-threatening angioedema. And
it\'s in the context of that life-threatening angioedema then that what
I worry about is even though I do see a favorable benefit-to-risk here,
it seems entirely plausible that you could readily alternatively achieve
the benefit without the risk.

It\'s speculation ‑‑ but for what we\'ve been talking about, and I think
this is the essence of question 4.2 ‑‑ whether or not it was a design
feature, so to speak, that led to these observed differences. I have
serious concerns that we might have been able to have provided
alternative management that would have had much lower differences in
blood pressure without the corresponding risk of life-threatening
angioedema.

DR. BORER: Okay. I think we\'ve given you a great deal of opinion.

Depending upon the committee\'s answer in question 4, identify a target
population and estimate the magnitude of expected benefit. I think
we\'ve discussed that. You don\'t really want us to define precisely
what it means to be refractory, and we\'ve all said refractory is what
we\'re talking about.

DR. THROCKMORTON: Well, you\'ve all at various times sort of said that
you believed that ‑‑ and obviously, the sponsor has made proposals about
target populations where the benefits were greater. I guess one useful
thing would be to comment on how you would go about doing that. The
sponsor has made one set of proposals, and you may find that credible.
You may have alternative ways that you might use to identify a
population that might most benefit from this drug.

DR. BORER: We\'ll split this into two parts then and get some opinions
about the target population and then make separately a comment about how
one would estimate the magnitude of the expected benefit.

Why don\'t we start out with the target population issue. Tom, do you
have an opinion about that?

DR. PICKERING: Well, obviously, I don\'t think anybody is suggesting
that it should be indicated as first line treatment for the general
population. So, there has to be some selection of people who are at
increased risk. I guess my problem with this is, again, OCTAVE was
designed I guess on the assumption that this was going to be something
that was approvable as a first line drug, and it wasn\'t intended
specifically to focus on any high-risk target population. So, any
information that\'s provided is a sort of retrospective analysis. Some
of the other studies that were done comparing it with other agents in
the high-risk population such as the one with people with very high
diastolic pressures gave data that were less convincing than some of the
other data that we\'ve heard.

So, the other area where I have a real problem is the issue of the
increased risk in blacks who obviously are going to be in this country a
very big portion of any high-risk population. And I\'m concerned that
the angioedema rate in these patients is I think 1 in 19, and I don\'t
know how one can separate out, to say that you shouldn\'t give this
patient this medication to blacks. I think that opens up a whole nest
egg of problems both political and how do you define who\'s black and
who\'s not and also other things like that. So, I have a problem trying
to define a specific high-risk population at this time.

DR. BORER: Steve.

DR. NISSEN: I don\'t think I can identify a target population based upon
what we now know. Part of the reason I say that is that if we tried to
do so by doing some kind of a subset or subgroup analysis from OCTAVE,
then what we\'re talking about is we\'re trying to make a decision based
upon lumping together some non-prespecified subgroups and saying, all
right, well, if you had all this and this and this, it looks like you
would benefit. I think that the level of evidence that you should look
for here is a target population should be prospectively defined not
retrospectively defined. So, I just don\'t like the idea of trying to
carve up the data we have and use that carved-up data to try to define a
population that would benefit. I don\'t think that\'s a proper in a drug
with this kind of risk level, and therefore I cannot identify a target
population.

DR. BORER: Susanna.

DR. CUNNINGHAM: All I can define is who probably shouldn\'t have it by
the risks of the angioedema, but I don\'t think I can really define who
should have it.

DR. BORER: Blase.

DR. CARABELLO: Yes, I agree. It seems silly to give this to blacks and
smokers unless there\'s a compelling reason to do so. And the sponsor
has already suggested that it be targeted at a population in whom other
therapies have failed to control their hypertension. I think that\'s a
start, but it has to be defined more carefully than that.

DR. BORER: Paul.

DR. ARMSTRONG: I think Steve and Blase have articulated my opinion.

DR. BORER: Mike.

DR. ARTMAN: Well, I think one population would be the population that
Dr. Black showed us, his patients in his clinic that are on multiple
drugs in a well-controlled setting that can\'t be controlled. I think
that would be a place to start with this, and I think that would be a
very sort of quick and easy study to do. So, I think that you could try
to get your hands around that defining patients who are on adequate
doses of at least three drugs and still are not controlled, that sort of
thing.

