**UNITED STATES OF AMERICA**

**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**PUBLIC HEALTH SERVICE**

**FOOD AND DRUG ADMINISTRATION**

**CENTER FOR DRUG EVALUATION AND RESEARCH**

**ENDOCRINOLOGIC AND METABOLIC DRUGS**

**ADVISORY COMMITTEE**

**MEETING #64**

**THURSDAY,**

**SEPTEMBER 26, 1996**

The meeting took place in Versailles Rooms I and II, Bethesda Holiday
Inn, 8120 Wisconsin Avenue, Bethesda, Maryland at 8:00 a.m., Henry G.
Bone III, MD, Chair, presiding.

[MEMBERS PRESENT]{.underline}:

Henry G. Bone III, MD, Chair

Kathleen R. Reedy, Executive Secretary

Colleen A. Colley, PharmD, Consumer Rep

Cathy Critchlow, PhD

D. Roger Illingsworth, MD, PhD

Robert A. Kreisberg, MD

Robert Marcus, MD

Mark E. Molitch, MD

Maria I. New, MD

Robert S. Sherwin, MD

[FDA CONSULTANTS PRESENT]{.underline}:

John M. Flack, MD, MPH

Joanna Zawadzki, MD

[FDA REPRESENTATIVES]{.underline}:

Eric Colman, MD

Solomon Sobel, MD

Bruce Stadel, MD MPH

Gloria Troendle, MD

[SPONSOR REPRESENTATIVES]{.underline}:

David Heal, PhD

Michael Lean, MA, MD, FRCP

Carl Mondel, MD

F. Xavier Pi-Sunyer, MD

Timothy Seaton, MD

Sylvia Smoller, PhD

[PUBLIC COMMENTERS]{.underline}:

Richard Atkinson, MD

Kris Ernst

John Foreyt, PhD

Barbara Hanson, PhD

Lynn McAfee

Valerie Rochester

[ALSO PRESENT]{.underline}:

Elliot Danforth, MD

Rodney E. Haddock, BSc, PhD, MRSC, CChem

Finian Kelly, MD

Damian McEntegart

Bramah Singh, MD, PhD

Michael Weber, MD

[A]{.underline} [G]{.underline} [E]{.underline} [N]{.underline}
[D]{.underline} [A]{.underline}

PAGE

Call to Order Chairman Bone 4

Introductions of Participants 5

Meeting Statement Kathleen Reedy 6

OPEN PUBLIC HEARING

Speakers: Dr. Richard Atkinson 9

Dr. John Foreyt 12

> Ms. Kris Ernst 15
>
> Dr. Barbara Hanson 19
>
> Ms. Valerie Rochester 22

Ms. Lynn McAfee 24

SPONSOR PRESENTATION - KNOLL PHARMACEUTICAL COMPANY

Introduction Dr. Mel Spigelman 30

Obesity Overview Dr. F.X. Pi-Sunyer 36

Pre-Clinical Pharmacology

Dr. David Heal 43

Pharmacokinetics/Efficacy

Dr. Carl Mendel 60

Safety Dr. Timothy Seaton 100

Epidemiologic Benefit/Risk

Dr. Sylvia Smoller 139

Clinical Benefit/Risk

Dr. Michael Lean 145

Phase IV/Conclusion

Dr. Mel Spigelman 156

AFTERNOON SESSION

FDA PRESENTATION

Introduction Dr. Gloria Troendle 168

Medical Dr. Eric Colman 173

Epidemiology Dr. Bruce Stadel 199

Hypertension Dr. John Flack 220

Committee Discussion and Questions 238

Meeting adjourned

P-R-O-C-E-E-D-I-N-G-S

8:08 a.m.

CHAIRMAN BONE: I just want to announce that this is the Endocrine and
Metabolic Drugs Advisory Committee Meeting. If you are here for one of
the other meetings that are occurring in the same facility, it\'s a good
time to leave because we\'ll be starting the Endocrinology and Metabolic
Drugs Advisory Committee Meeting in a few minutes.

Good morning. I\'m Dr. Henry Bone. I\'m the Chair and I\'m calling into
order the 64th meeting of the Food and Drug Administration
Endocrinologic and Metabolic Drugs Advisory Committee. As I mentioned
earlier, if you\'re here for one of the other meetings that are
occurring in this same hotel, they\'ve probably just about started.

The topic for today is the new drug application for sibutramine. We\'ll
be having presentations, of course, by the sponsor and by the Agency.

The first order of business will be the introductions by each of the
people here at the front table. Then we\'ll have the meeting statement
by Kathleen Reedy who is the Executive Secretary of the Committee.

If we could start at the far end on my right, please? If each person
will introduce him or her self and their affiliation.

DR. ZAWADZKI: My name is Joanna Zawadzki. I\'m an endocrinologist in
private practice in this area. I\'m a associate clinical professor at
Georgetown University Medical Center.

DR. KREISBERG: Bob Kreisberg, endocrinologist, Birmingham, Alabama,
clinical professor of medicine at UAB.

DR. CRITCHLOW: I\'m Cathy Critchlow, epidemiologist, University of
Washington, Seattle.

DR. MARCUS: Robert Marcus, endocrinologist, Veterans Affairs Medical
Center, Palo Alto, professor of medicine at Stanford University.

DR. ILLINGSWORTH: Good morning. Roger Illingsworth, Department of
Medicine in the Metabolism Division, Oregon Health Sciences University,
Portland, Oregon.

DR. COLLEY: Colleen Colley. I\'m a clinical pharmacist at the VA in
Portland, Oregon.

DR. SHERWIN: Robert Sherwin, endocrinology professor of medicine, Yale
University.

CHAIRMAN BONE: Henry Bone, the Henry Ford Hospital, Detroit, Michigan.

DR. REEDY: Kathleen Reedy, Executive Secretary of the Endocrinologic and
Metabolic Drugs Advisory Committee for the FDA.

DR. MOLITCH: Mark Molitch, endocrinologist and professor of medicine at
Northwestern University Medical School in Chicago.

DR. FLACK: John Flack. I\'m associate professor of surgery, Madison
Public Health Sciences and social director and medical director of the
Hypertension Center at Bowman Gray School of Medicine.

DR. COLMAN: Hi, I\'m Eric Colman. I\'m a medical officer in the Division
of Metabolism at the FDA.

DR. STADEL: Bruce Stadel, medical officer, FDA.

DR. TROENDLE: Gloria Troendle, Division of Metabolic and Endocrine
Drugs, FDA.

DR. SOBEL: Sol Sobel, director of the Division of Metabolic and
Endocrine, FDA.

CHAIRMAN BONE: Thank you.

Dr. Reedy?

DR. REEDY: The following announcement addresses the issue of 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 and information provided by the
participants, the Agency has determined that all reported interests in
firms regulated by the Center for Drug Evaluation and Research present
no potential for a conflict of interest at this meeting with the
following exception. In accordance with 18 United States Code 208(b)(3),
a full waiver has been granted to Dr. Mark Molitch. A copy of the waiver
statement may be obtained from the Agency\'s Freedom of Information
Office, Room 12A15 of the Parklawn Building.

In addition, we would like to disclose for the record that Dr. Mark
Molitch has an interest which does not constitute a financial interest
within the meaning 18 United States Code 208(a), but which could create
the appearance of a conflict. The Agency has determined, notwithstanding
this involvement, that the interest of the government in Dr. Molitch\'s
participation outweighs the concern that the integrity of the Agency\'s
programs and operations may be questioned. Therefore, Dr. Molitch may
participate fully in this meeting.

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.

CHAIRMAN BONE: Thank you.

The next part of the meeting is the open public hearing segment. This
is, as I remarked before, an extraordinary feature. If you look around
the world at the way drug reviews are conducted, this is an exceptional
characteristic of the United States that the opportunity is made
available to people who are interested in making comments and who make
arrangements in advance to be heard to do so.

We will have six presentations of five minutes each. I will make a
signal when one minute is remaining. Then we take note of letters from
five individuals or organizations, copies of which have been provided to
members of the Committee and additional copies of which are also
available outside along with the meeting programs.

The first speaker in the open public hearing segment is Dr. Richard
Atkinson. I will ask each speaker to state whether they have any
affiliation with financially interested parties, and if so, what.

DR. ATKINSON: Hello. My name is Dr. Richard Atkinson. As for conflicts,
I\'m currently receiving no research funds from drug companies. In the
past, I\'ve served as a consultant, have given CME lectures sponsored by
drug companies, and have gotten research funds. I\'ve consulted for
Knoll Pharmaceuticals in the past and given CME lectures sponsored by
them.

As I said, I\'m president of the American Obesity Association which is a
lay advocacy group representing the interests of the 70 to 80 million
obese American women and children and adults afflicted with the disease
of obesity. The missions of the American Obesity Association are
education, promotion of research and community action in the interests
of obese people. I\'m also a professor of medicine and nutritional
sciences at the University of Wisconsin at Madison. My area of research
is obesity, particularly in the use of drugs for the treatment of
obesity. I\'m currently participating in several studies evaluating
drugs for obesity that involve more that 2,500 patients.

The American Obesity Association strongly supports the development of
new treatments for obesity. The success rate of diet, exercise and
behavioral modification of lifestyle has been very poor over the
long-term. The data of Weintraub et al, our data and those of a number
of other investigators demonstrate that the addition of pharmacologic
agents enhances weight loss, the maintenance of weight loss, and reduces
the major risk factors associated with obesity.

Obesity has a strong genetic component and there are compelling data to
show that the biochemistry and physiology of obese people are different
from those of lean people. Just as with other chronic diseases, we
believe drugs will be necessary to alter the biochemistry of obese
people towards that of lean people.

Dr. Claude Bouchard has identified over 20 genes that contribute to the
etiology of obesity. Combinations of these genes make it likely that
there are numerous different types of obesity. We know almost nothing
about which drugs will be useful for which types of obesity, but it is
naive to assume that all obesity will be treated with one or a few
drugs. There has been only one drug approved by the FDA for the
treatment of obesity since 1973. Drug companies have devoted few
resources to this serious health problem. The NIH devotes only about
one-half of one percent of its budget to obesity research. For a disease
that kills 300,000 Americans per year, affects more than one-third of
the entire adult population, and affects about 25 percent of children in
America, this lack of attention by the government and by industry is a
national disgrace.

Clinicians and investigators need additional drugs and the research that
will accompany the development and marketing of new drugs. Many obese
patients respond poorly to the drugs currently available. Given the
diversity of obesity, this is not surprising. Chronic diseases require
chronic treatment. New agents, alone or in combination, must be tested
to determine their utility for controlling obesity and its comorbid
conditions. We urge the Endocrinologic and Metabolic Drugs Advisory
Committee to carefully consider the evidence on sibutramine. Should the
Committee find this drug to be safe and efficacious and to have an
acceptable risk benefit profile, we believe the addition of a new agent
for the treatment of obesity will be beneficial for Americans who suffer
from this disease.

Thank you.

CHAIRMAN BONE: Thank you, Dr. Atkinson.

The next speaker is Dr. Foreyt.

DR. FOREYT: Good morning. My name is John Foreyt. I\'m a professor of
medicine at Baylor College of Medicine in Houston. I\'m also the
director of the Bakee Heart Center and Nutrition Research Center at
Baylor. I\'m also a clinical psychologist and have an active clinical
practice.

My area of research expertise is in the behavior modification principles
with obese individuals for the development of healthy lifestyle. I have
in the past had funding from drug companies for research studies, also
for presenting educational programs including from Knoll. I don\'t think
I have any current conflict of interests. My thoughts and my words are
my own. I paid for the trip here myself and this is what I wrote.

I believe that successful weight management really requires healthy
eating and healthy physical activity, and the use of behavior
modification principles to best maintain that healthy lifestyle. I also
know very well the limitations of behavior modification principles.
Behavior modification does not work very well for most obese patients in
the long run, with success rates for obese patients somewhere in the
range of five percent to ten percent of individuals receiving the
behavioral principles. I believe that we need things more than behavior
modification, more than dietary advice, more than physical activity
consultation if we\'re ever going to stem the increasing prevalence of
obesity in our society. Last year, we published an article in the Lancet
where we looked at current prevalent state and predicted by the year
2230, 100 percent of Americans will be obese.

Obesity is the number one public health problem in the United States.
Obesity continues to kill Americans, disables increasing numbers every
year. I think we need all the help we can get. Behavior modification
works very well at helping adjust environmental behavioral affective
cues.

I think anti-obesity drugs like sibutramine help regulate internal cues
of hunger and satiety and help cognitively adjust people\'s thinking
patterns in reducing their obsessiveness with thoughts about food and
about eating. I think they help people push away from the table easier.
I think they help enhance satiety and help them eat less. One of my
patients, for example, told me recently who was on a drug \-- said
\"these drugs help me struggle like a normal person struggles.\" Before
that time, she had been unable to control her eating. She still
struggles even on the drugs, but I think the drugs help her make it more
manageable in terms of dealing with her eating.

I don\'t believe drugs like sibutramine are magic bullets. I don\'t
believe drugs like sibutramine are ever going to cure obesity. I think
much like high blood pressure drugs don\'t cure hypertension or insulin
doesn\'t cure diabetes or cholesterol drugs don\'t cure
hypercholesterolemia but they help manage the condition. I think these
drugs help, along with behavior modification, manage the condition. I
think anti-obesity drugs are adjuncts and they\'re simply adjuncts to a
healthy program of sensible eating and regular exercise. They help
produce modest drops in weight, but those modest drops in weight lead to
demonstrated medical benefits.

I think along with the limitations and side effects that all drugs have,
you need to be sure to consider, very strongly, the benefits of
producing modest weight losses. Although they\'re not cures, they
certainly can help and they can help manage this very terrible
condition. As an active researcher and an active clinician in this
field, I hope you\'ll approve sibutramine, given it\'s safe and
efficacious. I think these drugs like sibutramine can really help manage
this condition. We need all the help we can get.

Thank you.

CHAIRMAN BONE: Thank you very much, Dr. Foreyt.

The next speaker is Kris Ernst.

MS. ERNST: Good morning. I have no conflict of interest.

My name is Kris Ernst. I\'m a registered nurse practitioner and a
certified diabetes educator. I work full-time teaching people how to
live with the disease diabetes. I\'m the immediate past president of the
American Association of Diabetes Educators which is a multi-disciplinary
association of health professionals. I\'m here to talk today about what
I\'ve observed to be the impact of obesity on morbidity and mortality in
people with diabetes.

Obesity is highly associated with hyperinsulinemia and insulin
resistance. An increased relative weight has been implicated as an
independent predictor of diabetes. According to the second National
Health and Nutrition Examination Survey, the prevalence of diabetes is
2.9 times higher in overweight people than in non-overweight people. In
fact, according to Healthy People 2000 and the American Diabetes
Association Clinical Practice Recommendations weight reduction is the
treatment of choice in improving blood glucose control and in reducing
hyperlipidemia, hypertension and proteinuria and may moderate other
complications of the disease.

In 1986, the National Institute of Health consensus development
conference on diet and exercise in non-insulin dependent diabetes
concluded that there is an increased risk of non-insulin dependent
diabetes in individuals who are 20 to 30 percent overweight. This risk
increases with increased body weight and increased degree of obesity,
and the distribution of excess of body fat.

Upper body obesity is associated with an even greater risk for
non-insulin dependent diabetes. Non-insulin dependent diabetes is an
important cause of morbidity and mortality in the United States. Half of
all non-insulin dependent diabetes is estimated to be preventable by
obesity control. In fact, in June of this year, a multi-center NIH
funded trial, the diabetes prevention trial II was initiated. One arm of
treatment is aimed at preventing the onset of non-insulin dependent
diabetes in high risk individuals by reducing body weight through
dietary and exercise patterns.

Obesity has well established medical and psychological risk factors
besides diabetes, including an increase in hypertension, hyperlipidemia,
coronary artery disease, and general distress about weight. I see people
every day that are struggling with weight control. The total proportion
of disease attributed to obesity is quite high, with estimates ranging
up to 92 percent.

Dietary factors and activity patterns that are too sedentary are
together accountable for at least 300,000 deaths each year. Studies have
associated dietary factors or sedentary lifestyles with 22 to 30 percent
cardiovascular deaths, 20 to 60 percent of fatal cancers, and 30 percent
of diabetes deaths. The combined effects of obesity and non-insulin
dependent diabetes are deleterious. Consequently, the benefits of
aggressive treatment of obese or overweight individuals with non-insulin
dependent diabetes seems to be very well established. Weight reduction
is an indisputable goal in individuals with non-insulin dependent
diabetes improving metabolic functions and decreasing associated
complications. This goal may seem relatively concrete and achievable,
but weight reduction is actually a complex and illusive process to many.
Studies have demonstrated that a combination of caloric restriction,
behavior modification, a personalized exercise prescription, family
support, recognition and avoidance of high risk situations, are all
important components of a successful weight reduction program. However,
even with all of these elements in place, relapse are a common problem.
Consistently, the best predictor of long-term weight loss appears to be
the long-term maintenance of exercise.

Obesity must be viewed as a chronic disease requiring a multi-faceted
approach including ongoing clinical care and behavioral change.
Behavioral change is motivated not by knowledge alone, but also by a
supportive social environment and the availability of facilitative
professionals, services and resources. The American Association of
Diabetes Educators believe that sibutramine is one of the resources that
should be available to persons seeking to reduce their weight.

Thank you.

CHAIRMAN BONE: Thank you, Ms. Ernst.

The next speaker is Dr. Barbara Hanson.

DR. HANSON: I\'m the immediate past president of the American Society
for Clinical Nutrition. I have no financial interest in any
pharmaceutical firm. I have a conflict of interest with almost every
pharmaceutical firm in this room having given educational lectures or
received research support for the study of anti-obesity and
anti-diabetes agents. I am firmly committed to the importance of
expanding the armamentarium in the \--

CHAIRMAN BONE: Specifically, did your financial support include the
sponsor?

DR. HANSON: I have given educational programs in England for the sponsor
on two occasions\--

CHAIRMAN BONE: Thank you.

DR. HANSON: \-- but I have not received financial support for research
in my laboratory.

CHAIRMAN BONE: I\'m sorry to interrupt. Go ahead.

DR. HANSON: We clearly are faced with an epidemic of obesity. I love
John Foreyt\'s statistic that it\'s going to be 100 percent in the year
2030. Unfortunately, we all know how to lie with statistics and that\'s
really not a projection I would adhere to. But I would adhere to the
fact that we are increasing in our degree of obesity even as the year
2000 goals set forth six years ago now were supposed to stem obesity.
So, even as we were supposed to be stopping it and our national goals
were to stop it, it has been increasing. If I were going to put my guess
on it, I would guess we\'re heading toward the 40 percent level, not the
100 percent level. Even so, obesity is clearly the basis for a great
deal of pathology in the American community.

One of the things I have studied is the effects of preventing obesity.
We have studied it in non-human primates. We have shown unequivocally
that if you can simply prevent the development of obesity, you can
almost completely halt Type II diabetes. You can almost completely halt
dyslipidemia and hypertension in large measure. So, I think the evidence
is clear of the major contribution of obesity \-- obesity, per se \-- to
morbidity and mortality among the American people.

Until very recently, we have not dealt with obesity in that way. In
fact, my own upbringing was first in a department of psychiatry where we
spent several years attempting to change behavior and attempting to
admonish people who already were highly motivated to lose weight. As
John said, it is very clear that behavior alone will not solve the
problem of reducing obesity. And so, we have had to turn to what the
physiological and genetic bases of obesity are.

On that issue, it\'s also clear to those in the field of obesity that
we\'re dealing with a heterogeneous disease. That many different agents
are going to be needed, that agents one-at-a-time or in combinations
will ultimately be needed to sufficiently attack the problem of obesity.
So, we are strongly in support of research that will continue to enhance
the development of anti-obesity agents or agents that will help with the
mitigation or slow the development of obesity.

That\'s the area that the ASCN is concerned about. It\'s certainly one
of the major nutrition problems in our country. So, obesity is an
epidemic. It clearly can be and should be addressed with pharmaceutical
means as well as behavioral and social means. We urge the Committee to
consider obesity for the very high morbidity of producers and to look
carefully at the benefits and the risks associated with its treatment.

Thank you.

CHAIRMAN BONE: Thank you very much, Dr. Hanson.

The next speaker will be Ms. Valerie Rochester.

MS. ROCHESTER: Good morning. I\'m with the National Council of Negro
Women in Washington, DC. An organization that is dedicated to furthering
the advancements and opportunities for African-American women and
assuring quality of life.

One of the things that we are focused on primarily is health of
African-American women and their families. Obesity is a major concern
for African-Americans, particularly as it relates to African-American
women. It\'s a concern, however it\'s not viewed widely as a concern
among women. That\'s primarily due to the cultural differences in body
image and body ideals when it comes to African-American women. Body
size, attitudes and standards, as well as the rates of obesity, differ
among African-American women as related to Caucasian women.

In a study comparing body images, body size perceptions and eating
behavior among African-American and White college educated women, it was
found that White women reported greater body dissatisfaction, more
negative evaluations of appearance in general, and more body image
avoidant behaviors to control or conceal their weight. However, when we
look at the rates of obesity among Black and White women, almost half of
Black women, 46 percent, are overweight. Their average of being
overweight is 24 pounds. That is a concern, especially when it is not
viewed as being a major health condition.