DR. BORER: Tom.

DR. TEMPLE: Jeffrey, just on that last point, that\'s a different
proposal from what the company said.

DR. BORER: I understand.

DR. TEMPLE: It says the blood pressure is what defines the population,
not all these other things.

DR. BORER: I was going to comment on that just now myself.

I just made a suggestion a few minutes ago that maybe the data could be
teased out of the 25,000-patient study, which is a pretty big study. But
I must agree with my colleagues here who say that that may not be the
proper way to go. Maybe another trial is necessary although I hate to
say that, given the resources that would have to be lavished on such a
trial.

But I don\'t think there\'s anything unreasonable about the target
population that the sponsor has proposed, assuming that refractoriness
of blood pressure is defined. They said difficult to control. I\'m
saying refractory which is qualitatively maybe a little bit worse. I too
would say look at Henry\'s population that he can\'t control and see
which one of them have the other problems and study them and show that
omapatrilat adds something that wasn\'t added by the comparator.

I guess it would be very difficult to be reasonably certain that the
benefit that I\'m willing to impute to the drug, if it lowers blood
pressure by 3 over 2, can be imputed unless we actually see it in the
appropriate population. I think the best way to do that is to study it
prospectively. It may be that the sponsor can come back with a
subanalysis by searching its data that would be compelling. I don\'t
want to rule out the possibility that that could happen, but I think the
better way would be to do a trial.

DR. THROCKMORTON: Jeffrey, standard advice, when talking about sponsors
about resistant populations, has been three classes of drugs, maximum
doses, one ACE inhibitor, one CCB, and one diuretic, that sort of thing.
Is that the sort of general thing that people ‑‑ I mean, does that
define Dr. Black\'s clinic in some reasonable sense?

DR. BORER: That kind of construct would be reasonable to me. That
specific algorithm might not be, three drugs, three different classes.
But I would ask Tom for his opinion about that.

DR. PICKERING: I think that\'s a reasonable and commonly used criterion
for resistant hypertension.

DR. THROCKMORTON: Just to go back one more time. What Bob said was
important. That\'s a different way of thinking about a high risk or a
population that might benefit from drug, the one that the sponsor has
been putting forth which was looking at cardiovascular risks and then
possible benefit.

DR. BORER: No, that\'s not different. If I understood their proposal ‑‑

DR. THROCKMORTON: No. There were two separate sort of things.

DR. BORER: I thought it was not exclusive but inclusive. You had to have
the high blood pressure and you had to have the problem.

DR. TEMPLE: Yes, but that\'s the question. Do you have the problems or
is a systolic pressure of 160 uncontrolled by three classes of drugs bad
enough?

DR. BORER: Sufficient.

DR. TEMPLE: That\'s what I\'m asking.

DR. BORER: Why don\'t we start with Tom and let\'s go around.

DR. PICKERING: Well, I guess it\'s a question of what risk you want to
start with. Obviously if there\'s the additional risk factors as well,
which I suspect there will be in most of these patients, the risk will
be higher.

DR. BORER: Must we demand that those additional risk factors be present
to give the opinion that the drug is effective and has safety acceptable
for the intended use if all they have is refractory hypertension rather
than refractory hypertension plus these clinical evidence of these other
problems.

DR. TEMPLE: For those people who meet SHEP entry criteria, we know what
blood pressure lowering does in those people, and they weren\'t selected
because they had other risks particularly.

DR. PICKERING: I guess I would say other risk factors present as well.

DR. BORER: Steve.

DR. NISSEN: I actually agree with you, Bob. I think that you could
define a population here. We know that people with refractory
hypertension do very, very badly, and I think you could lower the bar
here a little bit and I would still be very comfortable if you said show
us that in a group of people we just can\'t control with the best drugs
we\'ve got, three of them, are still above some threshold and make that
threshold significant, not above 130 over 80. I\'m not sure where to set
that. Because we know that people that can\'t be controlled despite
everything we can throw at them do badly, and a drug that could get
those people to goal would have enough likely advantages that it might
well, in my view, if it were a robust study, outweigh the disadvantages
of angioedema. I think you could define such a trial, but it would have
to be very rigorously done.

DR. BORER: Susanna.

DR. CUNNINGHAM: So, let me clarify. We\'re not answering number 5 here.
We\'re defining what a future study might look like.

DR. BORER: What\'s the population that we want to define as appropriate
for getting this drug if it works in that population? Is it just a
refractory hypertension population, or do these refractory patients also
have to have cardiovascular problems or other end organ problems as was
proposed by the sponsor? Do we want to be that rigorous or just blood
pressure problems?

DR. CUNNINGHAM: I think just refractory hypertension would be enough.

DR. BORER: Blase.

DR. CARABELLO: I don\'t know how to answer the question. I\'m not too
concerned about the other risk factors.

I am concerned about how much demand we put on previous control of blood
pressure. If we say that the population to be tested in one in which
we\'ve minutely titrated every last drug before we add this one and
that\'s the only way in which we\'ll accept efficacy, I don\'t think
that\'s a very good standard because we\'ve got a whole bunch of folks
out there who have had reasonable medical therapy and still are
hypertensive. Now, could you get them a little lower if you beat the
hell out of them and their providers? Maybe? But is that actually going
to translate to benefit to the patient? I don\'t know. I think that this
has to be taken in the context of current good but not
impossible-to-reach standards.

DR. BORER: Just to ask for a further statement on that, the way it\'s
been set forward ‑‑ and Tom indicates that this is routine practice in
this area ‑‑ what we\'ve now suggested is that to be declared refractory
you should be on three classes of drugs, not necessarily five or six,
but three, and that the drugs should have been titrated up to their
maximally tolerable or maximally labeled doses. Would that be too much
of a standard?

DR. CARABELLO: Well, unless of course going to three drugs generates so
many additional side effects that now the patient won\'t take them.

DR. BORER: Then it\'s not tolerated, and I would think such patients
could be included in such a trial.

Steve.

DR. NISSEN: I was just going to say, Blase, there are an awful lot of
people out there that are on ACE inhibitor, diuretic, and amlodipine.
There\'s a world of people like that and some of them aren\'t controlled
on that. Some are still greater than 150 over 100 on 10 milligrams of
amlodipine and 40 a day of enalapril and 50 of hydrochlorothiazide,
let\'s say. I think if you could get those people down significantly
with a drug, it might mitigate the risk involved in a drug like
omapatrilat. So, I think such a trial would go a significant way toward
making that an approvable drug.

DR. BORER: Paul.

DR. ARMSTRONG: The patient that Steve just described is often controlled
with the addition of a beta blocker. So, the notion that three should be
the standard for refractory hypertension, and the addition of a new
class of drug is not necessarily for me adequate, but if the patient was
truly refractory to best medical therapy in a supervised hypertension
clinic environment and had evidence of target organ damage, I could see
taking the additional and unknown risk of adding a drug such as this,
especially if that patient was being supervised by experts who
understood the side effect implications and were following the patient
carefully.

DR. BORER: Mike.

DR. ARTMAN: Well, I sort of made the proposal and you guys refined it a
little bit. So I stand as suggested.

DR. BORER: Tom.

DR. FLEMING: If the question is in what population is it most plausible
that this agent could be established to have a role, I would accept the
logic of the sponsor saying that you would want to target a population
that simultaneously satisfied two criteria. First, it would be patients
at high risk for major cardiovascular events, i.e., so the setting where
the benefit is substantial; and where it\'s difficult to control
hypertension, i.e., where it\'s less likely that alternative available
therapies could yield that benefit. So, in the context of having a risk
of life-threatening angioedema, I want to identify a population where
there is substantial up-side benefit and simultaneously a population in
which I can more readily achieve that up-side benefit with this agent,
even though it carries the side effect.

DR. TEMPLE: Jeffrey, there really have been two slightly differing
themes, and it\'s important. We know from SHEP that being 70 and having
a systolic of 160 is a high-risk situation by definition. How much more
than knowing the blood pressure do you all think that the entry
population in this other study would have to have?

DR. BORER: You\'ve heard a couple of opinions already. I think there\'s
a slight preponderance in favor of blood pressure alone being
sufficient. And I\'m going to add my voice to that. While I\'d love to
see people with all the end organ problems in the population, I\'m sure
they will be, as Tom pointed out, just by the nature of the beast, but I
would accept uncontrollable blood pressure alone as the population to
study, uncontrollable by the definition that we\'ve used.