We all know that obesity directly relates to high incidence of diabetes,
high blood pressure \-- excuse me, my voice is failing this morning \--
heart disease and stroke, all conditions of which African-Americans are
disproportionately represented. When it comes to addressing this issue
in African-American communities, pharmaceuticals are important. However,
we do need to combine those with education and behavior modification
measures.

When it comes to addressing these conditions in African-Americans,
again, the combined approach of pharmaceuticals, education and behavior
modification methodologies will be very important. The National Council
of Negro Women does support the advancement of these pharmaceuticals. We
would be very interested in working further as far as developing the
corresponding educational programs and outreach programs to ensure that
not only is obesity made a major health awareness problem among
African-Americans, but that we also address it appropriately, culturally
appropriately and sensitively.

Thank you.

CHAIRMAN BONE: Thank you very much.

The final speaker is Ms. Lynn McAfee.

MS. McAFEE: Good morning.

As to conflict of interest with the diet and pharmaceutical industries,
I\'ve given them plenty of money. They\'ve never given me anything.

I\'m Lynn McAfee from the Council on Size and Weight Discrimination.
I\'d like to take this opportunity to address a number of issues
regarding anti-obesity drugs.

First, I\'d like to suggest that a way be found to include the dropout
rate in the effectiveness number. I find it very strange that a dropout
rate for a supposedly successful drug is 50 percent while placebo was 40
percent, as was the case with redux. If the drug works so well,
shouldn\'t it have a lower dropout rate than placebo, even taking into
account side effects? It just seems so unlikely to me that people who
were desperate enough about their weight to take an experimental drug
and were successfully losing weight, would wake up one morning and say
\"never mind. I\'ve decided I\'d rather be fat. Thanks, anyway.\"
Something else is happening here.

I also would like to see the drug studied in varied populations. Past
experience with other drugs such as anti-hypertensives have shown us
that more representative distribution of ethnic groups and gender is
important. Groups affected with comorbid conditions should be studied
and analyzed as to effectiveness as well as improvement of comorbid
condition. I would also like to see what happens to people with comorbid
conditions as they gain back weight. It\'s possible they would be left
worse off than if they had not taken the medication and lost weight.

My last point with regard to effectiveness is my concern with the
necessity of people sticking to a low calorie diet for a lifetime. This
has not proven possible until now. I wonder if even with medication it
is truly realistic for people to keep up that level of dieting intensity
indefinitely. The people in the Weintraub study pretty much dedicated
their lives to dieting, yet even they had trouble maintaining weight
loss by the end of the study.

The pharmaceutical companies are saying that if we don\'t live the life
of a Weight Watchers counselor, we have failed the drug. And while
Weight Watchers has taken a lot of money from us over the years, I
don\'t think even they can afford to hire all 34 million of us as Weight
Watchers counselors. It seems to me the point of using medication is to
make weight maintenance achievable. If people can not stay on this very
restricted diet then the medication has failed, not fat people. This is
an important point. Perhaps a group should be given medication and asked
to eat more normally so if we can see if the medication has an effect on
their caloric intake and weight over time. This might be a truer test of
what will happen in the real world.

I\'d also like to make a few comments about some of the morbidity,
mortality and economic impact figures that are often used by obesity
researchers. For example, Shape of America literature says \"medical
researchers have calculated the cost to society for obesity related
diseases at more than \$100 billion annually.\" But reading on you see
that \$33 billion of that money is for \"weight reduction products and
services.\" This number even includes diet soda. This is a classic case
of misdirection. In fact, since Shape Up America is sponsored largely by
various weight reduction products and services, their goal is to
increase this number not to decrease it.

Likewise, the widely touted Nurses Study takes what is a very small
number of deaths and creates some rather sensational relationships that
really need to be looked at with care. This study has been presented
without criticism as obesity research gospel but there are criticisms of
this work that should be heard. I am not saying the mortality figures
for fat people are the same as for thin people. I am saying that while
these sensational numbers may help to get much needed funded for obesity
research, we should be certain that these are the right numbers to use
when calculating the risks and benefits of these drugs.

Finally, I want to share with you some of my thoughts about sibutramine.
I have had three conferences with the Knoll people since January and
have been very pleased with their openness in showing me their data on
effectiveness and safety and answering my many questions. The best thing
to be said about this drug is that it\'s not redux. It\'s not a
serotonin releasing drug so I\'ve been told they won\'t have the
problems with neurotoxicity and PPH that redux has. The main problems
are hypertension and pulse rate. While these are worrisome problems,
they can at least be monitored.

The concern I have is regarding effectiveness. As a consumer advocate,
this is important to me. For many decades, we\'ve been paying billions
of dollars a year for weight loss technology that just plain doesn\'t
work. Because of the safety concerns I have about redux, I would have
gladly accepted sibutramine as long as the effective rate was roughly
equivalent. However, two days ago, I learned about a two-and-a-half year
effectiveness study that concerns me greatly. The sponsor will
undoubtedly be presenting to you shortly information on it. But based on
the abstract published in [Obesity Research]{.underline} last week, it
appears that sibutramine\'s weight maintenance ability is not
satisfactory. There was a mean weight loss of six kilograms at 40 weeks,
but by 60 weeks there was a steady weight regain. At 96 weeks, the
weight loss maintained was only 2.6 kilograms.

Of equal concern is the dropout rate. Only 15 percent of the subjects
completed the study. This is quite serious. Are these people going to
experience a worsening of their comorbid conditions when they regain
weight? In the same journal, a paper based on information from the
Swedish Obesity Study states \"all risk factors are improved by weight
reduction, but when measured after one year of weight stability, five to
ten kilogram reduction is required to detect the changes. The value of
small weight reductions is thus questioned.\"

CHAIRMAN BONE: Thank you.

I want to thank all the speakers for their clear and concise comments.

As I said earlier, I mentioned that there are letters from the American
Heart Association, the American Diabetes Association, Marion J. Franz,
Denise E. Bruner, and the North American Association for the Study of
Obesity which are provided in the way I described earlier.

The next stage in the proceedings will be the presentations by the
sponsor, Knoll Pharmaceutical Company. The sponsor has asked if the
Committee would be willing to ask questions in the following way. The
sponsor would like to have questions \-- not interrupt the presentations
\-- would like questions after each individual presentation, only those
questions which are related to specific questions of fact or
clarification, and discussion type questions deferred until after all
the presentations.

Is that agreeable to the Committee? Any objection? No? Fine, then we\'ll
proceed in that way.

The introduction will be given by Dr. Mel Spigelman from Knoll.

DR. SPIGELMAN: Thank you.

Dr. Bone, Dr. Bilsta, Dr. Sobel, Members of the Advisory Committee,
Members of the FDA, ladies and gentlemen, my name is Mel Spigelman, Vice
President of Research and Development at Knoll Pharmaceutical. I have
the pleasure of introducing the programs that we will be presenting
today on sibutramine.

As you are all aware, sibutramine has been submitted to the FDA for
approval for the treatment of obesity, a disease which has become a
virtual epidemic in this country. The magnitude of the problem can be
seen from the results of the NHANES III study which documented that the
prevalence of obesity, defined here as a BMI greater than 27.8 for men
and 27.3 for women, was approximately one-third of the American adult
population over the age of 20. Perhaps even more disconcerting however
is the fact that this prevalence is increasing.

The ramifications of this finding are profound as obesity increases risk
for a variety of outcomes. Not only those that are commonly associated
with obesity such as dyslipidemia, hypertension and Type II diabetes,
but even those such as arthritis, gallstones, cardiovascular deaths, and
even cancer deaths. It\'s noteworthy that weight loss is considered by
most to be the primary therapy for the obese individual with some of
these disorders, such as Type II diabetes, hypertension, or
dyslipidemia.

With that brief introduction, I would like now to actually introduce
sibutramine. Sibutramine is an SNRI, or seratonin-norepinephrine
reuptake inhibitor. It was synthesized in 1980 by Boots Pharmaceutical
Company and first went into men in 1984. Initially, this drug was being
tested clinically for its anti-depressant activities. Although it failed
to show activity in depression, it was noted that sibutramine produced
consistent weight loss. Therefore, in 1990, the development program was
focused on the area of obesity. With the acquisition of Boots
Pharmaceutical by Knoll, the IND was transferred to Knoll and the NDA
was submitted in August of last year.

Of note, the design of the clinical program was done in conjunction with
the neuro-pharmacology division, as that group originally reviewed the
IND. Subsequently, all of the CD compounds were transferred to the
endocrinology and metabolism division. Although the clinical program
presented in the NDA was completed prior to the 1995 Committee
Discussion on Guidelines for approvability of obesity compounds, our
results are compatible with the criteria for approvability. Furthermore,
the data that we will present will support the utility of sibutramine
both in producing clinically significant weight loss and in maintaining
that weight loss.

What I would like to do now is present the agenda for today\'s
presentations. Dr. Xavier Pi-Sunyer, professor of medicine at the
College of Physicians and Surgeons of Columbia University will give a
brief presentation on the clinical and epidemiological importance of
obesity. Dr. David Heal, head of CNS biology at Knoll Pharmaceuticals in
Nottingham, England will present the pre-clinical pharmacology. This
will be followed by Dr. Carl Mendel, who is director of endocrine at
Knoll who will present the efficacy summary including discussion of
pharmacokinetics. Dr. Timothy Seaton, senior director of endocrine
metabolism at Knoll will then present the safety summary. We have asked
Dr. Sylvia Smoller, professor of epidemiology and head of the Division
of Epidemiology and Statistics at the Albert Einstein College of
Medicine to present the results of epidemiological evaluations of the
benefit risk assessment of sibutramine.

Because of time constraints this morning, only one of the two
epidemiological models, which I\'ll present in detail in your briefing
package, will be formally presented this morning. Dr. Michael Lean,
professor of human nutrition at the University of Glasgow and a
sibutramine investigator, will then present the clinical benefit risk
discussion. I will then discuss the present status of our proposed Phase
IV post-marketing large simplified clinical trial, and conclude with a
brief summary.

We have with us today several other representatives, both from Knoll as
well as consultants and experts who have served as advisors. These
individuals may be called upon to address questions from the Committee.

Prior to beginning the presentations, however, I would like to call your
attention to the analytical processes which have been utilized to
evaluate the efficacy and benefit of sibutramine. After demonstration of
the efficacy of sibutramine in producing consistent and clinically
meaningful weight loss, we will proceed to evaluate the effect of
sibutramine on risk factors such as blood pressure, lipids and glucose
tolerance.

As clearly stated in the draft guidelines for the clinical evaluation of
weight control drugs, risk factors are expected to improve if weight is
lost. The logic is clear and persuasive. Risk factor improvement is
expected to occur in patients who lose weight. Whereas, patients who do
not lose weight are not expected to have improvement in their risk
profiles. Therefore, the analytical question that we will continually
pose in the presentations today is through patients who lose weight on
sibutramine, derive the expected benefit from their comorbid parameter.
This must be distinguished from a drug whose primary mechanism is to act
as a direct modifier of a risk factor, wherein one would expect to treat
a population as a whole to derive improvement in the risk factor.

For an anti-obesity compound, the treated population as a whole should
show improvement and efficacy in the parameter of weight loss. Whereas,
those who lose weight would be expected to show benefit in the
evaluation of their risk factor.

I would also like to call your attention to three areas in which our
proposed labeling for sibutramine has been changed from that originally
presented in the NDA. Based on discussions with the FDA, we have
recently concluded that the maximum daily dose should be limited to 20
milligrams per day. The recommended starting dose is five to ten
milligrams per day, which may be titrated upward in five milligram
increments every four weeks if there is evidence of inadequate weight
loss as measured by less than four pounds over the four week period and
good tolerability. Treatment should not be continued in patients who
either have unacceptable side effects or who, after an adequate trial of
therapy, will most likely not achieve clinically significant weight
loss. Data supporting this titration scheme will be presented in the
efficacy presentation.

Finally, in addition to not being recommended for patients with a
history of coronary artery disease and/or arrhythmias, we also present
that sibutramine should not be used in patients with inadequately
controlled hypertension.

I would now like to introduce our first speaker, Dr. Pi-Sunyer, who will
present an overview of the significance of obesity and the need for
pharmacotherapy.

DR. PI-SUNYER: Good morning. It\'s a pleasure to be here and be able to
continue the discussion on health risks of obesity and benefits of
weight loss. You\'ve heard during the open hearing, a number of speakers
allude to the relationship of obesity to a number of conditions which
are some of the greater killers in America today. I just want to go over
three or four of the epidemiological studies that deal with this and
then go on to talk briefly about some of the benefits with regard to
these comorbid conditions that occur with weight loss.

You can see in this first slide, the study from the Nurses Health Study
of hundreds of thousands of women who have been followed over the 16
year periods in this particular report with a BMI from below 22 to a BMI
greater than 35, and the relative risk of developing Type II non-insulin
dependent diabetes which you can see begins to rise steeply after a BMI
of 27. It very rapidly increases up to a relative risk that is close to
100 percent of the original.

If you look at the risk of hypertension \-- this is a study taken from
Witteman in Circulation published in 1989 of a number of American
individuals. Again, you see the direct relationship of increasing BMI
from below 23 to greater than 32 with an increased relative risk of
developing hypertension or having hypertension. So, the relative risk of
individuals with a BMI above 32 goes up five-and-a-half fold.

With regard to lipids, we also have an increased risk with primarily, a
manifestation of hypertriglyceridemia with increased chylomicron
remnants, increased VLDL remnants, decreased HDL and particularly
important, the production of small, dense LDL particles which are
significantly atherogenic.

With regard to gall bladder disease this, again, is taken from the study
by McClure & Colditz, you can see that the BMI \-- the relative risk
increases at a point of a BMI of 25 and essentially triples. Then at the
BMI of 32 and above, goes up six-fold. So, the increase risk of gall
bladder disease is greatly increased with increasing weight. This is
particularly true of women.

Now, finally, I just want to mention the data from the American Cancer
Society study which shows the mortality ratios for cancer sites at which
incidence of overweight is greater than for average weight. This is the
weight index calculated from the Metropolitan Life tables of 1959. The
group that was 110 to 119 percent above ideal, the group that was 120 to
129 percent, 130 to 139 percent, and greater than 140 percent. That is
40 percent above ideal body weight. In males, there is an increased
prevalence of colon and rectal cancer and of prostate cancer. In
females, the particularly important cancers that are at a greater
prevalence with regard to mortality is the endometrial cancer, uterine
cancer, cervical cancer and breast cancer. Breast cancer particularly
important in post-menopausal rather than pre-menopausal women.

Now, with regard to the benefits of weight loss, I just want to show you
a couple of studies. This first one is a study done by Dr. Henry of the
University of California, San Diego in which he measured fasting plasma
glucose before and during each block of a diet, of a very low calorie
diet, that was followed over a period of a month. Each of these bars is
a four day period. This is a group of non-diabetic matched obese
individuals. This is a group of diabetic obese individuals. You can see
the blood sugar began at a level of about 290 milligrams per deciliter.
It dropped by the end of the third, fourth day period \-- this is 12
days after the beginning of the diet \-- to about 120 milligrams
percent. Thereafter, it remained at a level of the normal individuals
showing the important effect of decreased food intake and beginning of
weight loss on glucose disposal. This is shown here. This is the glucose
disposal of the diabetic individuals before the diet. This is after the
diet, a very significant increase in glucose disposal rate. You get the
same effect on non-diabetic obese individuals whose glucose disposal
rate greatly improves. This is a group of normal individuals for
comparison.

If you look at systolic and diastolic blood pressure before and after
weight reduction, this is a study published by Staesson et all in
hypertension in 1989. Each bar is an individual. The red arrow is the
combined group. You can see that \-- this is before weight loss and
after weight loss. This is systolic pressure, diastolic pressure \--
that there is a consistent drop in blood pressure in individuals as
their weight measured shown here drops in terms of kilogram. So that we
have a very significant drop in blood pressure with drops in body
weight.

Finally, if you look at lipid lowering \-- this is from a study of
McMahon published in a group of young adult Americans \-- you can see
here with a weight loss, there was about six to seven kilograms on
average. There was a change in total cholesterol from baseline of minus
5.6 percent. There was an increase of HDL cholesterol of plus 6.1
percent. There was a decrease of the ratio of total cholesterol to HDL
cholesterol of ten percent. There was a decrease in triglycerides of 7.7
percent.

Now, we know on the basis of studies like the ones that I\'ve shown,
that we no longer need to bring a person\'s, an individual\'s weight
down to normal, to ideal body weight. We know that in a sense, this is
futile because they begin to escape from such a pattern of treatment. We
are now becoming more and more satisfied with a partial normalization of
weight with risk factor reduction. I think all of the trials, all of the
clinical programs that are going on today with regard to diet, exercise
and behavior modification, are aiming at a partial normalization with
risk factor reduction.

So that for the past two decades, the components of effective weight
management programs has been diet, physical activity combined with a
strong behavior modification program that will change lifestyle behavior
for these individuals, hopefully, permanently.

We have found more recently, however, that if you look at data of the
net weight loss over time in behavioral studies with follow-ups of more
than one year that the results are not very good. This is the
post-treatment result. This is at one year, two years, three years, four
years, five years. This is the number of studies that have been carried
out over that period of time. One year, eight studies. You can see at
the end of four or five years, very few studies are available. But you
also see that at post-treatment, the average weight loss is about 16
pounds. By the time you get out to four and five years, a good
two-thirds of that weight has been regained.

So, we have a handle on how to get people to lose weight. We have a very
poor handle on how to get people to maintain that loss of weight.
Because of this, we believe that, essentially, we need a new paradigm
for treatment. We have to understand that obesity is a chronic disease.
It will not be cured. It is a lifelong condition and probably needs to
be treated as such. That state-of-the-art treatment is comprehensive and
includes the behavior modification, dietary change and increased
physical activity but that there is an appropriate role of
pharmacological management of obesity. This is based on evidence of
safety and efficacy of the anti-obesity agent or agents.

So, we feel that at this time, at this state in the American health
scene, that the new paradigm for treatment allows for the addition to
diet, exercise and behavior modification, of effective and safe
anti-obesity agents. Thank you very much.

CHAIRMAN BONE: Specific questions related to Dr. Pi-Sunyer\'s
presentation?

Dr. Marcus?

DR. MARCUS: Yes. I was very interested in the graph that showed a linear
and inexorable rise in weight among people who are not treated whereas,
I had assumed that people would generally be in some sort of stable
equilibrium. Actually, how good is the evidence that weight gain
continues in a linear fashion essentially forever shown on the slide?

DR. PI-SUNYER: The data in the American epidemiological scene is that
essentially, the average American gains a half-a-pound a year from age
20.

DR. MARCUS: But your slide wasn\'t the average American, it was \--

DR. PI-SUNYER: No, no. This \--

DR. MARCUS: \-- obese people.

DR. PI-SUNYER: Obese people.

DR. MARCUS: Are they also, left to their own devices, gain in a linear
fashion essentially forever the way the graph looks?

DR. PI-SUNYER: There is not good data following long-term obese people
in that kind of a slide. So, I can\'t tell you that every obese person
\-- certainly, many obese persons plateau off at certain weights. But
there is a good natural history for suggesting that many of them
continue to inexorably rise slowly over time from age 25 or 30 \-- or
20, whenever they have their problem, up to the age of 60. After age 60,
there tends to be a plateau and a downward falling away.

DR. BONE: Thank you.

DR. PI-SUNYER: I\'d like to present, if I could have the next slide, Dr.
David Heal who will present the pre-clinical pharmacology.

DR. HEAL: Good morning, Dr. Bone, Dr. Sobel, Dr. Bilsta, ladies and
gentlemen.

The presentation on the pre-clinical pharmacological of sibutramine is
divided into four sections. In the first part, I will demonstrate that
in vivo sibutramine is a seratonin or 5-HT, a norepinephrine reuptake
inhibitor, an SNRI.

Sibutramine is aylcylcobutyl alkylamine. It is a tertiary amine and when
it is administered to either animals or man, it is rapidly deanimated to
form the secondary amine metabolite 1 and the primary amine metabolite
2. Metabolites 1 and 2 are the predominant active species in animals and
man.

When sibutramine is given repeatedly to animals, we can see that there
is a profound reduction in their body weight gain. The divergence of the
two curves indicates that there is no tolerance to the drug while the
animals are receiving treatment, in this case 30 days. Upon drug
withdrawal, we can see that there is only a very, very gradual increase
of body weight back to control levels. There is no evidence that
withdrawal induces profound rebound hyperphagia leading to very, very
rapid weight gain with rebound above control levels.

In the next 11 slides, I will discuss the mechanisms underpinning this
weight loss fact.

The monoamine neurotransmitters norepinephrine, seratonin and to a
lesser extent dopamine, are intrinsically involved in the regulation of
food intake and energy expenditure. There are three principle
presynaptic mechanisms whereby drugs can enhance central and peripheral
monoaminergic function.

Monoamine releasing agents enter the presynaptic terminal by the high
affinity reuptake carrier. There, they displace monoamines from storage
granules and this leads to massive reflux of monoamines into the
synaptic cleft. Monoamine releasing agents like dexamphetamine and
dexfenfluramine bypass the physiological control mechanisms of
inhibition of neuronal firing and negative order receptor feedback.

The major route of inactivation for monoamines in the CNS is to be taken
back up into the presynaptic terminal again by the high affinity
carrier. Reuptake inhibitors like sibutramine block this carrier
protest. This leads to enhanced concentrations of monoamines in the
synaptic cleft. Monoamine reuptake inhibitors do not bypass
physiological control mechanisms. Monoamine oxidase is the major
affecter for the catabolism of monoamines. Its inhibition by drugs leads
to enhanced concentrations of monoamines in the neurone and enhances
release on neuronal activation. Sibutramine and dexfenfluramine are not
inhibitors of MAO. Dexamphetamine is a weak inhibitor of this enzyme.

In rat brains, sibutramine is a weak inhibitor of norepinephrine
reuptake. However, its metabolites 1 and 2 are potent inhibitors of
norepinephrine reuptake being approximately as potent as the selective
norepinephrine reuptake inhibitor, desipramine. They are also moderately
potent inhibitors of 5-HT reuptake being approximately as potent as the
SSRI fluoxetine. In vitro metabolites 1 and 2 are also moderately potent
inhibitors of dopamine reuptake.

However, as I will show on the next slide, this pharmacological action
is not expressed in vivo at pharmacologically relevant doses. The
pharmacological profiles of metabolites 1 and 2 contrast markedly with
those of dexamphetamine which is a moderately potent inhibitor of
norepinephrine reuptake and a weight inhibitor of dopamine reuptake, and
with those of dexfenfluramine which is a weak inhibitor of both
norepinephrine and 5-HT reuptake.

Evidence from in vivo experiments demonstrates a clear potency
separation between sibutramine\'s actions as a reuptake inhibitor of
norepinephrine and 5-HT compared with dopamine. This figure shows the
doses at which there is efficacy in four rat behavioral models. The
widths of the lines indicates the dose ranges for efficacy and the lines
are color-coded to demonstrate the neurotransmitters involved. Thus,
norepinephrine and 5-HT is shown in blue, norepinephrine alone is shown
in green, and dopamine is shown in red.

Effective doses for prevention of reserpine induced ptosis yield an ED50
of 0.6 milligrams per kilogram. Inhibition of food intake between three
and five milligrams per kilogram, and induction of thermogenesis between
three and ten milligrams per kilogram. These doses are between two and
two-fold lower than those required to induce even minimal dopamine
reuptake inhibition in vivo as shown by the induction of circling in the
unilateral nigrostriatal lesion graphs. And this is a very well
established model for assessing enhanced central dopaminergic function.

This slide compares the in vivo effect of fluoxetine, sibutramine, and
dexfenfluramine on extracellular 5-HT concentrations in rat brains
measured by the sophisticated technique of in vivo microdialysis. At ten
milligrams per kilogram, the SSRI fluoxetine produces an approximately
400 percent increase in 5-HT eflux. The SNRI sibutramine produces a 200
percent increase at this dose. However, the 5-HT releasing agent,
dexfenfluramine at ten milligrams per kilogram, produces a massive 2,300
percent increase in 5-HT eflux.

Differentiation of sibutramine\'s mode of action from that of
fenfluramine is emphasized by this follow-up study. 5-HT releasing
agents like fenfluramine and dexfenfluramine into the presynaptic nerve
terminal by the high affinity reuptake transporter and this slide shows
the effect on eflux which are ten milligrams per kilogram fenfluramine
has. However, pre-treating the rats with a monoamine reuptake inhibitor
blocks this process. We can see that when the rats are being pre-treated
with either sibutramine or fluoxetine, we can ablate the effects of
fenfluramine treatment in these animals.

In this part, I will deal with sibutramine\'s actions to reduce food
intake by enhancing satiety. When given acutely to rats, sibutramine
produces a dose-dependent reduction in food intake. The ED50 for the
inhibition of 24 hour food intake is approximately five milligrams per
kilogram. Sibutramine and dexfenfluramine both reduce food intake by
enhancing post-ingestive satiety, the natural physiological response.
However, dexamphetamine disrupts the satiety response and reduces food
intake only at behaviorally activating doses.

A synergistic interaction of norepinephrine and 5-HT reuptake inhibition
on food intake is shown by this next slide. We have used the selective
norepinephrine reuptake inhibitor nisoxetine and the selective 5-HT
reuptake inhibitor fluoxetine. When given alone at high dose, neither
drug has any affect on drug intake. However when these drugs are given
in combination, it blocked both 5-HT and norepinephrine reuptake
equivalent to administering sibutramine. We can see that there is a
profound reduction in food intake and the magnitude of this response is
identical to that observed with sibutramine.

This section deals with sibutramine\'s action to increase energy
expenditure or thermogenesis by enhancing central sympathetic to brown
adipose tissue. Oxygen consumption is a good indicator of increased
energy expenditure or thermogenesis. Sibutramine given at ten milligrams
per kilogram produces a profound 31 percent and prolonged increase in
the energy expenditure of rats.

Thermogenesis is a norepinephrine mediated response and this is
demonstrated by the fact that it is blocked by high and combined doses
of atenolol and ICI 118,551 which block the atypical or beta 3 receptor,
in addition to blocking beta 1 and beta 2 receptors. This response was
not affected however by low doses of atenolol or ICI 118,551 which
blocked beta 1 and beta 2 adrenoceptors respectively. This effect is
mediated by a norepinephrine reuptake inhibition because neither
sibutramine nor its active metabolites have affinity for the beta 3
adrenoceptor.

In this section, sibutramine is clearly shown to be different in
pharmacological terms, from the monoamine releasing agents
dexamphetamine and dexfenfluramine. Sibutramine and dexamphetamine are
pharmacologically different because sibutramine does not release
dopamine or norepinephrine. Whereas, dexamphetamine is a potent releaser
of both catecholamines. Sibutramine reduces food intake at non-stimulant
doses, whereas dexamphetamine reduces food intake only at behaviorally
activating doses. Sibutramine enhances satiety, whereas dexamphetamine
does not. And Sibutramine inhibits food intake by inhibition of
norepinephrine and 5-HT reuptake. Dopaminergic mechanisms are not
involved. Dexamphetamines effects on food intake are mediated partly
through dopaminergic activation.

Sibutramine is pharmacologically different from dexfenfluramine.
Sibutramine\'s metabolites are potent seratonin and norepinephrine
reuptake inhibitors. Dexfenfluramine is a weak reuptake inhibitor of
both monoamines. Sibutramine is not a seratonin releasing agent.
Dexfenfluramine is. Sibutramine is not a norepinephrine releasing agent.
Dexfenfluramine is at high concentrations.

Thus, in conclusion we can say that sibutramine potently inhibits
norepinephrine and seratonin but not dopamine reuptake in vivo. It is
the first SNRI to be developed as an anti-obesity drug. Sibutramine
reduces food intake by enhancing satiety, a central effect mediated by
norepinephrine and seratonin reuptake inhibition. Sibutramine increases
energy expenditure by enhancing central sympathetic drive to brown
adipose tissue. Sibutramine\'s mode of action is different from that of
the monoamine releasing agents, dexamphetamine and dexfenfluramine. As
an SNRI, we believe that sibutramine will lack potential for primary
pulmonary hypertension, abuse and neurotoxicity.

Thank you very much.

CHAIRMAN BONE: Thank you.

Are there specific questions?

Dr. Kreisberg?

DR. KREISBERG: Yes. I wonder if it would be possible to go back to your
first slide? I think it\'s comparable to your Figure 214 in your
handout. Second slide \-- no, keep going. That\'s it.

You explain in your material that these are lean and growing rats.

DR. HEAL: That is correct.

DR. KREISBERG: Although the major portion of your presentation was not
on the actual response of the animals to the drug \-- you introduced the
subject \-- these are lean growing rats. I wonder whether that really is
a satisfactory experimental model for obesity since it would seem to me
that the best model would be a rat that had already achieved a stable
body weight?

The second question that I have, since it looks like the effect appears
so promptly within the time period of drug administration \-- that is,
it\'s almost maximum by five days or virtually most of the difference is
at five days. Then the lines are either parallel or slightly diverging
\-- whether this is a smaller animal or a compositionally more lean
animal? In other words, could the introduction of the drug lead to some
stunting in the size of the animal that allowed it to weigh less, or is
it actually a same sized animal that just has less body fat?

DR. HEAL: That\'s a very interesting set of questions. Although this
diagram here shows our effect in the growing animals, we can actually
demonstrate a weight loss in Zucker rats, cafeteria-fed rats, and other
types of obese animals.

What you see here is from the run-in period that, in fact, the growth
rates of the animals is identical in this period here leading up. So,
they\'re just pair matched animals. So, in fact, what you see here is
initially the marked drop in animals caused by, obviously, acute
administration of the drug. But I would point out quite clearly that the
difference here is smaller than the difference here, indicating there is
a divergence and the animals are continuing to lose weight.

I take your point entirely that this obviously demonstrates lean growing
animals. However, these are adults weighing in at 260 grams. We\'re not
talking about effects which occur in animals which are still in their
pre-adult stage.

CHAIRMAN BONE: Dr. Marcus?

DR. MARCUS: I\'d like to revisit the question of thermogenesis.
Certainly, the rat has a larger component of brown adipose tissue
activity than humans and I\'d like to ask about the effect of this drug
on other categories of thermogenesis. Specifically, can you show whether
there are differences in basal metabolic rate in food induced
thermogenesis or in activity induced thermogenesis by this drug?

DR. HEAL: We have not looked in any detail at activity-induced
thermogenesis. There does not seem from some preliminary experiments
that we have done to be any affect on food-induced thermogenesis, as you
will see in your pack. The actions of sibutramine to increase
thermogenesis in rats by brown adipose tissue is highly selective. It
seems to increase central sympathetic drive to brown adipose tissue. And
in fact, it leads in terms of glucose utilization studies to an increase
of 18-fold in glucose utilization specifically in brown adipose tissue.

CHAIRMAN BONE: Dr. Sherwin, you had a question?

DR. SHERWIN: Yes. I was just wondering how well does this drug cross the
blood brain barrier?

DR. HEAL: That is a question which will

have to be handled by one of my colleagues.

I\'d like to call on Dr. Rod Haddock from the Pharmacokinetics
Department to take the stand please?

DR. HADDOCK: We have some information on the transfer of material from
plasma into the brain. From the data that we have in the rat, it seems
that the concentrations are twice as high in the brain than they are in
systemic plasma.

DR. SHERWIN: So, it\'s concentrated. It\'s actively transported to the
brain, you\'re saying? Am I getting that straight?

DR. HADDOCK: The concentrations are twice as high which would indicate
that there is a preferential rate of transport, yes.

DR. SHERWIN: I\'m just curious. Obviously then the drug is having
central effects.

DR. HADDOCK: Indeed.

DR. SHERWIN: How much of a peripheral effect? I mean, if you locally
delivered desipramine for example, you can increase norepinephrine
tissues. Do you think this drug also works peripherally as well as
centrally?

DR. HADDOCK: May I defer to my colleague, Dr. Heal?

DR. HEAL: In terms of the two pharmacological actions which we have
demonstrated, they are both centrally mediated in origin. In the case of
the effect on food intake, we can demonstrate that central injection of
the metabolites of sibutramine leads to a dose related reduction in food
intake. In terms of the effects on brown adipose tissue and glucose
utilization, if we pretreat the rats with the ganglionic blocker
chlorisondamine, then in fact, we can abolish sibutramine\'s actions to
induce thermogenesis. This appears to be due to activation specifically
in the paraventricular nucleus of the hypothalamus.

Obviously, as a reuptake inhibitor, there is no difference
physiologically in the site in the central and the peripheral nervous
system. As a reuptake inhibitor, one would expect that sibutramine would
inhibit the reuptake of catecholamines into tissues where reuptake is a
major component of inactivation of transmission. We can certainly show
that it inhibits 5-HT uptake in platelets.

DR. SHERWIN: I just wonder will it have then an amplification effect on
the periphery only because now you\'re activating the central system
outflow and then you\'re blocking reuptake peripherally. That\'s sort of
what I\'m getting at.

DR. HEAL: Sure. That\'s a very interesting hypothesis and, in fact,
it\'s one that has been put forward by Professor Stock who did the
thermogenesis experiments. Where, in fact, what we observed was that the
magnitude of the effect which we saw with sibutramine was greater than
that observed with a direct beta 3 agonist. So, assuming that it was 100
percent efficacious \-- and we don\'t know that it is a full agonist \--
then it could indicate that peripheral uptake inhibition does play some
part.

Interestingly, reuptake inhibition in the periphery was not sufficient
to elevate glucose utilization in most of the other tissues. The only
other two tissues were one skeletal muscle, gastrocnemius and diaphragm.
And that was almost certainly due to increased respiration. Here, the
changes were only 20 or 30 percent. So, in tissues like the heart, there
was no increased glucose utilization.

CHAIRMAN BONE: Thank you.

Yes, Dr. Molitch?

DR. MOLITCH: I have three questions related, actually, to prior
questions by people, from Dr. Kreisberg\'s question. I didn\'t hear the
answer to the carcass analysis of the rats as to whether there\'s a
selective decrease in the fat compared to other tissues. Number two, I
presume, therefore, that the metabolites also have uptake into brain
tissue actively transported as well. Therefore, is there any serial data
looking at the brain transport to see if there is accumulation of drug
or does it achieve a steady state at a low level and then continues at
the same level in the brain?

DR. HEAL: I can answer one of those questions, certainly. The question
concerning the analysis of body composition, that has been done. It is
not due to a loss of lean mass. It is due to a loss of fat.

With regards to questions on kinetics and drug metabolism, then I once
again have to hand over to my colleague, Dr. Haddock.

DR. HADDOCK: In terms of transport of the metabolite and the
sibutramine, it is certainly true that the active metabolites are indeed
transported into the brain and the concentrations are some twice-as-high
as they are in plasma. In terms of time course, we don\'t have specific
studies analyzing time course extensively in brain and plasma. But
certainly from our radio tracer data we can say that the time course is
relatively short within the 24 hour period. So, at the end of 24 hours,
there is no accumulation or no significant accumulation of material in
the brain.

CHAIRMAN BONE: Thank you.

Dr. Kreisberg has a question.

DR. KREISBERG: One last question getting back to this issue of
thermogenesis. Can you account for the differences in weight between the
treated animals and the placebo animals strictly on quantification of
differences in food intake?

DR. HEAL: No. There is definitely, as time goes on, a contribution. When
we do energy balance equations there is definitely a contribution of
thermogenesis in these animals.

CHAIRMAN BONE: Just to clarify a point that came up with Dr.
Kreisberg\'s earlier question and your comment on carcass analysis. Is
the difference in weight between the animals shown in the growing animal
study entirely accounted for by fat?

DR. HEAL: There is no loss of lean growing mass in those animals.

CHAIRMAN BONE: Bob, does that answer your earlier question? Thank you.

All right, I think we\'re ready to go ahead.

DR. HEAL: The following presentation on pharmacokinetics and efficacy
will be given by Dr. Carl Mendel, the director of endocrine with Knoll
Pharmaceuticals.

DR. MENDEL: Good morning Dr. Bone, Dr. Sobel, members of the Advisory
Panel and guests.

I\'m here to tell you about sibutramine, its pharmacokinetics, its
weight loss efficacy, and the effects of sibutramine induced weight loss
on comorbidities and risk factors associated with obesity.

To start, a very brief summary of what we know about the
pharmacokinetics of sibutramine in humans. Sibutramine is efficiently
absorbed from the GI tract. It has a large first pass metabolism. This
generates two metabolites which mediate the pharmacological response of
sibutramine. These metabolites are formed by the cytochrome p450 enzyme
system and are further metabolized to inactive products before being
excreted in the urine as glucuronides.

Here we see the pharmacokinetics in healthy volunteers of a single oral
dose of sibutramine. Sibutramine itself has a short half-life,
approximately one hour whereas the half-lives of the active metabolites
are much longer, approximately 14 and 16 hours. Although not shown on
this slide, the pharmacokinetics of sibutramine are similar in obese
subjects and in non-obese subjects, in men and in women, and in the
elderly and in the young. On repeat daily dosing, steady state plasma
concentrations of the active metabolites are achieved within three to
four days with an approximately two-fold accumulation.

I\'d now like to direct your attention to the weight loss efficacy of
sibutramine. The data will show that sibutramine is an extremely
effective weight loss agent. Listed here are the eight major placebo
controlled studies in obesity which have been conducted and completed to
date with sibutramine. In each and every one of these studies,
sibutramine was found to produce statistically and clinically
significant weight loss in a dose dependent manner. The degree of weight
loss was remarkably consistent from study to study. Highlighted in
yellow are the two pivotal efficacy studies: BPI 852 and SB 1047, the
first of six months\' duration, the second of one year duration. If you
read down further to the left on the slide, you\'ll see SB 1049. This is
a third long-term study and was of one year duration. In all, more than
2,500 patients were studied in these trials.

Shown here is the design of BPI 852, the pivotal dose ranging and
efficacy study of six months\' duration. More than 1,000 patients were
randomized to placebo or sibutramine in doses ranging from one to 30
milligrams. Ancillary therapy in the form of dietary counseling,
recommendations for an exercise program and suggestions for behavioral
modification was provided. Patients completing the study were allowed to
enter an open label, long-term extension study that allowed additional
monitoring of safety.

The inclusion and exclusion criteria are shown here. As you can see,
patients with major comorbid diseases were excluded in this study. The
baseline demographics indicate that the groups were well matched at
baseline. The majority of patients were female and the BMI was
approximately 35 kilograms per meter squared. The median weight was
almost 100 kilograms. Therefore, please keep in mind as we looked at
weight loss curves, a five percent decrease in weight would equal
approximately a five kilogram decrease in weight. Mean percent change of
body weight in this study is shown in this slide for the last
observation carried forward or LOCF analysis. The amount of weight lost
increased with dose and was marked. At the 20 milligram dose, for
example, mean weight loss approached seven percent in this analysis,
whereas weight loss on placebo was minimal. The rate of weight loss was
most marked during the first three months of therapy. For the five to 30
milligram doses, weight loss was statistically significantly greater for
sibutramine than for placebo at all time points.

In this slide, we see the weight loss curves for completers. These data
appear even more compelling. At the 20 milligram dose, for example,
there was a mean weight loss of almost nine percent, again, with only
minimal weight loss in the placebo group. In the interest of time and to
be conservative, I will present only LOCF data from this point on.

Now, an analysis of the data in this study \-- and I\'ll show you the
slide in a minute \-- suggests that we can predict early-on which
patients will achieve clinically significant long-term weight loss on a
given dose of sibutramine. In particular, those patients who lose four
pounds or more in the first four weeks of treatment generally went on to
achieve clinically significant long-term weight loss.

Now, if we look at the ten milligram dose here, for example, more than
60 percent of patients lost more than four pounds in the first four
weeks. Of these, almost 70 percent went on to achieve clinically
significant \-- that is greater than or equal to five percent weight
loss \-- by week 24. Conversely, of those who did not lose four pounds
in the first four weeks, the vast majority \-- over 80 percent \-- did
not go on to achieve more than five percent weight loss at week 24.

Data from our other long-term studies, SB 1047 and SB 1049 confirm this
paradigm. Thus, subjects who will not respond well to a given dose of
sibutramine can be identified early and taken off that dose of
sibutramine. Patients on sibutramine in this study also experienced
marked dose related decreases in body mass index or BMI. In the
interests of time, BMI slides for other studies will not be shown in the
primary presentation but of course, in all of our studies, the observed
changes in BMI paralleled the observed changes in weight.

If we look at the percentages of patients losing at least five percent
of their baseline weight, we see that already at a ten milligram dose,
approximately half the sibutramine treated patients lost more than five
percent of their weight. This compares to only 13 percent in the placebo
group. And at the 15 milligram dose, approximately one-quarter of the
sibutramine treated patients lost more than ten percent of their body
weight as compared to none in the placebo group.

Now, changes in waste circumference are generally thought to reflect
changes in visceral fat and visceral fat is associated with many of the
comorbidities of obesity. Sibutramine induced reductions and waste
circumference were marked dose related and commensurate with the amount
of weight lost. Overall, in BPI 852, sibutramine doses of five to 30
milligrams produced marked weight loss, marked decreases in body mass
index, and marked decreases in waste circumference. Observed decreases
in serum lipids and passing blood sugar will be discussed later in the
presentation.

I now want to turn your attention to the second pivotal efficacy trial.
Shown here is the design of SB 1047, the one year placebo controlled
efficacy study. Almost 500 patients were randomized to treatment with
sibutramine, ten or 15 milligrams or placebo for one year. Ancillary
therapy consisted of dietary counseling. The inclusion and exclusion
criteria were similar to those of BPI 852 except that stable
hypertensives were allowed in this study. More than 100 hypertensives
were, in fact, enrolled, approximately half of them on anti-hypertensive
medication. The baseline demographics in this study were similar to
those of BPI 852. The treatment groups were well matched at baseline.

Statistically and clinically significant weight loss was observed in
this study with the magnitude of weight loss very similar to that seen
at comparable doses in BPI 852. As you can see, the rate of weight loss
again was greatest during the first three months of treatment. Active
weight loss continued out to six months and then was maintained out to
one year. More than half the patients at the 15 milligram dose lost at
least five percent of their body weight. Fully one-third of the patients
at this dose lost at least ten percent of their body weight compared
with only seven percent in the placebo group.

Marked reductions in waste circumference were observed in the
sibutramine treated patients as compared to placebo. Although not shown
on this slide, the waist to hip ratio also declined statistically
significantly in sibutramine treated patients compared to placebo. To
summarize, in both pivotal studies, BPI 852 and SB 1047, marked
reductions in body weight, BMI and waste circumference were observed.