DR. NISSEN: Jeff, if I could just add. It would be nice also to have
that trial not be a 24-week trial because I think one of the things that
really limited the current design was there really wasn\'t enough time
to see potential differences emerge here. If we\'re going to do it, it
ought to be pretty solid.

DR. TEMPLE: That\'s a very important question. If you\'re not looking
for end organ damage and you\'re really just now looking at the
substitution of one drug for something else in the regimen, you don\'t
need a very long trial to do that. Why would it have to be more than 8
weeks?

DR. NISSEN: Well, because I would not want to preclude the addition of
other drugs to either regimen. In other words, some people like the idea
of adding a beta blocker, and I\'d like both arms to have that open to
them.

DR. TEMPLE: No. That should be done before they even get into it.

DR. NISSEN: That means four drugs, though.

DR. TEMPLE: Whether it\'s three or four is no matter. They\'re
refractory and then you randomize to substituting this and keeping the
same regimen.

DR. NISSEN: That would be certainly one way to approach it. I don\'t
think we can design the trial at this table, but I think what you\'re
getting from us I think is the sense that showing efficacy in a truly
refractory population, well studied would be meaningful.

DR. TEMPLE: No. I\'ve got that. It was the 26 weeks that threw me.

DR. NISSEN: Well, I guess part of it is that I\'m always more
comfortable when the exposure is a little longer and when you have a
little more observational time. Part of it relates to the fact that I
think there are some major risks associated with this drug. I guess I
don\'t think we\'ve characterized them very well.

DR. TEMPLE: Yes, but the study we\'re talking about is going to be small
compared to OCTAVE, as is any study in the world. So, it\'s not going to
get you much more safety information, at least as I\'m hearing it. It\'s
going to document unequivocally that you control people that were
uncontrolled before. That\'s a very limited thing. It\'s not very hard
to do if it\'s true and it shouldn\'t take 26 weeks if that\'s enough.
But you need to be clear.

DR. NISSEN: Let me see if I can be more specific. Again, I hadn\'t
really thought of this before I came in here. But also we\'d like to
know that the differences are stable, that they\'re not differences that
are closing with time. Tom Pickering raised this question earlier. So, I
personally would be a lot more comfortable if I knew that you could
sustain for a year an advantage in blood pressure because it\'s going to
be a smaller population, so it\'s easier to follow them for a little bit
longer and see if you can get that kind of sustained benefit in this
population. If they escape after 24 weeks, then you don\'t gain very
much.

DR. BORER: I\'d like to comment on that also. I\'d love to see a very
long trial. On the other hand, that\'s not a standard that we\'ve ever
set for an antihypertensive drug because there hasn\'t been any
compelling evidence that problems develop late because we didn\'t run
the trials long enough.

I would be perfectly happy with a 6-month trial, which is longer than
the usual antihypertensive trial. I\'m concerned, as Steve says, about
exposure for safety, but if it\'s a small trial, we\'re not going to get
much from that. I\'d like to know, though, from the sponsor of the
25,000 patients involved in the trial, 12,000 were on omapatrilat. Have
they been continued in an open-label experience or any subset of them?

DR. LEVY: No, they haven\'t.

DR. BORER: You did show us, though, some 1-year data in a withdrawal
study that showed persistence of effect at 1 year, which I find sort of
compelling.

DR. TEMPLE: I was going to ask you that. There\'s a lot of data that
goes long. There isn\'t any suggestion that whatever effect there is
goes away. It\'s really important. For one thing, I would be damned
uncomfortable allowing a trial to continue that showed a difference and
not doing something else to get those people under control. I think that
would be dubious. We allow 8-week trials against placebo, but we don\'t
allow 26-week trials against placebo.

DR. NISSEN: But, Bob, you\'ve already said these are people that can\'t
be controlled any other way.

DR. TEMPLE: No. There\'s a fifth and sixth and seventh and eighth drug
too. Somebody would have to go do something.

But my fundamental question is, what\'s the question? I thought, from
all the previous discussion, the question was can you take people who
are bona fide refractory and who are refractory at entry ‑‑ they\'re on
all these drugs at entry ‑‑ and get control when you couldn\'t before, a
question that I would have thought could be answered in 6 to 12 weeks
tops.