Now let\'s look at an additional one year efficacy study, SB 1049. The
purpose of this study was to examine the efficacy of sibutramine in
conjunction with a very low diet or VLCD. Patients who lost at least six
kilograms of body weight on a VLCD were randomized to 12 months of
therapy with sibutramine 10 milligrams or placebo. The groups were well
matched at baseline. Of note, the mean weight exceeded 100 kilograms and
the mean BMI approached 40 kilograms per meter squared.

Marked weight loss was seen during the VLCD phase of the study before
drug therapy. Treatment with sibutramine then resulted in substantial
additional weight loss by month six with maintenance of that weight loss
out to month 12. Thus, patients who combined a VLCD with a ten milligram
dose of sibutramine lost on average more than 12 percent of their body
weight. This study demonstrates the significant additive effects of
sibutramine and effective non-pharmacological therapy.

More than half the sibutramine treated patients in this study lost at
least ten percent of their body weight. Almost one-third lost 15 percent
of their body weight and there were even a significant number of 20
percent responders. As in other trials, waist circumference also
declined markedly and significantly in the sibutramine treated patients.
All-in-all, the results of this study show just what sibutramine can do
when combined with effective non-pharmacological therapy.

I now want to turn your attention very briefly to two studies designed
to compare sibutramine with dexfenfluramine, the only agent approved in
this country for long-term weight loss. SB 1052 shown on the left was a
small pilot study. The largest study, SB 2053, was designed as an
equivalence trial. In both these studies, a relatively low dose of
sibutramine, ten milligrams, was compared with the full recommended dose
of dexfenfluramine, 30 milligrams per day for 12 weeks. The yellow is a
sibutramine curve; the green is the dexfenfluramine curve. In both
studies, the observed placebo subtracted weight loss on dexfenfluramine
was similar to that reported in the literature. In both studies, weight
loss on sibutramine was numerically superior. Furthermore, in the larger
study SB 2053, the appropriate equivalence analysis showed that
sibutramine was at least as good as dexfenfluramine.

I\'d now like to deal with a slightly different subject, the effects of
sibutramine induced weight loss on the comorbidities of obesity,
including serum lipid profiles, diabetes, hypertension, and serum uric
acid. In the presentation that follows it is important to keep in mind
that sibutramine is not being evaluated here as a lipid luring drug, an
anti-diabetic drug, or an anti-hypertensive drug. Rather, sibutramine is
being evaluated here today as a weight loss agent.

In the presentation that follows, we will examine the effects of
sibutramine induced weight loss rather than the effects of sibutramine
itself on these comorbidities of obesity. Some of the analyses that I
will present in this section were completed only recently, the result of
questions generated in our ongoing discussions with the FDA.

Changes in fasting serum lipids in sibutramine treated patients in BPI
852, our single largest study, are shown in this slide. This is a
difficult slide and I\'ll help you through it in a minute. But what it
shows is that there were marked statistically significant differences
between the all-sibutramine group and the all-placebo group for
triglycerides, cholesterol, and HDL cholesterol. More importantly, the
improvements in serum lipids in sibutramine treated patients who lost
significant amounts of weight were even more pronounced.

And if I can just help you through the slide, the all-placebo group is
shown on this slide for triglycerides, cholesterol, LDL and HDL. The
all-sibutramine group is shown on this line with the significant changes
shown. As we go down on these columns, we see more weight loss. We have
the no change, zero to five percent, five to 10, 10 to 15, more than 15
percent weight loss, and we see the lipid changes increasing as the
weight loss increases. Now, in general, we see the same thing in the
placebo group. We have no 10 and 15 percent responders in the placebo
group.

Thus, serum lipids improve as weight loss increases on sibutramine just
as on placebo. Within a given category of weight loss, there were no
differences between sibutramine and placebo. Of course, since more
weight was lost on sibutramine, serum lipids improved more on
sibutramine than on placebo. Overall, these data suggest that
sibutramine itself, independent of weight loss, does not positively or
negatively affect serum lipids. But that sibutramine induced weight loss
results in the full measure of lipid changes expected on the basis of
weight loss alone. A meta-analysis of the serum lipid changes in our
entire database resulted in very similar findings.

Another way of looking at this issue is to examine the weight changes
and corresponding lipid changes in our database and ask whether the
lipid change associated with the given weight change is similar in
sibutramine treated patients and in placebo treated patients.

Turning to this slide, the percentage of weight change is shown on the
X-axis and the percentage lipid change is shown on the Y-axis. And I\'ll
just focus you here. If we take a point here, this would mean that for a
20 percent decrease in weight, we would be getting a ten percent fall in
cholesterol shown here. A steeper slope indicates a greater lipid change
for a given weight change and that would look something like this. If
sibutramine induced weight loss results in the lipid changes expected on
the basis of weight loss alone, then the slopes of the sibutramine
curves and the placebo curves should be identical. Certainly, the slopes
of the sibutramine curve should not be flatter than the slopes of the
placebo curves.

Turning back to this slide, looking at the data collected from our
placebo controlled obesity studies comprising more than 2,000 patients,
it can be seen that sibutramine and the placebo slopes are virtually
identical for both cholesterol and triglycerides indicating that for a
given amount of weight loss on sibutramine, the improvement in serum
lipids expected on the basis of weight loss alone is obtained in full
measure.

And in this slide, we see the corresponding findings for LDL and HDL \--
LDL here, HDL here \-- with the slopes of the lines, again,
statistically similar but even favoring sibutramine numerically. Thus,
we conclude from these data that sibutramine induced weight loss results
in the full measure of improvement in serum lipids expected on the basis
of weight loss alone.

There is one sibutramine study that was conducted specifically in
dyslipidemic patients. That study, SB 2059, was a short-term trial
conducted in Spain in mild dyslipidemic subjects who met the Spanish
criteria for mixed lipidemia shown here on the slide. The study duration
was four months. Patients taking hypolipidemic agents were excluded.
Weight loss is shown in this slide. Compared to our other studies, the
placebo group lost a great deal of weight with the mean weight loss on
placebo approaching six percent. As in other studies, however, the
sibutramine group did lose significantly more weight.

The serum lipid changes observed in that study are shown in this slide
and are consistent with the weight loss achieved. As expected, since
both groups lost significant amounts of weight, both the sibutramine
treated patients and the placebo treated patients experienced
improvements in their serum lipids with the expected numerical
superiority of sibutramine. Those patients on sibutramine who lost more
weight tended to have greater improvements in their serum lipids. The
same was true for placebo treated patients but, of course, more
sibutramine treated patients lost significant amounts of weight. This
study shows that sibutramine can be used effectively in patients with
dyslipidemia.

Now let me direct your attention to SB 3051, a study that compared
sibutramine 15 milligrams and placebo in obese diabetic patients. The
study was 12 weeks in duration. It contained an open label extension
that allowed additional monitoring of safety. There was a larger
proportion of males in this study than in most of our other trials and
the patients were somewhat older. The mean fasting blood sugars
approached 200 milligrams per deciliter and mean hemoglobin A~1~ levels
approached ten percent. Approximately 75 percent of the patients in this
study were on either insulin or sulphonyureas.

Statistically significant weight loss was obtained on sibutramine as
compared with placebo, although weight loss in both the placebo and the
sibutramine groups was somewhat smaller than that seen in other studies.
The weight loss in sibutramine treated patients was accompanied by
numerical decreases in fasting blood glucose with a treatment effect of
-30 milligrams per liter for glucose shown here, and -0.4 percent for
hemoglobin A~1~. Patients who achieved weight loss on sibutramine
experienced greater treatment effects in fasting blood sugar and
hemoglobin A~1~, although all of the changes shown represent numerical
trends rather than statistical superiority. In addition, a significantly
greater number of patients on sibutramine than on placebo experienced
hemoglobin A~1~ declines of more than one percent as shown here.

Serum lipids also improved on sibutramine as compared with placebo.
These improvements were greater in those sibutramine treated patients
who lost significant amounts of weight. Although most of these findings
represent numerical trends that did not reach statistical significance,
they remain consistent with our findings that sibutramine induced weight
loss results in the full measure of improvement in serum lipids expected
on the basis of weight loss alone.

We also examined retrospectively the effect of sibutramine induced
weight loss on fasting blood glucose in patients with mildly abnormal
fasting blood glucoses above 110 milligrams per deciliter in BPI 852,
our single largest study. Patients on sibutramine, and particularly
those who lost significant amounts of weight shown here, experienced
significant decreases in their fasting blood sugar as compared with the
all-placebo group. These findings suggest that sibutramine induced
weight loss results in the changes expected on the basis of weight loss
alone, not only for serum lipids but also for serum glucose.

Lastly, let me direct your attention very briefly to a study conducted
in obese hypertensive patients. This study, SB 2057, examined the
effects of sibutramine ten milligrams compared with placebo over a 12
week period. The treatment groups were well matched at baseline.
Approximately one-third of the patients were receiving anti-hypertensive
medication. As expected, sibutramine induced significant weight loss in
this group.

Treatment related changes in blood pressure are shown in this slide.
Blood pressure declined in sibutramine treated patients as a whole and
in placebo treated patients as a whole, but declined more in the placebo
treated patients despite a significantly greater weight loss in the
sibutramine group. And I\'ll come back and help you look at the numbers
in a second. Nevertheless, in the sibutramine treated patients who lost
significant amounts of weight, blood pressure declined more than in the
placebo group as a whole, although less than in placebo treated patients
who lost similar amounts of weight.

So, if we look at systolic blood pressure, for example, the
placebo/sibutramine difference 0.4 when we look at the group of entire
patients. In those sibutramine treated patients who lost weight, the
blood pressure effect is less. Actually, the blood pressure is lower
even compared to the all-placebo group although it\'s not lowered as
much as in the placebo patients who lost similar amounts of weight. The
effect of sibutramine on blood pressure will be examined in more detail
in the safety presentation, but these data indicate that controlled
hypertensives can be treated safely and effectively with sibutramine.

Finally, serum uric acid is another more recently recognized risk factor
for cardiovascular disease and was identified as an independent risk
factor in the NHANES study. This slide shows the highly statistically
significant improvements in serum uric acid in sibutramine treated
patients compared with placebo treated patients in our database as a
whole and in each of our three long-term studies. As expected, those
sibutramine treated patients who lost significant amounts of weight did
even better.

To summarize, sibutramine produces pronounced weight loss in conjunction
with diet and exercise clearly fulfilling the criteria of a successful
weight loss agent as established in the FDA draft guidance for weight
control drugs. A significant number of sibutramine treated patients
achieved more than ten percent reduction in body weight. Waste
circumference, an indicator of visceral fat declines proportionately
with weight loss in sibutramine treated patients. The dose response
curve for sibutramine is broad and efficacy is maintained for at least
one year. Sibutramine also produces significant weight loss in patients
with dyslipidemia, Type II diabetes and hypertension. Although blood
pressure does not improve commensurate with weight loss on sibutramine,
serum lipids, glycemic control and serum uric acid improve markedly in
patients who lose weight on sibutramine.

Thank you.

CHAIRMAN BONE: Specific questions? I\'m sure there will be several.

Dr. Zawadzki?

DR. ZAWADZKI: I have a couple of questions to start. Number one, what
was the diet these patients were placed on?

DR. MENDEL: In the different studies, it was somewhat different. In the
BPI 852, there were individualized diets depending on whether patients
were males or females. It was basically a diet, a diet-she. Women were
given a 1,500 kilocalorie diet. Men were given an 1,800 kilocalorie
diet.

DR. ZAWADZKI: So, there was basically a weight reduction diet imposed in
all the studies?

DR. MENDEL: Yes. All studies were conducted in conjunction with some
form of dietary intervention.

DR. ZAWADZKI: In the study that you described with individuals with
hypertension, were beta blockers excluded as anti-hypertensive agents?

DR. MENDEL: In that study, beta blockers were not excluded. In all of
our database, we have only about 30 patients who were treated with beta
blockers while receiving sibutramine in obesity studies.

DR. ZAWADZKI: And in terms of looking at those data, was there a similar
weight loss?

DR. MENDEL: Yes. The numbers of patients were small but looking at the
data weight loss was essentially identical to those not on beta
blockers.

DR. ZAWADZKI: Now when one looks at the data from the animal study which
showed that there was some blocking of thermogenesis with beta blockers,
how do you explain the weight reduction in these clinical studies?

DR. MENDEL: I think in terms of the pre-clinical studies, I\'ll let Dr.
Heal comment on those.

DR. HEAL: From the pre-clinical studies, it\'s important to point out
that neither beta 1 nor beta 2 antagonists actually prevented the
thermogenic effects of sibutramine. It was only when these drugs were
given at very, very high dose to block beta 3 receptors that we saw a
blockade of thermogenesis.

In terms of actions on food intake, beta 1 antagonists have only a very,
very small attenuation of this affect of sibutramine. This is
predominantly reversed by alpha 1 antagonist and 5-HT 2A, 2C
antagonists. So, from the animal studies, we would predict that this
should not actually block sibutramine\'s effects in people.

CHAIRMAN BONE: Dr. Kreisberg, I think, is next. We\'ll go around and
make sure everybody gets a chance.

DR. KREISBERG: The majority of the patients that you studied were women.
I don\'t know what the exact overall breakdown was, but maybe perhaps
500 of the 2,500 that you cited at the outset as participating in these
trials were men. I wondered if you\'ve looked at the pattern of weight
loss in men and contrasted that to women, and whether your
generalizations in terms of efficacy refer to men as well?

DR. MENDEL: Yes, we\'ve looked separately. There are between 300 and 500
males in the database. We\'ve looked separately at their weight loss. It
is quite similar to the weight loss of the group as a whole.

CHAIRMAN BONE: All right, I think Dr. Flack had a question.

DR. FLACK: I have several questions and a comment. Can you explain how
the dosing sequence, titration sequence of four weeks was arrived upon?
Because when you look at those curves, the rapid fall occurs early-on
but there\'s still a lot of weight loss ongoing at weeks eight and 12.
I\'m afraid that we\'re about to march down to the same thing we did
with blood pressure drugs, titrating them far too fast.

Can you explain why four weeks was chosen?

DR. MENDEL: Yes, this was essentially an empirical observation. I mean,
we did look at different time periods as well. Four weeks seemed to be a
reasonable predictive time period. Again, the predictability really at
all doses \-- I focused you on the ten milligram dose but the
predictability was, you know, in the range of 60 to 70 percent of those
patients that did go on to achieve long-term weight loss. Of those who
didn\'t \-- I mean, really, about 80 percent didn\'t.

Now, clearly, the longer out you go, you do increase the predictability
a little better. If you wait until six months, you\'re at endpoint. So,
this is really an empirical observation on which this is based.

CHAIRMAN BONE: Dr. Flack, weren\'t you referring to the interval for
adjusting the dose, not this interval for determining whether the
patient is likely responding.

DR. FLACK: Right. I\'m talking about the interval that a physician would
be asked or a practitioner would be asked or told that they could
increase the dose, the titration interval. Because you\'re leaving a lot
on the table there. I understand the model. I\'ve reviewed that model.
But the average change after that, for two months after that, is still
very impressive.

DR. MENDEL: Yes, and in terms of dose titration, let me ask Dr.
Spigelman to come up.

DR. SPIGELMAN: Yes, I think what we\'re really looking at here is a
question of risk benefit, in essence, when we look at the dose titration
scheme. The empiric observation is there that at four weeks, one has
high predictability to say whether, in fact, the dose that the patient
is on will or will not be successful in achieving the desired weight
loss aim. What we\'re saying is that in that time period over four
weeks, one can make a clinical decision at that point in time as to
whether or not that dose is going to be an effective dose. If it is not
going to be an effective dose probabilistically, then what we\'re saying
is that it is not worth the further risk of exposure at that dose for
the probability of benefit. Therefore, to move on.

DR. FLACK: I guess I would view it differently in that the benefit of
achieving weight loss in a faster than a one or two month period really
is going to confer probably no long-term benefit over the lifetime
treatment of the patient and that you probably ought to wait and slow
the titration down.

CHAIRMAN BONE: We can go into that in more detail this afternoon.

DR. FLACK: One final issue is the lipid effect. Really, the lipid
effect, when it is displayed by weight loss, is really different than
what it is by dose because the dose and the weight loss are related but
not perfectly with one another. Looking at the overall compilation of
data here, my conclusion, certainly, under 15 milligrams a day is that
the lipid changes are relatively inconsistent. They\'re not consistent
across dose. There\'s really no dose effect. They are there at certain
doses in a positive way, but it seems like they\'re really more
inconsistent.

DR. MENDEL: Yes. We actually don\'t believe that the proper way to look
at it is by dose. Really, the question is whether in sibutramine treated
patients who lose weight, do we get the expected lipid effects? In order
to answer that question, we have much greater power if we pull the data
across doses. We believe that\'s the appropriate way to look at these
data.

CHAIRMAN BONE: Are there other questions from members of the Committee?

I think Dr. Marcus?

DR. MARCUS: Yes, I would like first to get some clarification on Dr.
Zawadzki\'s question with particular respect to study 1049. After the
very low calorie diet phase, what was the diet that the patients was on
for the duration of the drug treatment phase? It\'s never stated in any
of the documents so far.

DR. MENDEL: You\'re right.

Dr. Kelly, can you answer that question please?

DR. KELLY: Finian Kelly from Knoll Pharmaceuticals in Nottingham of the
United Kingdom.

After the very low calorie diets, these patients continued to attend
specialist obesity centers on a monthly basis as the study was carried
out. They had a low calorie diet prescribed and the low calorie diet
tended to be in the region of 1,500 catacalories per day.

DR. MARCUS: Thank you.

Can you tell me anything about ethnicity or racial characteristics of
the subjects of these various studies? Have you done any analysis to see
whether there is a differential response according to racial group?

DR. MENDEL: Yes. Again, the vast majority, about 80 percent, were
Caucasian throughout these studies. We have approximately 150
African-Americans in the database. When we look at their weight loss
separately, it\'s very similar to the weight loss in the group as a
whole. In terms of orientals and other ethnicities, we really have too
few patients in the database.

DR. MARCUS: I am particularly concerned about the last observation
carried forward strategy in your pivotal study number 1047 because it
suggested \-- it stated here that 49 percent of the placebo group and 55
percent of the sibutramine groups are those who completed the study.
That means you essentially had as many people drop out as complete the
study. Although you say it\'s typical completion rate for a year long
study in obesity, nonetheless, it can be highly confounded if they
dropped out at some point after a weight loss \-- for whatever reason
they dropped out, if you\'re carrying the observation forward to the end
of the year. On one hand, it could be a conservative guess that they
wouldn\'t be losing more. On the other hand, they could have been
regaining. You give us no opportunity in the data that you\'ve submitted
to understand what really went on. I wonder if you can clarify some of
that?

DR. MENDEL: We have three different types of analyses. All yield very
similar curves. Basically, a true intent to treat where patients are
followed for the duration of the time after they drop out really wasn\'t
feasible in these studies. So, the three different ways of looking at
the data are a completer\'s analysis, the last observation carried
forward analysis, and an observed analysis. All three analyses on the
curves for all the studies looked very, very similar. In general, the
completers analysis looks best.

CHAIRMAN BONE: Well, let\'s see \-- did you have any further questions?

DR. MARCUS: Well, I\'m just trying to process the answer to that
question.

DR. MENDEL: Would you like to see some of the other curves?

DR. MARCUS: Yes, I think so.

DR. MENDEL: Okay.

CHAIRMAN BONE: I think the other correlated question \--

DR. MENDEL: With the chairman\'s discretion here.

CHAIRMAN BONE: Well, the other correlated question would be whether, in
any of your studies, you in fact had a true intent to treat analysis by
rounding up the dropouts at the end of the planned observation period?

DR. MENDEL: No, we didn\'t. That\'s very hard to do in these studies.

CHAIRMAN BONE: Yes. Could we make an arrangement to have those \--

DR. MENDEL: Surely.

CHAIRMAN BONE: \-- slides shown in the beginning of the afternoon
session? Would that be all right?

DR. MARCUS: Yes. I have one final question that just addresses what
would seem to be a rational strategy for the use of this drug, but your
analysis doesn\'t show what would happen if you modeled it that way.
That is, a physician prescribes up to your maximum dose, 20 milligrams.
And at the end of a period of time on that drug, the patient has not
lost weight, then you would think that the physician would then stop the
drug. For those that did meet that, then you would have anticipation
that the amount of weight loss would even exceed what your mean weight
loss that you\'ve shown in your curves would indicate.

Now, your non-pivotal studies actually give some hint as to how many
patients would actually have lost 20 or more percent. It looks pretty
good, but I\'d like to know whether you can give us some similar
information about the much larger pivotal studies to see whether that
degree of weight loss in so-called responders is actually what you
observed.

DR. MENDEL: I\'m not aware of specific analyses that have been done on
that question.

Do the statisticians have \-- Bob?

MR. McENTEGART: Damian McEntegart, Hattert Statistics from Nottingham in
the United Kingdom.

Could I have statistic slide number two, please?

CHAIRMAN BONE: While that slide is being put up, I think for the rest of
the time here, perhaps what we\'ll do for things that require more
extended discussion or information that wasn\'t actually presented in
the talks is we can perhaps set aside a little time immediately after
lunch to review those points. We\'ll deal directly with the content of
the talks for now just to make sure we keep following here. That way,
all those can be put together by the company and be ready.

Well, it\'s up now, let\'s go ahead. I think that\'s fine.

MR. McENTEGART: Okay.

When we planned the analysis for study SB 1047, we were very aware of
the kind of issues that have just been raised. Our primary analysis was
what determined outcome analysis. We called it this because it\'s based
on the patients\' response outcome in the trial. This outcome analysis
was identified as our principle measure of efficacy in the study
protocol. It was based on an article by Larry Gould in the 1980
Biometrics paper.

In the analysis, patients are ordered according to their outcome in the
trial. The best outcome is considered to be withdrawal due to treatment
of success whereby either the patients or doctor does not consider it
beneficial for the patient to receive any more weight. Patients who
complete the trial are then ordered below this best outcome of treatment
success withdrawal according to their actual month 12 weight loss or
gain. So, the highest weight loser has the second best outcome. The next
highest weight loser has the third best outcome and so on, until the
outcome of highest weight gain is reached.

Patients who withdraw from the trial for reasons other than treatment
success are then assigned outcomes below that of the patient with the
highest weight gain. Definite treatment related withdrawals due to
adverse events and/or lack of efficacy are assigned to the worst
outcome. Other withdrawals are assigned the next worst outcome on the
grounds that they may be related to treatment. In these set of ordered
actions that we\'ve compiled is then compared between treatments using
the Kruskal Wallis test overall and Wilcoxon rank sum tests for pairwise
comparisons.

So, in effect, what this outcome analysis is doing is just giving us a
different way of handling the dropouts than last observation carried
forward. We didn\'t present this in our presentation for consistency
with the other studies. The FDA statistical reviewer herself quotes a
view that no single analysis can be taken as a valid comparison of
efficacy. Rather, what we\'re looking for is consistency of results
across approaches that use different ways of handling withdrawals.
Indeed, the results for 1047, which I can show if you\'d like to see, do
have this consistency for sibutramine.

If I could have statistic slides number three and four, please?

So these, then, are the ordered outcomes in the trials defined as I\'ve
just described. At the top, we have the one or two withdrawals due to
treatment success. And the next best outcome is the patients who lose
more than 20 percent weight loss. We can see there is a supremacy for
sibutramine in that category and so on through the completers of the
trial, down to the patients at the bottom who withdrew due to lack of
efficacy and/or adverse events. They are assigned the worst outcome in
the analysis.

If I could have the next slide, please?

Comparing the treatment groups overall by Kruskal Wallis test, the
pairwise comparisons by Wilcoxon and Rank sum tests, we can see that
indeed, overall, there is a significant difference between the treatment
groups and in the pairwise comparisons. Sibutramine 10 milligram and
sibutramine 15 milligrams are very superior to placebo.

CHAIRMAN BONE: Thank you.

Let\'s see, I think Dr. Illingsworth had a question.

DR. ILLINGSWORTH: In your study SB 1049 \--

CHAIRMAN BONE: Excuse me, Roger.

Dr. Zawadzki, did your question pertain to this exactly? No? All right,
we\'ll come back to you. You started so we\'ll give everyone else their
first chance.

DR. ILLINGSWORTH: In your study SB 1049, the slides indicate there was a
three month follow-up. What happened to the patients in whom the drug
was stopped? Did they regain weight? If so, do you have data on this?

DR. MENDEL: Yes. Can I have backup slide 22, please?

Essentially, what this slide will show is that when drug is stopped,
patients do regain weight. We interpret that to mean that the drug is
continuing to be effective out to at least one year. This slide only
shows the weight regain out to one month. It continues up with the
weight regain out to three months. You can see the placebo subjects also
regain weight, but the sibutramine subjects regain more weight.

CHAIRMAN BONE: Thank you.

Did you have another question, Dr. Illingsworth? No.

I think Dr. Colley had a question, did you? No?

Dr. Flack had a question. We\'ll come back to him. Dr. Zawadzki \-- if
no one else \-- actually, the Chair had one or two questions and hasn\'t
had a chance yet. So, I\'ll take a turn.

Would you discuss what occurred during your run-in periods? Exactly what
was done during the run-in periods and what were the criteria for the
patients going into the randomized study?

DR. MENDEL: The run-in periods were very short, usually only about two
weeks. What was done during the run-in periods was simply initiation of
the ancillary therapy. In some cases, that was diet only. In other
cases, it was diet, exercise, and behavioral modification.

CHAIRMAN BONE: And were there criteria for the patients to be entered
into the randomized phase at all?

DR. MENDEL: No, there were no criteria based on what they did during the
run-in period.

CHAIRMAN BONE: And how many people entered the run-in period but didn\'t
go into randomization, typically?

DR. MENDEL: In some cases, actually, the randomization occurred before
the run-in period. So, typically, most patients entering the run-in
period entered the randomization. Even in the VLCD study where patients
had to lose six kilograms to enter the protocol, more than 90 percent of
the patients did, in fact, lose six kilograms. Of those, a total of
about 80 percent were randomized.

CHAIRMAN BONE: Thank you.

Dr. Zawadzki and then Dr. Flack.

DR. ZAWADZKI: Were there any quality of life measures done in any of
these studies?

DR. MENDEL: No, there were not.

CHAIRMAN BONE: Dr. Flack?

DR. FLACK: It would seem that the drug would be an ideal drug to use in
diabetics, yet the weight loss threshold didn\'t really exceed five
percent for the treated group over the placebo group in the one diabetic
study.

My question is, one, do you have an explanation for that? Two, are there
any studies ongoing, or perhaps additional data you have, demonstrating
better efficacy in diabetics?

DR. MENDEL: I think in terms of the diabetic population, it\'s well
recognized that diabetics are quite resistant to losing weight. So, both
the placebo group in the diabetic study and the sibutramine group did
not do as well as groups in other studies.

In terms of whether or not \-- and so, it is possible that in diabetics
as a whole, they will respond more poorly in terms of weight loss than
the population as a whole. However, the key to using this drug will be
to use it and continue using it only in those patients who are
responding to the drug. Even if there are fewer diabetics who respond
well to the drug, those that do respond should have a good outcome on
sibutramine.

CHAIRMAN BONE: Dr. Sherwin had a comment.

DR. SHERWIN: Yes, I would differ with you in terms of benefit to people
with diabetes. Since this drug seems to work through increasing
sympathetic outflow, that produces insulin \-- impairs beta self
function. So, one would not anticipate that a drug that would increase
sympathetic outflow would benefit people \-- there would be confounding
factors both ways.

DR. FLACK: I think that\'s the issue on a number of disease conditions
and I was speaking simply from the narrow focus of weight. Because there
are a number of conditions \--

DR. SHERWIN: Well, you said ideal, and that\'s the reason \--

DR. FLACK: Well, they\'re ideal in the sense that many of the diabetics
are overweight. But your point is well taken and I appreciate that.

DR. MENDEL: We actually don\'t believe that the pre-clinical
pharmacology indicates that there should be any adverse effects on
diabetes control.

I\'d like Dr. David Heal to comment on that.

DR. HEAL: Once again, I\'m going to have to ask for two slides for this.
So, if you would like this to be deferred to this afternoon\'s session,
I will present it then. But if you want the issue dealt with now \--

CHAIRMAN BONE: Well, why don\'t we do this? Let\'s go on to the next
question while you\'re getting those slides ready, if there is a next
question.

Any other questions or comments from members of the Committee?

DR. HEAL: I\'m not by training, someone that is skilled in the art of
diabetes and its management. However, I present this information to you.
It\'s in very preliminary form and it has been experiments which have
been conducted by Dr. Cliff Bailey who is very eminent in this field.

What it shows is the effect of 24 hour incubations of L-6 cells with
sibutramine and metabolite 2 which is the primary amine on the uptake of
2-deoxyglucose. The study used 2-deoxyglucose as a measure of glucose
uptake by L-6 rat muscle cells. The cells were exposed to increasing
concentrations of either sibutramine or metabolite 1.

In the absence of added insulin, you can see that there is a clear
increase in the uptake of glucose by these cells. The L-6 muscle cells
are also sensitive to insulin, and as a submaximal stimulation 10^-8^
molar, we can see that this increases glucose uptake by about 50
percent. This effect is actually significantly increased by sibutramine
at 10^-8^ molar and metabolite 2 at all doses. These concentrations are
very similar to the concentrations which are circulating in plasma at
steady state. Thus they argue that sibutramine and the metabolite 2 have
a direct action to improve insulin sensitivity in cultured muscle cells.

This slide shows the effects of sibutramine on body weight, food intake
and plasma glucose concentration in the ob/ob mouse. This slide shows
you effects of sibutramine 10 milligrams per kilogram on these three
parameters when given daily for a period of 28 days. The ob/ob diabetic
mouse produces a model of severe insulin resistance and
hyperinsulinemia. During the treatment period, this dose of sibutramine
did not significantly affect either food intake or body weight. However,
it significantly decreased plasma glucose concentrations as you can see
here, without significantly altering plasma insulin levels. This study
provides evidence to show that sibutramine also improves insulin
sensitivity in vivo.

DR. SHERWIN: That\'s very interesting. I\'m surprised. Do you have \--
well, I guess we can discuss it later in terms of the clinical.

As far as the isolated muscle cells, I would think that since this drug
is working on the nervous system, an isolated muscle cell wouldn\'t be
terribly relevant or may not be the best approach. But the animal study
is interesting and surely is unexpected for me from my perspective
anyhow.

DR. MENDEL: Right, we also have \-- I\'m sorry.

DR. HEAL: It seems that this may be actually a direct structure effect
of sibutramine as a molecule because those muscle cell cultures
wouldn\'t be expected to contain catecholamines.

DR. SHERWIN: Right.

DR. MENDEL: We also have looked at the data in the diabetes study and we
have a presentation prepared that show that trends actually favor
increasing insulin sensitivity rather than decreasing it. I don\'t know
whether you\'d like to present that now or later?

CHAIRMAN BONE: Certainly not. Let\'s talk about that later. Otherwise,
we\'re going to compromise the rest of your presentation. That was a
point that Dr. Spigelman asked me to avoid.

Are there further questions?

Dr. Critchlow?

DR. CRITCHLOW: Yes, just one, a clarification on the titration. I just
want to be sure I understand this. You would propose that people be
started on the five milligram dose. If they don\'t lose sufficient
weight, they would increase to ten? Otherwise they stay on five or what?

DR. SPIGELMAN: The starting dose of the vast majority of the patients
\-- and we can get into this in a discussion or now, as Dr. Bone prefers
\-- would be ten milligrams with five reserved for special populations.
Then the schema would be as I described it earlier. For those patients
who do not lose the four pounds over four weeks but who do have very
good tolerability of the drug, the dose would be escalated. But those
patients who do lose four pounds in four weeks, they would continue with
good tolerability on that same dose.

CHAIRMAN BONE: I think that\'s a little bit contrary to the suggestion
that was made earlier and we\'re going to have to discuss that
extensively this afternoon, I\'m sure.

Further questions or comments before we go on to the next speaker?

DR. MENDEL: I\'d like to then introduce Dr. Timothy Seaton who will
deliver the safety presentation.

DR. SEATON: Good morning, Dr. Bone, Dr. Sobel, members of the Advisory
Panel and guests.

The safety presentation will demonstrate that sibutramine is a safe and
well tolerated drug. The presentation will include a description of the
safety database, the patient exposure, baseline demographics of the
study population, and the adverse events which include the incidence and
discontinuation due to adverse events. We will also discuss the vital
sign changes, the major safety issues seen with sibutramine, and other
safety information related to these changes.

The safety data presented in the discussion are from the database with a
cutoff date of September 30, 1994 for the NDA submitted in August of
1995. The data we have seen subsequent to the cutoff date remain
consistent with the results of this database. All serious adverse
events, however, are current. That is, if we received a report since the
cutoff date, it is included in today\'s discussion. The data from the
Holter Study which will be presented later on in the presentation was
obtained after the cutoff date, but was included in the four month
safety update of the FDA.

Over 2,500 patients received sibutramine in obesity studies. Of these,
almost 2,000 received sibutramine in controlled trials. In the
comparator trial, dexfenfluramine was given to patients in obesity
studies and desipramine or imipramine were given to patients in
depression trials. Overall, in the NDA database, there were over 4,200
exposures to sibutramine.

The largest group of subjects were Caucasian females between the ages of
31 and 50. Most other groups of the population were well represented.
Approximately 500 males, 250 Blacks, and over 700 patients over the age
of 50 years were involved in sibutramine clinical trials. Ten percent of
patients receiving sibutramine discontinued due to an adverse event
compared to eight percent of the placebo patients. Six percent of
patients receiving placebo discontinued due to a lack of efficacy
compared to four percent of patients receiving sibutramine.
Approximately one-third of the patients in both placebo and sibutramine
group discontinued the studies prematurely. These differences were not
statistically significant.

This table presents the adverse events in placebo control obesity trials
which cause discontinuation rates of at least a half-a-percent. These
events include hypertension, insomnia, depression and dizziness. The
incidences of discontinuation for each of the events was not
statistically significant between sibutramine and placebo.

There were three deaths in the clinical program. Two were suicides in
depression studies. The third was a patient with a history of coronary
heart disease and angioplasty who died of a myocardial infarction 15
days after receiving his last dose of sibutramine. The EKG at the last
on treatment visit was unchanged from baseline. None of these deaths
were attributed to sibutramine therapy.

This slide summarizes the incidences of adverse events occurring with a
frequency of greater or equal to one percent in sibutramine treated
patients. The majority of these adverse events, such as dry mouth,
anorexia, constipation and insomnia were predictable based on the
pharmacologic action of the drug. These events were typically mild to
moderate in severity and self-limiting. The incidence of adverse events
by demographic subgroups was not affected by gender or race. There was
no evidence of primary pulmonary hypertension, neurotoxicity, or abuse
potential.

I will now direct discussion to vital signs. The topics that will be
discussed include the mean change in blood pressure, analysis of
outliers, the frequency of discontinuation and dose reductions due to
elevated blood pressure, ambulatory blood pressure monitoring, changes
in pulse rate, and the incidence of clinical events potentially related
to blood pressure and pulse rate.

Consistent with the sibutramine mode of action, there were observed
increases in mean systolic and diastolic pressure in the range of two to
three millimeters of mercury and three to five beats per minute in pulse
rate across the dose range studied.

This slide shows a meta-analysis of placebo subtracted mean change from
baseline to the last on treatment measurement in blood pressure in all
placebo controlled obesity studies. With sibutramine therapy, the
systolic blood pressure increased from .7 millimeters of mercury in the
one milligram dosage range to 4.1 millimeters of mercury in the 30
milligram treatment group. In sibutramine treated patients who lost five
percent of their initial body weight, the systolic blood pressure ranged
from a decrease of 2.9 millimeters of mercury to 2.8 millimeters of
mercury in the 30 milligram dosage group.

The changes seen in diastolic pressure are of similar magnitude as those
seen as systolic blood pressure. The diastolic blood pressure change
ranged from a decrease of .2 millimeters of mercury in the one milligram
dosage group to a 2.5 increase in the 20 milligram dosage group. In
sibutramine treated patients who lost at least five percent of initial
body weight, the diastolic blood pressure ranged from reduction of 1.6
millimeters of mercury for the one milligram group to 2.6 millimeters of
mercury for the 30 milligram group.

It is important to point out that only patients who achieved weight loss
will be treated with sibutramine. In the group of patients who lost five
percent of their body weight, the change in blood pressure ranged from a
decrease of 1.2 for the five milligram dosage group to an increase of
2.3 for the 20 milligram dosage group.

This slide shows the effect of sibutramine in a 12 week placebo
controlled study in hypertensive patients. Both placebo and sibutramine
groups had mean decreases in systolic and diastolic pressure. While
there was no statistical difference between treatment groups, the
decrease is numerically lower in the placebo group.

This slide shows an analysis of the data from the 239 additional
hypertensive patients treated in other placebo controlled obesity
studies. Hypertension for this analysis is defined in the footnote at
the bottom of the slide. The systolic blood pressure in the placebo
group decreased 7.6 millimeters of mercury compared to a decrease of 4.5
millimeters of mercury for the ten milligram group, and a decrease of
4.7 for the 15 milligram dosage group. The diastolic blood pressure
decreased 2.6 millimeters of mercury in the placebo group compared to a
decrease of 1.4 in the ten milligram group, and an increase of .1
millimeters of mercury in the 15 milligram dosage group.

This slide illustrates the percent of patients who had increases,
decreases, or no change in diastolic blood pressure from baseline to the
last on treatment visit in the placebo controlled obesity studies.
Thirty-seven percent of the placebo group had increases in diastolic
blood pressure at the end of the study, compared to 46 for the combined
sibutramine group. For the ten milligram dosage group, 39 percent of the
patients had a decrease in diastolic blood pressure and 20 percent had
no change. Over the whole dose range study, more than half the
sibutramine treated patients had a decrease or no change in diastolic
blood pressure at the end of the study. A similar pattern was seen for
systolic blood pressure changes.

This slide illustrates an outlier analysis done in two pivotal trials.
For this analysis, an outlier was defined as any reading of systolic
blood pressure greater than or equal to 140 millimeters of mercury or a
diastolic blood pressure reading greater than or equal to 90 millimeters
of mercury at any visit.

In BPI 852, the six month US dose ranging study in which hypertensive
patients were excluded, we can see that in the five milligram dosage
group, there were 3.4 percent more outliers than in the placebo group.
In the 20 milligram dosage group, there were 13.3 more outliers than in
the placebo group. A similar pattern is observed in the UK one year
efficacy study. In the ten milligram group, there were 5.2 percent more
outliers than in the placebo group and in the 15 milligram dosage group,
there were 3.3 percent more outliers than in the placebo.

This slide illustrates another outlier analysis. For this analysis, an
outlier is defined as any increase of 15 millimeters of mercury above
baseline for two consecutive visits. The frequency of outliers increased
slightly with increasing dosage of sibutramine for both systolic and
diastolic blood pressures. This increase in frequency in outliers is
consistent with the small mean change seen in diastolic and systolic
pressure.

This slide will illustrate that when blood pressure is assessed by
individual treating physicians, clinically meaningful increases in blood
pressure are rare. In the whole placebo controlled database, there are
only 17 discontinuations on \-- for elevated blood pressure. In study
BPI 852, the large US dose ranging study, dose reduction or
discontinuation was mandated if the systolic blood pressure was greater
than or equal to 160 millimeters of mercury, or the diastolic blood
pressure was greater than or equal to 95 millimeters of mercury at a
single visit.

In that study, 1.4 percent of the patients were discontinued because of
these criteria, compared to .7 percent in the placebo group. The
frequency of dose reductions was the same in sibutramine and in placebo.
Approximately half the dose reductions and discontinuations were in
patients taking 30 milligrams of sibutramine, a dose which is now not
being recommended. If the 30 milligram dosage group is eliminated from
the 852 analysis, the frequency of discontinuations would be .8 percent
with sibutramine compared to .7 percent as seen with placebo.

If we now look at placebo controlled studies for discontinuation of
blood pressure were at the discretion of the investigator, we see there
is only .5 percent discontinuations in the sibutramine treatment group
compared to two percent of discontinuations in the placebo treatment
group. Overall, this indicates a discontinuation for hypertension even
when mandated by protocol were infrequent with sibutramine treatment.

It is also important to be able to identify patients who have an
elevation of blood pressure early in treatment. This slide illustrates
the time to the first reported occurrence in patients who had an
increase of ten millimeters of mercury at two consecutive visits in BPI
852. Most of these increases in either systolic or diastolic pressure
occurred within the first four weeks of treatment. Therefore, patients
with potentially significant elevations in blood pressure can be
identified early and discontinued from treatment if so indicated.

Ambulatory blood pressure monitoring was carried out in two pilot
studies. In BPI 822, a crossover study done in six normal volunteers,
given 20 milligrams of sibutramine over a one week treatment period,
there was no statistically significant difference found between systolic
or diastolic blood pressure between the sibutramine and placebo groups.
BPI 855 was a small pilot study designed to evaluate blood pressure in
hypertensive patients.

As BPI 855 was extensively discussed in the FDA medical review, I would
like to comment on the technical problems encountered in this study.
Information that was unknown to the FDA medical reviewer is that the
instrument used to measure ambulatory blood pressure, the Takeda TM
2420, is now rated unacceptable by both the Association for the
Advancement of Medical Instrumentation and the British Hypertension
Society because the ambulatory measurements do not correlate with
simultaneous blood pressure measurements obtained with a mercury
sphygmomanometer. Our conclusion to the study is that there were no
unexpected effects of sibutramine on blood pressure in hypertensive
patients and that the diurnal variability was maintained.

To summarize the effect of sibutramine on blood pressure, the mean
change from baseline ranged from two to three millimeters of mercury
across the dose range studied. In patients who lost greater than five
percent of the weight, the group of patients who received sibutramine
for long-term treatment, the increase were in the order of one to two
millimeters of mercury. Patients with hypertension had reductions in
their blood pressure, however these reductions were not as a great as
those seen in the placebo group. The frequency of outliers was slightly
higher in sibutramine treated patients which is expected from the small
increase seen in mean blood pressure. The incidence of discontinuations
was less than one percent for all sibutramine treated patients. Over
half the discontinuation of blood pressure were in the 30 milligram
dosage group, a dose which is now not recommended. Clinically
significant changes in blood pressure were rare and seen early in
treatment.