DR. ARTMAN: I think that\'s right. I think that is the question and I
think it could be done in a relatively short trial because I think under
that circumstance, we would be happy to see that incremental reduction
in blood pressure if it were true in that population.

DR. FLEMING: In the absence of angioedema, I could be persuaded to
accept that, but part of the fundamental issue at hand here is to be
convinced that we\'re going to get a difference, sustained for adequate
duration, that it will offset a very real and important side effect. So,
coming back to what you were saying, Jeff, this isn\'t the standard
situation. If there wasn\'t angioedema, one would be more permissive
here and would be less concerned.

DR. THROCKMORTON: Absent angioedema, we wouldn\'t be here.

DR. TEMPLE: But you already have data on whether the effect of this drug
is evanescent. So, why do you need to answer that question again?

DR. NISSEN: We have that data relative to placebo I think. We have it
relative to an active control arm with three drugs. Do we know that?

DR. TEMPLE: Well, you could say OCTAVE answers that question to a
degree, couldn\'t you? They didn\'t add on other drugs or push the dose,
but you do have that difference persisting.

DR. BORER: I may have missed something, but I thought the withdrawal
study you did was in a trial against enalapril, was it not?

DR. LEVY: No. Let me just clarify. I did show you data from a
1-year-long losartan controlled trial in which the blood pressure
differential was maintained. I commented on the results of a withdrawal
study. That was conducted in patients being followed in a long-term
open-label extension, and they were randomized to continue treatment
with omapatrilat or to withdrawal to placebo, and a difference in blood
pressure emerged very quickly.

DR. BORER: That\'s fine. Thank you for the information.

To me those are pretty important pieces of information if you were able
to maintain for a year a differential against an active comparator and
you were able to show a difference on withdrawal to placebo after a
year, I\'m not sure that we have any information from any body of data
that would suggest that people who are really severely ill would be less
likely to maintain the effects of a drug. They may be less likely to
remain in control, but then again that\'s what blood pressure cuffs are
for, to find that out, and then you can alter the regimen.

But, Tom, is there any reason to expect that a severely hypertensive
population put on a drug and responding to the drug will lose their
responsiveness to that drug after a year as compared with somebody with
mild to moderate hypertension?

DR. PICKERING: I don\'t think so necessarily, no.

DR. BORER: I would say, although I absolutely agree we\'d like long-term
experience so that we can get a better sense of safety and all those
things, I don\'t think it\'s necessary to mandate a long-term trial to
show the persistence of effect. I think they\'ve already done that.

But you want to get the opinions of everybody around the table. You\'ve
just heard Tom\'s. Susanna.

DR. CUNNINGHAM: I think I\'d take 6 months\' worth.

DR. BORER: Steve, you already gave your opinion. Mike, Tom. Okay.

I think we\'ve sort of dealt with 6, but I think we need to do it
formally. Should omapatrilat be approved for the treatment of
hypertension? Let\'s deal with that first, and then depending upon the
answer, we may go to 6.1, 6.2, and 6.3. Steve.

DR. NISSEN: My answer is no, and I think the reasons have come out in
the discussion. Mainly they relate to the fact that we have limited data
on the effect of the drug on events which would have strengthened the
argument and that the risk of angioedema is substantial enough to
mitigate against the potential benefit of the lower blood pressure.

I would like to say that I see two potential routes to approvability
from my perspective. One we\'ve already discussed, which is a trial
showing that people that are absolutely refractory can be controlled or
have a better blood pressure result when omapatrilat is substituted for
an ACE inhibitor adequately done.

But the other which I think should not be ruled out is to show that in
fact in a broader population, there is a morbidity and mortality
advantage that outweighs the angioedema. Tom and others and the company
have tried to estimate the ratio of benefit to risk, but measuring it
would be the most compelling evidence of all. So, if one could define a
population ‑‑ if I were going to do such a study, I\'d probably pick
people at pretty high risk, and I\'d try to show that there was a
morbidity and mortality advantage in that population that really quite
significantly outweighed the very real risk of angioedema.