I would now like to turn our attention to the pulse rate changes seen
with sibutramine therapy. This slide is a meta-analysis of the placebo
subtracted change from baseline in pulse rate for all placebo controlled
studies. In all patients, the increase in pulse rate ranged from .7
beats per minute for the one milligram dosage group to 5.5 beats per
minute for the 30 milligram dosage group. In patients who lost at least
five percent or more of their body weight, the pulse rate ranged from a
decrease .1 beats per minute to an increase of 6.3 beats per minute for
the 30 milligram dosage group.

To better understand the observed heart rate changes, a Holter study in
21 obese patients was conducted in which all subjects had a baseline 24
hour Holter recording. Each subject received sequentially at two week
intervals, the sibutramine in escalating doses of five, ten, 15, 20 and
30 milligrams. At the end of each two week period before the subject
received the next successively higher dose, a 24 hour Holter was
repeated. The results of this study show that there was a dose related
increase in heart rate. The peak heart rate occurred approximately
between four and six hours following doses of sibutramine which
parallels the peak concentrations of metabolites 1 and 2. Importantly,
the normal circadian pattern is maintained.

The following table shows the mean change from baseline in daily mean
heart rate from the Holter study. The mean heart rate change from
baseline in the five milligram group was .4 beats per minute and rose to
4. beats per minute for the 20 milligram dosage group. These data are
consistent with the pulse rate data seen in the clinical trials.

In summary, the circadian pattern of heart rate was maintained. In
addition, no clinically significant changes in PR, QRS, or QTC intervals
were seen in this study. No proarrhythmic potential was identified.

I would now like to present data on clinical events which may be
associated with vital sign changes. The following table illustrates the
incidence of cerebral vascular events including patients in ongoing
clinical trials. When we look at the incidence in placebo controlled
studies, we see that the placebo group had an increase of .11 percent
\-- an incidence of .11 percent compared to an incidence of .10 percent
in the sibutramine group. The incidence in this table is lower than
shown in the briefing document as one patient originally listed as a
possible cerebral vascular accident has now been definitely diagnosed as
having spondylitic myelopathy. Overall, the incidence of cerebral
vascular events is .11 percent in over 5,600 exposures to sibutramine.

The following table illustrates the incidence of chest pain, substernal
chest pain, and angina pectoris reported in all placebo controlled
studies. The incidence of these three events in the sibutramine group
was comparable to the incidence in the placebo group. The following
table illustrates the incidence of arrhythmia seen in placebo controlled
trials. The incidence of these rhythm disturbances range from .2 percent
for those classified as arrhythmia to .4 percent for those classified as
ventricular extrasystoles. These incidences were similar to those found
in placebo group. There have been two reported cases of super
ventricular tachycardia to date, one in a placebo patient and one in a
sibutramine treated patient.

In conclusion, there have been over 4,000 exposures to sibutramine in
the NDA database which is equivalent to over 1,300 patient years. The
vital sign changes and the most common adverse events reported were not
unexpected being consistent with sibutramine\'s mode of action. The mean
blood pressure increases two to three millimeters of mercury, and pulse
rate increases three to five beats per minute across the dose range
studied. The number of patients with clinically significant elevations
in blood pressure are small and can be identified early in treatment. No
proarrhythmic potential has been identified. There\'s no difference in
the incidence of cerebral vascular accidents or overall cardiovascular
events between sibutramine and placebo groups. Overall, these data show
that sibutramine is a safe and well tolerated medication.

Thank you.

CHAIRMAN BONE: There may be one or two questions from members of the
Committee.

Dr. Flack first, then Dr. Kreisberg.

DR. FLACK: I\'d like for you to clarify something for me about the
ambulatory blood pressure monitoring. There is a fall at night, looking
at these graphs, with sibutramine. Throughout much of the night, at
least with this ambulatory data supplied here in the graph, the pressure
is higher. Is that a fair interpretation based on your looking at this
graph? Because I\'m having trouble reconciling that there\'s no affect
on the nocturnal dip looking at this weak \-- systolic blood pressure
change here.

DR. SEATON: Well, we have data \-- the 855 study was a very early study.
It was the pilot study done in hypertensive patients. There were ten
patients studied. When we did the study, the reports that were in the
literature said the equipment was very good. Subsequent to that, we
found the equipment was not very good. So, the conclusions we can draw
from that is that there is a diurnal pattern.

I think there\'s another way we could also look at the diurnal pattern.
If you look at the pulse rate changes which, again, also reflect a
potentially similar mechanism diurnal pattern, it is maintained in the
Holter monitor study.

Perhaps Dr. Singh would be willing to comment on another way of looking
at this data in the spectral analysis which again suggests that there\'s
no reason to think why the diurnal pattern would not be maintained with
sibutramine therapy.

DR. FLACK: Is it also true that the dosing for the blood pressure
medications in these studies where hypertensive patients were on
medication really wasn\'t standardized across patients?

DR. SEATON: In the hypertensive studies?

DR. FLACK: Yes, where the patients were asked to take their medicine
within a narrow time range during the day for comparability.

DR. SEATON: That\'s true. There were a number of different medications
they could be taking and there were no standards. They were not supposed
to change their medication but, again, it was not standardized.

CHAIRMAN BONE: Excuse me. Exactly what was the problem with this
equipment?

DR. SEATON: The problem with the equipment is that when you look at
sphygmomanometer readings comparing them to the readings obtained with
the instrument, they do not correlate.

CHAIRMAN BONE: Well, is there a systematic error or what kind of
discrepancies were observed?

DR. SEATON: Well, maybe I could have Dr. Weber comment on that, please?

DR. WEBER: Mr. Chairman, just for the record before I comment on that
question, I should declare that I am a current active member of the
Cardiovascular and Renal Drugs Advisory Committee of the FDA. But I\'m
not here in any sense in that capacity but simply as an expert in
hypertension and ambulatory blood pressure monitoring.

The problem with the Takeda instrument is that it was, according to the
tests done by the British Hypertension Society, inconsistently
inaccurate. They had difficulty studying it because the frequency of
mechanical breakdown during tests lead to the fact that most readings,
in fact, could not be obtained. They gave it a classification of \"D\",
which meant that it could not even meet minimum standards that would
allow it to be compared with other equipment.

I must say, having said that, that the design of the studies and the way
in which the studies were done created so many problems that even if the
equipment was good, they would be almost impossible to interpret. I
guess we\'ll discuss that a little later. But one answer to Dr. Flack\'s
questions on it was that the baseline was done institutionalized and the
treatment effect was done ambulatory. That, alone, could explain the
very marked discrepancy.

CHAIRMAN BONE: Well, excuse me, just to pursue this question for a
minute. If I understand correctly, you said that the major reason for
deciding that this equipment wasn\'t useful was that the instruments
that were tested by the British Hypertension Society \-- is that right?
\-- broke down frequently during the testing? Is that correct that it
was the major problem?

DR. WEBER: That they identified as the biggest single concern.

CHAIRMAN BONE: Was there a problem with the equipment breaking down
during the study that was conducted with this drug?

DR. SEATON: No, but at least five percent of the readings were
considered abnormal. In other words, there were readings that would go
from 140, 150 to shoot up to 200 on one reading and then drop back down
to normal. This is a very large percentage of unacceptable readings.

CHAIRMAN BONE: Did this introduce a systematic bias or just more
uncertainty in the measurements?

DR. WEBER: According to them, the comparison with the mercury
sphygmomanometer was inconsistent in both directions.

I am not a huge fan of those sorts of validation studies because the
sphygmomanometer itself in the hands of many observers is not exactly a
gold standard either. My feeling is that the problem with the ambulatory
monitoring studies, you don\'t need to invoke problems with the
equipment to see the problems with the studies. I agree with what Dr.
Seaton has said that it\'s very poor quality equipment and certainly
would no longer be used, but I think there are other easily identified
problems with the ambulatory studies.

DR. SHERWIN: And what are they because I\'d like to get that straight?

DR. WEBER: Well, I think the first very dramatic problem is that there
was no basis of comparability between the baseline observations and the
treatment observations. The baselines were done in an institution with
patients essentially at risk. The treatment readings were done with
patients ambulatory.

The second problem is that \--

DR. SHERWIN: But aren\'t there two different groups? I mean, are you
comparing one group to another group so that they were both, you know,
treated the same way even though they were different baseline and
experimental?

DR. WEBER: Yes, indeed that\'s correct.

If you\'ll allow me, Mr. Chairman, there is a slide with a very long
number called 5440. If that could be called up, that actually shows the
actual data that we\'re talking about.

CHAIRMAN BONE: Well, let\'s get that because I think there\'s a lot of
interest in this question. It seems like a technical question, but it
sounds like it\'s an issue about whether a lot of data should be
included or excluded from our analysis. I\'m not convinced yet about it.

DR. WEBER: Okay, these are the data in the placebo group. You can see
that the baseline is shown in blue and the eight week ambulatory values
are shown in yellow. These are the systolic data and they seem
moderately similar to each other. You could argue that during the day,
the patients when they\'re ambulatory do have a somewhat higher blood
pressure. At night, maybe they have a fractionally lower blood pressure.
But you\'re guessing and remember the n is only ten here.

DR. SHERWIN: And this is the different between \-- blue is hospital and
yellow is outside the hospital?

DR. WEBER: That\'s correct, yes.

DR. SHERWIN: Okay.

DR. WEBER: Okay, so you can see when your ambulatory pressure is a
little by day and maybe a little lower by night for what\'s that worth.
But it\'s all over the place. That\'s systolic.

If you look at the diastolic which is the next slide \-- oh, oh \--

CHAIRMAN BONE: Maybe we\'re going the wrong direction.

DR. WEBER: Well, make it 5441.

These are the diastolic data. Now, these are actually different. What\'s
a little scary to me is if you look at between hours 2:00 and 4:00,
there is a huge plunge in blood pressure for reasons that I have no
explanation for. You can see about 93 to the mid-70s, a fall of about 20
points which I suspect may have been one or two aberrant patients.
Remember, these are people on placebo. Then at night, there is a big
fall in blood pressure. You didn\'t see it that much at baseline. You
see it more in the ambulatory patients. But if you just look at the
ambulatory patients and see the tremendous variability, it\'s really
just \-- to work with.

CHAIRMAN BONE: What happened in the treated patients?

DR. SHERWIN: Yes, let\'s take a look at the treated patients.

CHAIRMAN BONE: Can we see the treated patients\' results, please?

DR. WEBER: Yes, the next slide.

These are the sibutramine patients. These are the systolic values. You
can see that they are somewhat higher at eight weeks than on the
baseline. But it\'s interesting that unlike the placebo people, there
was actually a fall in the systolic pressure in the sibutramine people
when they were in the institution. That\'s something we didn\'t see with
the placebo group.

If we go to the next slide, we have diastolic. You can see, again, there
is a slight increase in blood pressure with sibutramine compared with
its baseline. But again, remember this is ambulatory as opposed to
institutionalized.

Mr. Chairman, I\'d have to say I\'m very reluctant in a sense to start
trying to analyze it and dicker with these data because I just think
that the number of patients in the study, the way in which it was done,
just don\'t allow us to reach any conclusion. If you say that to now go
ahead and start playing games with it, to my mind is not appropriate.
The numbers of patients are too small. There were also gender
differences between the placebo and treatment group. There were just too
many problems.

And I don\'t think the study was ever intended \-- correct me if I\'m
wrong \-- to be used for this purpose. I think it was originally
intended to be \--

DR. SEATON: It was the first time the drug had been given to
hypertensive patients. It was a pilot study. It was really to look to
make sure there would be no major untoward effects in patients with
hypertension.

CHAIRMAN BONE: Well, I\'m sure that we\'re going to come back to
discussion of this issue. I think the technical question that was asked
here about disqualification, in effect, of the study based on the
instrumentation is hard to understand. Because it seems as though from
what we\'ve been told, the instrument problem would have, if anything,
increased the randomness and perhaps created more overlap between groups
rather than less. But I think we\'ll have a further discussion later on
about the implications of this and what weight to give the studies.

Further questions?

I know that Dr. Kreisberg and then Dr. New had questions and I think
others may.

DR. KREISBERG: It seems to me that the patients for participation in
these studies were \-- can everybody hear me all right? \-- largely
selected to be free of physical or comorbid medical problems. And so,
the safety data is a best case scenario. Most of these patients have
comorbid medical problems and they were more-or-less systematically
excluded from the evaluation.

So, the questions I have relate to do you have any information about how
renal insufficiency, co-existent liver disease, or co-existent
cardiovascular disease influence either drug disposal or side effects?
And if you don\'t have any of that in humans, do you have any studies in
animals with renal insufficiency or other problems that would give us an
idea about how the drug might be used in obese patients who would be
candidates but would have comorbid problems?

DR. SEATON: I\'d like Rod Haddock to address that, please?

CHAIRMAN BONE: Did the transcriptionist get the name?

DR. HADDOCK: My name is Dr. Rod Haddock. I\'m head of pharmacokinetics
of Knoll, UK.

Yes, we\'ve carried out a standard pharmacokinetic study in hepatically
impaired subjects.

Could I have slide eight, please?

This slide shows the mean plasma profiles of subjects with moderate
hepatic impairment. That\'s Child Pugh score five to five versus normal
hepatic impairment. On the top in yellow you can see the metabolite 2
concentrations. Those in red are the impaired which are pretty well
superimposable. There\'s a slight delay in the removal of material but
that did not reach statistical significance. In fact, against the
standard statistical text, these two curves were superimposable.

In terms of metabolite 2 \-- metabolite 1 which is the minor metabolite,
as you can see below here. There was a minor difference in Cmax between
the impaired and the non-impaired. Overall, the bioavailability when you
add these two curves together, there\'s an overall deficit in the
hepatic impaired. The bioavailability is up by a factor of about 25
percent. So, in kinetic terms, the drug is handled very similarly by
hepatic impaired people. And there was a minor increase in the overall
bioavailability of these pharmacologically active metabolites.

CHAIRMAN BONE: Were there further studies along the lines, Dr. Kreisberg
asked about, for renal impairment?

DR. HADDOCK: With regard to renal impairment, the active metabolite of
sibutramine are removed from the body by further metabolism. So, we
would not anticipate that renal impairment would have any effect on the
termination of the pharmacological response. However, we have a study in
renal impairment ongoing and a small, again, standard pharmacokinetic
type study in moderate and severe renally impaired subjects.

CHAIRMAN BONE: Was that a satisfactory answer, Dr. Kreisberg? Yes.

Thanks. I think Dr. New has the next question.

DR. NEW: I need some clarification on the presentation that indicated
that there were differences of one and two millimeters blood pressure.
When you saw the great variability that was presented in the ambulatory
\--

DR. SEATON: I\'m sorry, I can\'t hear.

CHAIRMAN BONE: Speak into the microphone.

DR. NEW: Of course, I\'m sorry.

I need clarification on the one millimeter to two millimeter changes
that you\'re reporting in the various groups. Then we\'ve just seen that
the ambulatory changes are extremely variable \-- there being as much as
20 millimeters of difference. So, what I need, I guess, is a standard
error or a standard deviation of those measurements to know how you came
out to one to two millimeter difference.

DR. SEATON: The standard error in those measurements was similar in the
placebo group and in the treatment groups and was a range between 10 and
14 millimeters of mercury. I\'m sorry, the standard deviation \--
that\'s not the standard \-- standard deviation.

CHAIRMAN BONE: Just to pursue this question of the magnitude of the
change in blood pressure, the largest chunk of your experiences in terms
of patient years of exposure is 852 and this extension?

DR. SEATON: Yes.

CHAIRMAN BONE: And I note from the table that was prepared that in that
study \-- I\'m particularly referring to a couple of issues. One is, the
issue of looking at the change in blood pressure across the entire dose
response curve as opposed to at the doses which were efficacious. Of the
doses that you were recommending, those that were efficacious were the
15 and 20 milligram dose according to the five percent criterion.

Sorry?

DR. SPIGELMAN: No, the recommended dose range is five to 20.

CHAIRMAN BONE: I think you said that you would have a starting dose of
ten. If you look at the doses that actually achieved five percent mean
reduction in blood pressure, they were 15 and 20 milligrams.

DR. SPIGELMAN: Depending on the study and the parameters that are used
in the guidelines, then different parameters were met by different
doses. If a categorical analysis is used based on five percent
responders, then five milligrams even met the guidelines in 852. If
other analyses are used, then it sometimes is ten milligrams. Or if
other criteria are used \-- if it\'s five percent placebo subtracted,
then it would be a higher dose.

CHAIRMAN BONE: I understand your point. For the purposes of my question,
it will be the doses at which at least 50 percent of patients met the
five percent reduction or where the mean was five percent. By both of
those criteria, it would be 15 milligrams, I think, overall?

We can discuss what the dose is later but I\'m just referring to the
fact that at 15 and 20 milligrams, the changes in blood pressure in that
very large study were a little greater than you\'ve suggested at 15
milligrams, and substantially greater at 20 milligrams. And when we look
at the extension phase which goes to this point about whether the
changes occur early or late, they\'re actually greater in the subjects
that participated in the extension in the six to ten millimeter of
mercury range at the 18 month time point for the systolic blood pressure
and five to eight percent for the diastolic blood pressure. I note that
the lowest dose in that extension was 15 milligrams, apparently on the
basis of efficacy. Also, at 12 months, a similar experience was noted.

So, I guess the question here is whether using a two millimeter increase
in blood pressure, as the basis for estimating the risk of the pressor
effect is really as solid as it might be?

DR. SPIGELMAN: Well, I think, you know, when we looked at the extension
study, this was an open label study so it\'s very difficult to compare
what blood pressure changes would have been. I think when we look at our
whole placebo controlled database, while you\'ve not seen this
meta-analysis \-- this was recently completed \-- we thought it was the
best way of trying to capture all the data. Particularly when we see in
the hypertensive studies that there was a lowering of blood pressure in
the group, but the lowering was not as great as we saw in the placebo
group.

We thought the best way of presenting the data was really to combine all
this data in a meta-analysis to really look at what the changes were. We
think that\'s the best way of really trying to assess what it is \--
placebo controlled trials and not to use, you know, one extension trial,
particularly since we have not completely re-analyzed the extension
trial. Data is being cleaned up right now. We don\'t have all the
results back from that trial.

CHAIRMAN BONE: All right.

Dr. Sherwin?

DR. SHERWIN: Two questions. First of all, have there been any patients
at all that in long-term use have had primary pulmonary hypertension?

DR. SEATON: No. There\'s been one case with sclera derma who developed
hypertension which was attributed to the sclera derma. But there have
been no cases of primary pulmonary hypertension.

Perhaps Dr. Heal would care to address this issue?

DR. SHERWIN: Is there any potential, let\'s say \--

DR. SEATON: Well, Dr. Heal will, I think, address this issue for you.

DR. HEAL: Could I have the third carousel and slide number five, please?

CHAIRMAN BONE: Is this going to answer Dr. Sherwin\'s question?

DR. HEAL: I hope so.

CHAIRMAN BONE: Okay.

DR. HEAL: As I pointed out in the pre-clinical discussion, we need to
think about the mode of action of sibutramine as well as thinking about
the actions of drugs which are associated with pulmonary hypertension.

Sibutramine is a seratonin and norepinephrine reuptake inhibitor. SNRIs
have been around in various forms for 40 years now. We know that there
are tricyclics which are selected for nordrinolin, selected for 5-HT, or
they\'re mixed uptake inhibitors. Primary pulmonary hypertension has
never been an issue with these drugs.

We know that there are new generations of drugs such as the SSRIs
fluoxetine. As I showed you in my presentation, there\'s nothing unusual
about sibutramine\'s actions on body weight and feeding. These can be
mimicked by giving fluoxetine with a norepinephrine reuptake inhibitor.
There have also been new SNRIs like venlafaxine. In fact, sibutramine\'s
actions can be mimicked by high doses of venlafaxine.

We know of no case reports associated with fluoxetine and PPH despite
the many million exposures to Prozac which have occurred. In addition,
the Case Control study that showed the association between
dexfenfluramine and other weight reducing agents showed no association
between fluoxetine and PPH, even though there was sufficient patients
exposed to assess this.

Now, we are uncertain at present about what the reasoning behind the
induction of pulmonary hypertension is. But if we take a look generally
amongst the drugs which produce this, they appear to fall into two
categories. They are the 5-HT releasing agents, fenfluramine and
dexfenfluramine, and there are patical releasing agents like mazindol,
diethylpropion, clobenzurex, phenmetrazine, and fenpropurex.

As I clearly pointed out in my introduction, sibutramine is not a
releasing agent for catecholamines and it is not a releasing agent for
5-HT. Therefore, it should be thought of in terms of the other SNRIs. I
believe that its potential for pulmonary hypertension will be exactly
the same as drugs of that class.

CHAIRMAN BONE: Thank you.

DR. SHERWIN: That was a good answer.

My second question relates to the fact that blood pressure, as we all
know, can vary enormously if you lift weights or do something like that.
Blood pressures can rise dramatically, exercise has dramatic effects.
Most of the focus, except for the ambulatory blood pressure readings,
are resting type blood pressure.

Have you looked systematically at factors that would promote blood
pressure elevations? I would expect that in a situation where you have
that, you would release norepinephrine and then you couldn\'t get rid of
it very easily. So, my biggest concern about this drug relates to
induced \-- sort of physiologically induced increases in blood pressure
that would occur with activities like lifting packages.

DR. SEATON: That\'s an interesting question. We have some data on
physiological testing. I\'d like Dr. Bramah Singh to address this,
please?

DR. SINGH: There has been one study with treadmill exercise, twenty-four
patients with three groups. One was placebo, one at low dose, five
milligrams of sibutramine, and the other one 20. The patients were given
the drugs for a whole week.

DR. SHERWIN: One week?

DR. SINGH: One week and the baseline pressures were taken and all the
other parameters. Now, an interesting pattern emerged that at the
maximal exercise, there was no difference in terms of the 0~2~
consumption. The only effect that was seen was at the maximal exercise,
the heart rate increase was about seven beats higher than compared to
the placebo. Actually, the diastolic blood pressure actually fell. All
the other parameters, in fact, there were no differences between the
placebo responders and the responders of the five or 20 milligrams of
sibutramine. And the exercise capacity was not altered.

CHAIRMAN BONE: Thank you.

DR. MARCUS: Excuse me. This was treadmill exercise?

DR. SINGH: This was on Bruce protocol, the standard kind of treadmill
that we do in patients with coronary \--

DR. MARCUS: So, you don\'t have information regarding resistance
activity of the sort of lifting or Valsalva, or other things which are
well known to really send the systolic pressure up?

DR. SINGH: No, those were not done. This study was purely on treadmill
exercise.

DR. FLACK: Right. Was this only after one week?

DR. SINGH: After one week.

DR. FLACK: Are you planning to look at them later \-- this group or any
other group at a later point in time after they\'ve been on the drug for
a longer period of time?

DR. SEATON: These are all studies that are being considered for Phase
IV.

CHAIRMAN BONE: But that study is done and you didn\'t do that, right?

DR. SINGH: No, in this particular study, that was the end of it.

CHAIRMAN BONE: Right, thanks.

Dr. Colley?

DR. COLLEY: I\'ve got a question about the blood pressure response and
age. The average age of your subjects was relatively young, although
this drug would presumably be used in older patients especially if we
consider this to be a treatment that would be used chronically.

Did you notice any difference in ages in terms of the incidence of blood
pressure increase?

DR. SEATON: No, there is no effect of age on the blood pressure effects
of sibutramine.

DR. COLLEY: How about in patients who were hypertensive versus normal,
or in treated versus untreated hypertensive?

DR. SEATON: Well, in the one study where we had patients in the
hypertensive trial, one-third of those patients were on
anti-hypertensive medications. The changes were no different between
patients who were on hypertensive medications or off hypertensive
medications. We saw the similar pattern. In general, there was
reductions in both groups but the reductions were not as great with
sibutramine treatment as we saw in the placebo group. They were not
statistically different, but numerically they were higher.

CHAIRMAN BONE: Thank you.

I think Dr. Molitch had a question?

DR. MOLITCH: Yes. I noticed in the earlier presentation that the p450
enzymes were involved in the generation of the active metabolites. I was
wondering if any medications that would induce those enzymes would
result in higher blood levels? And would that then alter the blood
pressure responses, perhaps, of these patients?

DR. SEATON: Yes, I\'d like to have Rod Haddock address this question,
please?

DR. HADDOCK: Could I have slide 11, please?

We\'ve examined the p450 isozymes that are involved in the metabolism of
sibutramine and the major enzyme involved is an enzyme called CYP3A4.
There was a minor contribution from CYP1A2 and CYP2C9. There is no
contribution from CYP2D6 and a known low capacity in enzyme of genetic
\-- which also shows genetic polymorphism.

Because CYP3A4 was the major enzyme involved, we decided to carry out a
study in vivo in LB subjects whereby we would coadminister CYP3A4
competitor substraits erythromycin or ketoconazole. The results are as
indicated on the slide here. There was a negligible effect of
erythromycin on the plasma concentrations of the active metabolite
though there was a trend to slightly higher levels in the erythromycin
treated patients when erythromycin was added to sibutramine treatment at
steady state.

In respect to ketoconazole, which has a potent potential to inhibit
CYP3A, there was a minor effect on the active metabolite concentrations.
But this effect overall was some 23 percent increase in active
metabolite concentrations when ketoconazole was added at normal regimen
and to sibutramine regimen.

CHAIRMAN BONE: All right, thank you.

Are there further questions from the Committee before we go ahead with
the remainder of the company\'s presentation?

Fine. Then I think we\'ll be ready to hear the epidemiology benefit and
risk analysis.

DR. SEATON: Yes. I\'d like to introduce Dr. Sylvia Smoler who will
present an epidemiologic risk/benefit analysis.

DR. SMOLER: To assess the public health risks and benefits of
sibutramine, we used two models, the Nurses Health Study and the
Framingham model. In this presentation, I\'m going to concentrate on the
Framingham model. The reason for doing this is that sibutramine
treatment is associated with a small increase in population mean blood
pressure and a concomitant improvement in lipids in those losing weight.
The Framingham model allows us to examine the interrelationships between
changes in blood pressure and lipids and changes in the risk of coronary
heart disease and cardiovascular disease.

Now, in the absence of large, long-term clinical trials that would have
these endpoints as outcomes, the only way to assess the risk is really
through proportional hazards regressions and logistic regressions based
on models in established populations. That\'s why we\'re using these two
models. The Framingham study is one on which many national policies with
regard to risk factor, control and prevention have been based. So, it\'s
widely used and it\'s a very important database.

In order for it to be useful, however, we have to demonstrate that it is
generalizable. There have been a number of studies that indicate that
Framingham models are generalizable to the population and I\'ll just
mention two of them. The NHANES epidemiological follow-up study, which
was the first national cohort study based on a medical examination of a
probability sample of US adults and included over 14,000 people showed
that the events predicted by Framingham predicted remarkably well for
this NHAMES follow-up study sample.

In the Western Collaborative study group which was a prospective study
of middle-aged men with about eight years\' follow-up \-- the NHANES had
about 10 years\' follow-up. But in the Western Collaborative group,
again, the events \-- the observed coronary heart disease events did not
differ from those predicted from the Framingham equations. So, that\'s
why we\'re using that.

The two events I\'m going to be discussing are coronary heart disease
which consist of angina, unstable angina, MI, and sudden death; and
cardiovascular disease which is CHD plus congestive heart failure,
cerebrovascular disease and intermittent claudication. Now, the
independent variables which are controlled in these models are age,
systolic blood pressure for the cardiovascular disease, cholesterol, LDH
by ECG, diabetes, and so on. In coronary heart disease, there\'s also
the added variable of HDL cholesterol which was not measured early-on in
Framingham.

We\'re going to have a prototype scenario which we\'ve devised for a 40
year old woman who is a non-diabetic, non-smoker, and has no LVH, has a
diastolic blood pressure of 80 millimeters of mercury, a cholesterol of
220, and an HDL of 45. Those are all the variables that are entered into
the CHD model. As you can see, the risk of CHD in eight years per
million for such a woman is 13,450. With an increase of two millimeters
blood pressure, the risk rises to 14,260. This two millimeter increase
is based on the sibutramine trial data.

Now, with a concomitant weight loss of five kilograms which would result
in a decrease of ten milligrams in cholesterol and an increase of two
milligrams in HDL, the risk would drop to 11,982 per million. These data
are from the meta-analysis of the effect of weight loss in the
publication shown here and are also consistent with the sibutramine
trial data. So, subtracting then this from this, we have a net event
diverted in eight years per million of 1,468 or a 10.9 percent reduction
in CHD rates.

I\'m going to walk through this slide because the rest of them follow
the same pattern. Here on the left, is a graph version of what I\'ve
just shown you on the prototype slide. Again, the DBP of 80, cholesterol
is 220, HDL of 45. The rise in risk with an increase of two millimeters
blood pressure and then the drop of risk with that decrease of
cholesterol and an increase in HDL, resulting in the 10.9 reduction in
CHD shown on the previous slide. This is applied to the CVD model which
does not have HDL in it, and which uses systolic blood pressure. And
again, the rise in CVD risk with a two millimeter increase in blood
pressure, a drop, resulting in 617 events averted in eight years per
million, or 4.1 percent reduction in cardiovascular disease.

This shows the same kind of data for a man aged 50. For him we have
assumed he has a diastolic blood pressure of 85, a cholesterol of 230
and an HDL of 40. The scale is different here and there\'s no zero
point. But the absolute number of events averted are greater for the man
because he is at higher risk, 7,179 and that results in an 8.2 percent
reduction in CHD and a 4.4 percent reduction in CVD.

Here, we have looked at the same thing for the 40 year old woman who has
no LVH, but who is a diabetic and is a non-smoker. Again, the rise in
risk and then the drop in risk with the lipid changes resulting in a 9.3
reduction in CHD. Here it is for a smoker who is non-diabetic. Again,
there\'s the rise and the drop with the lipid changes for a 9.9 percent
reduction in CHD. If it\'s a diabetic smoker, the same kind of pattern
applies.

Okay, this shows the trade-offs between an increase in blood pressure
and a beneficial effect on lipids. So, the yellow line here pertains to
a 50 year old, non-smoking, non-diabetic man who has a cholesterol of
230 and an HDL of 40. The percent CHD risk rises with the rising
diastolic blood pressure. The green curve is the similar kind of thing
for the man with cholesterol of 220 and HDL is 42.

The dashed line is the line of equivalent risk. So, you can see that the
risk at 84 millimeters diastolic blood pressure for the man with the
baseline lipids is equivalent to the risk for the man with the better
lipid profile who has a 90 millimeter diastolic blood pressure. Meaning
that this six millimeter rise in diastolic blood pressure is offset by
the benefit on the lipids of the weight reduction. We did the same thing
for a woman and that amounts to five millimeters being offset by the
benefit due to the lipids.

So, in summary, the increase in risk of CHD or CVD with the increase in
blood pressure that results from the sibutramine is more than offset by
the beneficial effect of the weight loss on the lipids alone, with a net
decrease ranging from four to ten percent. Similar effects were found
for men and for women, for diabetics and for smokers. These data are
based on the actual results obtained in the meta-analysis of the
sibutramine trials and they are consistent with the effects of weight
loss as analyzed in the meta-analysis of weight loss.

So, it\'s wonderful when you see everything consistently pointing in the
same direction. The Nurses Health Study model which you have in your
briefing document yields similar results in that there is a nine percent
reduction in mortality. So, in summary, all of the data really are quite
consistent and for an epidemiologist, that\'s always a great pleasure.
Thank you.

CHAIRMAN BONE: Thank you, Dr. Smoller.

I have a question. I know you said this and I think I just missed it.
You said that the estimated lipid benefit that you used for your
calculation would approximately offset a five millimeter increase in
blood pressure for men.

DR. SMOLER: For women.

CHAIRMAN BONE: Yes.

DR. SMOLER: Six for men.

CHAIRMAN BONE: So, five to six millimeters, okay. Five millimeters for
women and six millimeters for men. Okay, thank you.

Questions?

All right, very good. Thank you.

DR. SMOLER: Let me introduce Dr. Michael Lean.

DR. LEAN: Thank you very much. My presentation is going to be from the
perspective of a practicing clinician. My background is as a physician
with specialist training in general medicine, diabetes, and
endocrinology. I have a continuing consultant practice in a busy general
hospital. I also have research training in human nutrition with a
special interest in obesity. I\'m the head of a fairly large,
multi-disciplinary university department of human nutrition in Glasgow.

I\'m heavily involved in developing clinical guidelines for weight
management in the United Kingdom and I\'ve had clinical and research
experience with most of the drugs available and under development at the
moment. I\'ve had some experience with sibutramine in the context of a
double blind, placebo controlled trial in dyslipidemia which has gone on
to a two year open extension which is ongoing. At present, we\'ve
recruited 150 subjects into the study, of whom 115 have proceeded into
the open extension phase. In this trial, it has not been possible to
distinguish those patients who are on placebo from those on active drug
therapy. But my experience in the open phase of that study is that the
drug is extremely well tolerated. Both the patients and the staff are
extremely happy with the way it is progressing.

From the evidence I\'ve seen presented today and from my own experience,
I believe that sibutramine would be a valuable adjunct as part of a
structured, multi-disciplinary program of weight management. The
evidence showing the likelihood of specific benefits for patients with
diabetes or hyperlipidemia is interesting and worthy of further
research. But it is important to recognize that this submission, the aim
of today\'s submission, is to obtain a license for weight management and
not as primary treatment for these conditions.

Now, in my clinical practice, I regularly see patients with important
improvements, clinical improvements associated with weight loss which
can be achieved routinely using our standard approaches. Clinical
observations of that kind have been confirmed in a vast number of
published studies. For example, those in looking at the metabolic
control in Type II diabetic patients. I believe it is very important for
doctors and for patients to be aware of the medical benefits from modest
but sustained weight loss without the need to convert very obese people
into very thin ones.

I conducted a study which was published in 1990 in [Diabetic
Medicine]{.underline} which carried out the survival analysis to look at
the life expectancy in patients who were overweight and had non-insulin
dependent diabetes. These subjects were recruited at the mean age of 64
and this was a total population study. So, it reflects the relative
kinness of Scottish diabetic patients compared with those, perhaps, in
the United States.

At that age, they had a life expectancy without any weight loss of eight
years. What we found was that those who lost weight under advice in the
first year of treatment went on to a longer life expectancy and this was
highly significant. The data had been controlled for pre-existing heart
disease, for age, for sex, and for blood pressure. So, this study
illustrated for me that quite modest weight loss, of the kind achieved
routinely, was of great value for patients at high risk.

The benefits of each kilogram of weight loss were equivalent,
approximately, to three to four months\' survival. By the time these
patients had lost nine or ten kilograms, their survival had increased to
much that of the background population. So, the impaired life expectancy
of non-insulin dependent diabetes was abolished by weight loss of the
order of nine to ten kilograms.

This slide shows data from David Williamson from the Center for Disease
Control published last year, which gives really quite striking similar
benefits from relatively modest weight loss. Firstly, in people who
already had obesity related diseases, those who lost five to nine
kilograms of weight loss had a reduction in all cause mortality of about
20 percent. Those who had no secondary diseases, the analysis was able
to find that for those who lost nine kilograms or more, a staggering 25
percent reduction in mortality combined both from heart disease and from
cancer risks. It is important to recognize that the benefits in both
these groups included reductions in obesity-related cancers. A lot of
our discussions today have focused on risk factors for coronary heart
disease and that\'s only one part of the story.

More recently, we\'ve conducted studies using dietary approaches. This
is just one where a dietary study produced a weight loss of between four
and five kilograms. We looked at patients with angina and those who were
simple overweight and we found in the study a quite significant
reduction in clotting factor VII, another factor which may be associated
with long-term mortality. So, again, another factor in addition to the
lipid improvements which we also found in the same study. It applied
both in patients who already had angina and those with simple obesity.

Now, my patients come to me in clinical practice, really in two sorts.
In the next part of this presentation, I would like to suggest that some
of the risk factor analyses that we\'ve been concentrating on today are
a little bit remote from the problems that my patients present to me. If
you\'ll excuse the familiarity, I\'m going to describe two patients.

The first one here is a hypothetical Mr. Johnstone. He\'s aged 60. He
has developed non-insulin dependent diabetes and is on treatment with
sulfonylurea. He\'s hypolipidemic, on treatment with lovastatin. He\'s
hypertensive on enalapril. He also has arthritis and is on regular
analgesics. He has a body mass index of 36. He\'s unemployed. He\'s
unhappy and he\'s expensive for the health care system. I see Mr.
Johnson as a new patient two or three times every week, and I think
that\'s a familiar experience for many of my colleagues.

On the next slide, Mr. Johnstone\'s daughter, who we\'ll call Ms.
Johnstone is aged 35. Her body mass index has reached 30 and she\'s
coming complaining of tiredness, of back pain, of shortness of breath.
But we note, the worrying family has a history of diabetes, hypertension
and coronary heart disease.

Now, when I see a patient like the first one, Mr. Johnstone, who is
already on life-long therapies for three or four direct consequences of
obesity, I wish I could have done something constructive at a much
earlier stage. There\'s, of course, a lot that I can do for him and I
have a medical responsibility to do it. But I feel that earlier
treatment with an effective agent for patients like Ms. Johnstone here,
who have not yet developed or required treatment for secondary
complications would be more rewarding, or would ultimately be more cost
effective.

The next slide shows the sort of trajectories of weight change which we
see in adults as they grow older. In some ways, it is similar to the
slide which was shown earlier by Dr. Pi-Sunyer which was commented on by
Dr. Marcus. The patients I\'ve described are following the trajectory of
the top 10 percent. We find that in the UK at least, around 20 percent
of our 20 year olds already have a body mass index which is exceeding
25. That is destined to follow this high trajectory and they\'ll run
into symptoms before they run into the more medical, if you like,
complications.

Our aim of therapy should be to reduce the level of trajectory to a
lower one. We remember that less than half of all adults remain within
the range of body mass index which is considered healthy or normal. I
would like to think that if we could treat Ms. Johnstone when she is at
approximately this point, we could reduce her body mass index to that of
a lower point. Whether we can continue it steadily or not I\'m not sure.
I think instinctively that it is likely that we would reduce the body
mass index, and we would see it then climb up along a lower trajectory
as she grows older.

I\'d like to pause for a moment to look in a bit more detail at these
symptoms which, again, to some extent, are neglected except by
clinicians who see obese patients regularly. The list is very long.
They\'re very familiar and often attributed to other diseases rather
than being recognized as direct consequences of obesity itself. They\'re
expensive and cause a lot of unhappiness in our patients who are already
discriminated and don\'t like to complain directly about their symptoms
and relate them to their weight.

Without professional help, the treatment for overweight and obesity are
limited in success, and we heard something about that earlier. Mr.
Johnstone or his daughter have only about a ten percent likelihood of
maintaining a ten percent weight loss and they\'re referred to me after
they\'ve failed. My approach to these patients would always be to
provide the very best dietary and behavioral care I can offer, including
physical activity.

Most of my patients can, in fact, lose five or 10 percent of their
weight under this sort of regimen but the difficulty is in preventing
regain in the long-term and maintaining that weight loss. To combat
that, I would, I believe, be ready to add a therapeutic trial of a drug
such as sibutramine. Hitherto, I\'ve been unenthusiastic about the use
of very low calorie diets on the basis that weight regain is usual and
the long-term results are generally poor. But I have been impressed by
the data we\'ve seen today which suggests that it may be possible to
maintain quite rapid weight loss, which is attractive to patients, by
the use of drug therapy.

I am very attracted by being able to identify non-responders to drug
therapy as an early stage. I think that\'s extremely important partly
from the point of view of efficacy and partly from the point of view of
avoiding unwanted side effects, particularly from the point of view of
blood pressure, are more apparent in those who do not lose a lot of
weight. I was always taught at medical school that whenever I start a
drug therapy of any kind to any patient, this should be regarded as a
therapeutic trial, should be evaluated at follow-up, as there are
non-responders to virtually every drug that we prescribe. The data
we\'ve seen today suggests a very simple and effective way of ensuring
that sibutramine would not be given to non-responders indefinitely.

Now, some of the principles of weight management I\'ve mentioned are
relatively new. In teaching medical students and doctors, I stress the
need to address our own attitudes towards obesity and its management.
They\'re summarized on this slide.

We need to recognize the symptoms of the overweight. We need to treat
the disease process and not wait for an end result which might be a body
mass index over 30. We need to start management at an earlier stage, not
necessarily with drug therapy. We need to treat the underlying cause,
which in this case is overweight, before we treat complications for
waiting for them and there are lots of them. We need to recognize the
medical benefits of five to ten percent of weight loss. I would add to
this slide, the need to focus on prevention, including both primary
prevention and the secondary prevention of regain and the maintenance of
weight loss.

In summary, I feel that the long-term benefit risk ratio is clearly of
benefit and positive for sibutramine in proper clinical use. The
potential side effects are mild and they should be easily managed. I
recognize that they are outweighed by the achieved weight loss and the
concomitant improvement in risk factors such as lipids. There are other
benefits which haven\'t been measured.

Obesity is a serious disease with serious consequences. I am happy to
have available another anti-obesity drug for my patients. I will, of
course, observe all the usual cautions and monitoring required for any
new medication as a part of routine good medical practice. I recognize
the need to keep an eye on the blood pressure, as I would with any other
drug, and that the fall in blood pressure expected with weight loss \--
which I see routinely in weight loss in other settings \-- in blunted in
patients on sibutramine. But I accept that the net benefit of losing
weight outweighs the hazards of a fairly small elevation in blood
pressure. I\'m also greatly reassured by the clinical safety data that
there is no increase in strokes, cerebrovascular accidents on the
sibutramine treated patients.

I\'m personally not very worried about the small increase in heart rate.
It\'s not as great as that which we see when treating patients with
other drugs including such things as salbutimol which we do routinely. I
would never prescribe sibutramine without recommending dietary change
and physical activity which would help to lower the resting heart rate
and blood pressure.

There remains some interesting questions about sibutramine which will be
addressed in Phase IV post-marketing trials.

I will hand over to Dr. Spigelman to take over an outlined description
of those trials. Thank you very much.

CHAIRMAN BONE: Any immediate questions from the Committee at this point?
No? Thank you.

Go ahead, Dr. Spigelman.

DR. SPIGELMAN: Thank you, Dr. Lean.

What I\'d like to now present is the status of our proposal regarding
post-marketing clinical research with sibutramine.