The advantage of such a development program is that it would allow this
drug to be used in a broader population, not just in the absolutely
refractory patients, but in other patients because it may be that the
company is right. There may be an order of magnitude benefit greater
than risk in a relatively broad population. And if that were proven,
then I think it would be a slam dunk that we\'d accept the angioedema
and we\'d counsel about how to do everything possible to prevent it and
all that risk management stuff, but we would be pretty comfortable that
that overall would help the health of this population.

DR. TEMPLE: Just to be sure, would this be a trial in which people were
allowed to be better controlled on omapatrilat than on the other drug,
or would this be a case where they would have to show that using that is
better than the other thing even though there\'s equal control?

DR. NISSEN: You know, I\'d have to think about this. Again, I\'m not
sure I can design the trial at the table here, but I guess I would like
to see in such a trial a design ‑‑ because it would be a longer-term
trial ‑‑ then the opportunity for titration of the active control arm
would continue as would the opportunity for titration of the omapatrilat
arm. So, you\'d really be looking for whether or not a regimen
containing omapatrilat, when optimally delivered over a long period of
time, would have a better efficacy at preventing morbidity and mortality
than a conventional regimen titrated to optimal effect over time.

DR. TEMPLE: But their hope is that the way it would do that is by giving
better control, and if you obliterated better control, then it would
have to be through some magic thing.

(Laughter.)

DR. TEMPLE: They don\'t have a proposal like that.

DR. NISSEN: And if it obliterated better control, then there\'s no
reason to ever use omapatrilat. So, I guess the point would be if you
can\'t produce a persistent differential in blood pressure, then
there\'s no reason for us to use this drug in a population we can
achieve that control with conventional agents in.

So, I think you have to let both arms be titrated and you\'d probably
want to do it more rigorously than was done in OCTAVE, meaning mandate
up-titrations. I have to think about it a little bit, but the idea is to
try to show that there is a clinical advantage to regimens containing
omapatrilat with respect to some harder endpoints other than just blood
pressure.

Again, I\'m not putting down the surrogate. I\'m with you, Bob. I think
the surrogate is a good surrogate, but it\'s only relevant when you have
a drug that has comparable risks to what else is out there. So, when you
don\'t have that, then I think you\'ve got to go to those harder
endpoints. I think it could work. I think you could find that over 3
years or 4 years that a regimen containing omapatrilat will end up with
a blood pressure differential that\'s maintained and that leads to a
difference in hard events, in which case this drug would be a good drug
to make available for a broader population.

DR. BORER: Tom Fleming.

DR. FLEMING: I agree very much with the essence of what Steve has said,
and in the interest of avoiding repeating that and other things that
I\'ve said before, I\'ll just state that for those reasons I vote no.

DR. BORER: Mike.

DR. ARTMAN: I would vote no at this time.

DR. BORER: Susanna.

DR. CUNNINGHAM: No.

DR. BORER: Blase.

DR. CARABELLO: I\'ll be the one dissenter and vote yes. I believe that
if the drug were added to the community now, it would result in a
substantial fall in blood pressure in our hypertensive patients. For me,
it\'s not the question can it, under the rigorous controls of the trial,
make a difference, but what difference would it make in the community in
which apparently we as a medical group are doing a lousy job of
controlling people\'s blood pressure. And I think it\'s that group of
people that I\'m most interested in. I think that the risk of truly
life-threatening angioedema could be controlled.

DR. BORER: Reluctantly I\'m going to vote no, and this is a very
difficult vote and sort of a close call because my intuition is that
this drug would offer a benefit that we don\'t get with other agents.
But I\'d like to see the data in a refractory population, defined as
we\'ve all discussed, that it does indeed improve blood pressure control
because there\'s a countervailing risk which I think can be superseded
by the benefit of the additional blood pressure lowering, but I\'d like
to see that. So, I don\'t think this is not an approvable drug, but I
don\'t think it\'s an approvable drug today.

We don\'t have to go to 6.1, 6.2, and 6.3.

Bob.

DR. TEMPLE: I just want to thank the committee for struggling with what
was a very difficult set of issues.

DR. BORER: Doug.

DR. THROCKMORTON: Yes, I\'d just echo that. The materials and the issues
you\'ve been asked to look at over the last couple of days have been
very challenging, and the agency really thanks you for your help. It\'s
truly valued.

DR. BORER: And it\'s only 3:53 and 52 seconds.

(Whereupon, at 3:53 p.m., the committee was adjourned.)