Some months ago, we began to consider what were the most relevant issues
that we felt could be best addressed in the Phase IV post-marketing
setting. The two issues that really became most prominent in our
thinking on this topic were expanding the safety database and
specifically, in this regard, to beginning to look at non-surrogate and
longer term endpoints and also beginning to measure what I\'ll call the
real world effectiveness of the compound. Although the criteria for
approvability are based on showing weight loss and improvement in
comorbid parameters like lipids and blood pressure, I think the effects
on other non-surrogate parameters like mortality or like morbidity such
as myocardial infarction or stroke, are clearly the ones that many of us
are very interested in.

Similarly, it\'s well known that the artificial context \-- somewhat
artificial context really of a double blind placebo controlled clinical
trial is excellent for answering certain scientific questions but really
doesn\'t always predict exactly what will happen when a drug is placed
in the real world setting of clinical practice.

In trying to approach these issues, we really, initially began by
looking at three study designs that we considered scientifically valid
and potentially feasible. Either following a cohort of patients on
sibutramine, doing a classical case control study, or doing a large
simplified clinical trial. Without going into detail, we concluded that
the large simplified clinical trial, although it clearly is the most
difficult and the most expensive, would also be the most likely to yield
the most valuable and unconfounded information.

Why don\'t we briefly just run through some of the hallmarks of large
simplified clinical trials. They\'re usually randomized. By definition
they\'re large. They are of relatively long duration, require innovative
data collection because of, really, the sheer size of the trials.
They\'re usually intended to measure either small important effects or
long-term non-surrogate endpoints. They focus on a few critical
variables rather than the massive data collection that\'s usually done
for each patient in the Phase III clinical trial setting. Examples of
large simplified clinical trials include the ISIS beta blocker trial,
the metforman acidosis study, and the physician\'s health study of
aspirin for MI prevention.

Before going further, I just want to take a minute to thank the FDA, and
specifically Dr. Stadel, who really provided very constructive critique
on our initial proposal.

As you\'re aware, in that regard, there really are very difficult
decisions that have to be made in the design of any clinical trial.
Today, what I\'d like to present is simply our current thinking on some
of the more crucial issues that surround the proposed Phase IV trial.

The first issue is that of the comparator arm. We believe that the most
instructive, as well as probably the most feasible design to do a
randomized trial that would compare sibutramine with what would be the
only other product approved for the long-term treatment of obesity, that
is dexfenfluramine. The proposed duration of the study is two years.
There would be a relatively simple schema for visit schedules and
follow-up which I will describe in more detail in the next slide. This
would be an open label trial. Projected accrual at this time is 10,000
patients, 5,000 patients per arm. Endpoints would be all cause
mortality, all cause hospitalization as a measure of morbidity, CVD
mortality, CVD hospitalization, and we would measure weight loss.

We have done power calculations and with this design would be able to
detect differences between the arms of 19 CVD deaths or 57
hospitalizations.

After randomization and initiation of therapy, projected follow-up would
consist of protocol mandated week four, eight, 24, 48, 72 and 96
recordings, exposure status, weight, history of hospitalizations, and
death. Every six weeks, there would also be telephone follow-up that
would include exposure status, weights and hospitalization. For any
hospitalization or death, medical records would be obtained and
carefully scrutinized.

To give you an idea of the magnitude of the effort that such a study
would entail, the projected requirement to do this is 500 physicians in
order to recruit the required 10,000 patients. There would be
approximately 34,000 office visits included, 120,000 at least completed
telephone calls, follow-up of approximately 800 to 1,000
hospitalizations. Clearly, as I alluded to earlier, there are many
issues regarding study design that are really judgment calls and can be
subjected to a great deal of discussion. If sibutramine is approved, it
is certainly understood that the process that we have undertaken must
continue as an iterative one to more fully consider all the
ramifications of the various possibilities. I just want to emphasize,
this is a work in progress at this time.

At this point, I would now like to conclude by briefly summarizing the
morning presentations on sibutramine. Sibutramine is a novel
pharmacological approach to the treatment of obesity. The first
seratonin, norepinephrine reuptake inhibitor that has been, to my
knowledge, proposed for the treatment of obesity.

It produces clinically meaningful weight loss and weight loss
maintenance, both of which meet the guidelines for weight loss. The data
shows consistent reduction in waist and hip circumference, which is
confirmed by the DEXA data that is present in your briefing documents
that we have not actively presented today. The expected benefits from
weight loss are seen in the lipid profiles and in glycemic control and
additional benefits of decreased uric acid.

The adverse event profile is predictable based upon the pharmacology of
sibutramine. The adverse events that have been seen are mild to moderate
in severity and they are self-limited. Modest increases in mean blood
pressure and pulse rate which, even though they may be clinically
important, are easily measurable and easily measured.

The epidemiologic evaluations that have been performed predict uniformly
that the benefit/risk will remain favorable, not only over the short
period of time of one year that this drug has been studied in controlled
clinical trials, but over longer periods. The benefit/risk furthermore
though can be markedly enhanced through judicious clinical use which has
not been factored into any of the epidemiologic models. The proposed
Phase IV large clinical trial will further expand our knowledge base and
do it very importantly in an actual practice setting.

In conclusion, in light of a clear positive benefit/risk ratio, we would
conclude that sibutramine is safe and effective for the treatment of
obesity. Thank you very much.

CHAIRMAN BONE: All right, thank you.

Are there specific questions related to the last presentation?

Then what we\'ll do, obviously, is break for a shortened lunch break and
return for the FDA presentations after. I don\'t think we\'re going to
get through those.

Is that right? That\'s what I thought.

Right. Dr. Kreisberg has a question.

DR. KREISBERG: I think John was first.

CHAIRMAN BONE: Oh, Dr. Flack does.

DR. FLACK: Could you tell me which endpoint you based your sample size
on for power considerations? Also, even though this is a Phase IV, is
there any consideration at all given to a dummy pill group in the sense
that this trial will never let you know if the treatment is actually
better than doing nothing? It will simply give you the relative
difference in benefit on all the endpoints between two treatments, but
both could be worse than doing nothing, or could be better, or could be
the same.

DR. SPIGELMAN: Yes. No, those are excellent questions and those are
questions that we\'ve struggled through, you know, over the past period
of time. The simple one, or relatively straightforward one is that the
numbers that I mentioned to you were for all cause \-- I\'m sorry, for
CVD and for all cause mortality. For those endpoints, we would be able
to detect a difference of 19. For all cause hospitalizations, 57.

Now, the answer to the double dummy technique, or double blinding, et
cetera, gets to the heart of what are we really trying to measure in
this sort of a trial? Is it a trial that is geared toward seeing what
will happen in terms of the effectiveness of the drug when used in as
close as we can come to the actual clinical practice? Or are we trying
to learn sort of a step removed, more theoretical questions about what
the drug could do but may not necessarily do when applied to people who
really will get the drug in a more normal clinical practice setting?

At this time, our thinking is that what is needed more is to find out
what anti-obesity drugs can really do when they\'re used by practicing
physicians in as close a setting to the real life situation as possible.
Therefore, our priority is to do this in an open label randomized, but
not double dummy type of situations that would markedly restrict the
real life extrapability of the results. But obviously, those are the
sorts of issues that need to be honed in and further defined and thought
through before coming up with a final study design.

CHAIRMAN BONE: Thank you.

Dr. Kreisberg?

DR. KREISBERG: Well, one of my questions is quite similar to John\'s. I
wonder, can you tell me how many morbid and mortal events that you would
project for a two year study with a population of the size that you\'ve
calculated, so I can have a frame of reference to some of the other
large studies that look at similar endpoints?

It seems to me that you\'re going to have to have a relatively large
event rate in order to do this. I wonder if you really know what the
event rate is going to be?

DR. SPIGELMAN: Yes. I\'m not sure I can pull the slides out right now,
so I can get them to you after the break. The numbers are calculated
primarily from the Nurses Health Study which we felt was a comparable
population in terms of expected events. I will pull those out and get
them for you.

CHAIRMAN BONE: Other questions or comments before we recess?

Dr. Illingsworth?

DR. ILLINGSWORTH: One question concerns the need for adequate follow-up.
In looking at the data that\'s been presented this morning, I\'m struck
by the lack of knowledge about what\'s happened to patients who drop
out. I think you should look at, say, the 4S trial as the gold standard
for clinical trials where everyone is identified. I compel you to do
this with this kind of trial, too. So far, the data that\'s presented
from the clinical data shows that to be lacking in my view.

DR. SPIGELMAN: Yes, no question. That is a sine qua non of the proposed
trial. And again, with help from Dr. Stadel and some advice, death
should be 100 percent virtually attainable through the various
techniques that are available to detect death. Telephone follow-ups are
made independent of whether the patient stays on drug or does not
throughout the whole projected two year period of time. So, follow-up is
intended to be independent of status on or off drug. We are optimistic
that with that sort of plan, we can get as close as possible to full
follow-up. But that is clearly the intent of doing this study.

CHAIRMAN BONE: Thank you.

I will reassure people that the generous allowance for Committee
discussion and question time in the afternoon will allow us to finish in
a timely manner because we accomplished much of that, obviously, in the
course of following along with the presentation.

It\'s now 12:03. We, I think, should plan to reassemble here at 12:45.

Is there a problem with that? No? Okay.

(Whereupon, the meeting was recessed at 12:03 p.m., to reconvene at
12:45 p.m., this same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

12:43 p.m.

CHAIRMAN BONE: Will everyone please take their seats?

The meeting will be in order. The next order of business is the
presentations by the Food and Drug Administration. The first FDA
presentation will be presented by \-- let me see, is Dr. Troendle here
to make an introduction?

DR. REEDY: Attention to Committee members who are sitting at the table.
I want to call your attention to in your folder, there is the 1997
schedule and the remainder of the 1996 schedule. I want to call your
attention to the fact that the meeting that we had scheduled on November
8th has been postponed to November 22nd. In other words, no meeting on
November 8th, but there will be one on November 22nd, then again in
December, and then next year. Those are all firm issues including the
first one in February.

CHAIRMAN BONE: I\'m sorry. There\'s one person we\'re waiting for.

The introduction to the Agency presentation will be given by Dr. Gloria
Troendle. We\'ll please be in order for that. She\'ll be followed by
Drs. Eric Colman, Bruce Stadel, and John Flack.

Dr. Troendle is kindly distributing copies of the current draft guidance
document which this Committee considered and discussed with the Agency
last year. Most of the members of the Committee participated in that
discussion, although we do have one or two new members.

Thank you, Dr. Troendle for that.

Obviously, for persons who are interested in obtaining copies of the
draft guidance document, they can be obtained from the Agency.

If we can turn off Dr. Colman\'s slides please, we will be able to look
at Dr. Troendle\'s overheads. Okay.

Dr. Troendle?

DR. TROENDLE: Hi. A recently updated version of the Guidance for the
Clinical Evaluation of Weight Control Drugs has been provided for the
information of the Committee. The guidance was reviewed by this
Committee and recommendations for the Committee were incorporated into
it. It requires some rewriting from time-to-time principally to clarify
issues about which we get questions.

The recent revisions were to ensure that the guidance does not suggest
that it consists of requirements for drug approval. It is only our
current thinking and is suggestions. I believe that the basic points
remain as they were originally written and subsequently modified by this
Committee. The important points are as follows, subject to modification
for special situations.

\(1\) The population study should be representative of the target
population for weight control drugs and usually meet a definition of
moderate to severe obesity.

\(2\) Trials should be of a size and duration to allow an assessment of
the long-term benefits and risks of drug use because an indication for
long-term use is usually desired. Double blind, randomized dose-finding
and efficacy studies are generally needed to identify the optimum dose
and to establish efficacy. It is particularly important to establish the
lowest effective dose when the drug will be used in an otherwise
relatively healthy population such as is true of many obese patients.

\(3\) Weight loss or maintenance of weight loss should usually be the
primary endpoint as recommended by this Committee. The study of other
endpoints may lead to meaningful indications in addition to weight
control. Such endpoints might be the prevention of or improvement in
diabetes, hypertension, osteoarthritis or sleep apnea. Improvement in
quality of life or in physical performance on, say, walking or stair
climbing may be a desirable endpoint. Measurement of obesity associated
cardiovascular risk factors: lipids, blood pressure and glucose
tolerance can readily be done and may have a place in determining the
balance of benefit versus risk for the drug. If one or more of these
factors deteriorates or is not improved, the risk associated with this
deviation must be considered in making a benefit to risk decision for
the drug.

\(4\) At least two weight loss outcomes are possible. First, a
demonstration that the mean drug effect is significantly greater than
the mean placebo effect, and that the mean drug associated weight loss
exceeds the mean placebo weight loss by at least five percent. The
second one, demonstration that the proportion of drug treated patients
who lose at least five percent of their initial body weight is
significantly greater than the percentage of placebo patients who lose
at least five percent of their initial body weight.

The second efficacy demonstration may help to identify efficacy of drugs
that are effective in only a portion of obese patients and it reflects
our expectation that obesity may be a disease of diverse etiologies so
that a given drug benefits only subjects with a particular abnormality.
When the efficacy of any drug is established, benefits of the drug are
compared to risks. Depending on the indication that is sought, several
roots are possible for establishing efficacy of a drug that is broadly
intended for weight control but all decisions ultimately come down to
whether the population has been identified in whom benefits outweigh
risks.

And that\'s all I\'m going to say about the guidelines. Those are just a
few of the points. The rest of the presentation will be made by Dr. Eric
Colman on the medical aspects, then Dr. Bruce Stadel on the
epidemiologic aspects.

CHAIRMAN BONE: Dr. Colman?

Thank you, Dr. Troendle.

Were there questions from members of the Committee concerning Dr.
Troendle\'s presentation?

Dr. Marcus appears to have a question.

DR. MARCUS: I would just like to submit that I think a stronger
statement about ethnic diversity should be inserted. You can not get an
NIH grant involving a human study. You can not even, in theory, get a
clinical trial through an institutional review board now without paying
attention to that issue. I mean, I fully understand that the studies
we\'re hearing today came out prior to the initial guideline. But I
think for the future, it would be very important particularly for a
disease like obesity where, clearly, any drug action that we take over
the next few months on this drug are going to be applied to Hispanic and
Black populations \-- that is, populations who are said uniquely to have
a pre-disposition towards it. I think we need to have adequate data in
those ethnic groups for sure.

DR. TROENDLE: Right. Yes, we do mention a couple of times in the
guidance that minorities, Blacks and Hispanics in particular, and both
males and females should be studied. But we put it very mildly, it is
desirable to have that.

DR. MARCUS: I am requesting that you make it a more stringent \--

DR. TROENDLE: So that it\'s required.

CHAIRMAN BONE: Thank you.

Are there specific questions related to today\'s discussion from Dr.
Troendle? No?

Thank you.

Dr. Colman?

DR. COLMAN: Good afternoon. My discussion is going to focus on two main
topics. The first is efficacy. I\'m going to briefly discuss the results
from the one year pivotal study, SB 1047. I will not comment on the
second primary or pivotal study, BP 852. You heard the results from the
sponsor earlier today. I\'d like to spend the bulk of my time discussing
aspects of the risk/benefit analysis and in particular, the effects of
the drug on blood pressure and lipid levels and spend a little bit of
time discussing two studies that looked at the effects of the drug in
patients with Type II diabetes.

As for efficacy, once again, SB 1047 was a one year study. It involved
485 patients. These patients were randomized to one of three arms,
either 10 or 15 milligrams a day of sibutramine or to placebo. The
baseline characteristics of the three groups were well matched. The mean
age was 42 years. They were primarily female and nearly all Caucasian
and the mean VMI was 33 kilograms per meter squared.

This next slide illustrates the percent weight loss from baseline for
subjects who completed the one year study. Just to give you an idea of
how many people completed the study, roughly 50 percent of the placebo
patients and 50 percent of the ten milligram patients completed the one
year study. Fifty-nine percent of the subjects in the 15 milligram group
completed the one year study.

As you can see, there was significantly more \-- or greater weight loss
in the two drug treated groups versus placebo. At month 12, the
differences between these two groups versus placebo was statistically
significant. However, it\'s interesting to note that at month 12, there
were no significant differences in weight loss between these two groups.

Now, in addition to looking at percent weight loss as a gauge of
efficacy, one can look at the number of individuals who lose at least
five percent of baseline weight. This has been called the responder
analysis, or five percent responder analysis. The next slide illustrates
these data. As you can see, 20 percent of placebo patients lost at least
five percent of initial body weight. Thirty-nine percent of the subjects
in the ten milligram group lost at least five percent of body weight,
and 57 percent of subjects in the 15 milligram group met that criteria.
Again, the two drug treated groups, one compared to placebo, was
statistically significantly different.

Thus, to quickly summarize the efficacy from this one year study, for
subjects who completed the one year study, the 15 milligram dose
resulted in a percent weight loss that was five percent greater than
placebo. Regarding the responder analysis, compared to placebo, a
significantly larger proportion of subjects who took 10 or 15 milligrams
a day of sibutramine lost at least five percent of initial body weight.

Now, at this point, I\'d like to move from efficacy and discuss
risk/benefit. We\'ve heard this morning some talk about blood pressure.
I think this is the critical component with sibutramine. I\'ll spend a
fair amount of time discussing blood pressure. I\'ll also discuss some
aspects of lipids \-- again, two studies that looked at the effects of
the drug in patients with Type II diabetes.

There\'s a massive amount of data in this NDA regarding blood pressure
and innumerable number of ways to look at blood pressure data. When I
was looking at the data, I thought three questions would be reasonable
to keep in mind and try to answer. The first question is does
sibutramine increase mean blood pressure? The second question, does
sibutramine lead to large increases in blood pressure in a subset of
patients? The third question was, does sibutramine alter the 24 hour
diurnal variation in blood pressure?

Now, as far as the first question is concerned, the sponsor has stated
sibutramine does increase mean systolic and diastolic blood pressure by
approximately two to three millimeters of mercury relative to placebo.
I\'m not going to show any data to support that. I think it\'s a fair
assessment and I will simply leave this question here.

The second question, does sibutramine lead to large increases in blood
pressure in a subset of patients? That\'s a little more difficult
question to answer, however, this slide represents data from all placebo
controlled studies with patients who had uncomplicated obesity. Again,
this involves all doses of sibutramine. What is shown is the number of
patients who had an increase in resting blood pressure that was at least
30 percent greater than their baseline measurement at some point during
treatment. If we look at systolic blood pressure, 6.5 percent
sibutramine treated patients had a significant increase in blood
pressure at some point during treatment. This is in contrast to only 2.5
of placebo patients. Again, with diastolic blood pressure, 7.4 percent
of patients on sibutramine had a significant increase from baseline in
their blood pressure at some point during treatment. Again, this is in
contrast to only 1.9 percent of placebo patients. These p values
indicate that these differences are unlikely to be due to chance.

Now, the next slide may be difficult to read, but I think it\'s an
important slide. I\'ll walk you through it. These are data from the one
year study, SB 1047 that I reviewed a minute ago. Again, recall that
these subjects were on either 10 or 15 milligrams a day of sibutramine
or placebo. This is a scatter plot of month 12 data. These are actual
data points at the last month of the study. What is shown along the
Y-axis is a change in body weight in kilograms. This represents a
reduction from baseline body weight. Along the X-axis is the change in
systolic blood pressure from baseline. Again, this direction is an
increase from baseline and this is a reduction from baseline.

Now, the placebo subjects \-- hard to make out, are shown by crosses
here. The stars represent sibutramine treated patients.

CHAIRMAN BONE: We\'re going to ask for a budget increase so we can have
a color slide next time.

DR. COLMAN: I\'m going to help you out. I\'m going to direct your
attention just to this quadrant. It\'s a little easier. People who fell
into this quadrant lost at least five kilograms of body weight or more.
Yet, at the same time, they had an increase in systolic blood pressure
of greater than ten millimeters. Now, once again, I\'ll test your visual
acuity. There\'s only one placebo subject in this quadrant. This
individual represents roughly 1.4 percent of all placebo patients on the
graph. The 20 or so sibutramine patients represent 12 percent of all
sibutramine subjects on this graph. If you want to be statistically
proper \-- we did do statistics \-- comparing 12 percent versus 1.4 was
statistically significant. P equaled .006.

Now, this was a concern to me. These are individuals who have gone
through a year of treatment on 10 or 15 milligrams. They\'ve had a
significant reduction in weight, anywhere from five kilograms all the
way up to over 20. Yet, at the same time, they\'ve had substantial
increases from baseline in systolic blood pressure, 20 millimeters here,
25, et cetera. Again, these represent single measurements, but this is
somewhat worrisome. A clinical question is can you effectively and
easily and early-on in treatment screen these individuals out so that
you don\'t expose someone to potentially a year of blood pressures in
this range? But I think these data, the data on the previous slide,
suggests that there is a subgroup of patients who have a substantial
increase in blood pressure and that is of concern.

Now, back to our favorite study. The third question I asked was does
sibutramine affect the diurnal variation in blood pressure? This
question may be answered, to some extent, in this study BPI 855. This
was a small study. It was eight weeks. It involved 20 patients with a
history of hypertension and they were controlled on a single,
anti-hypertensive. Most were on a diuretic. Half the subjects received
20 milligrams a day of sibutramine, half received placebo. In addition
to having a manually measured or cuffed measured blood pressure, they
had 24 hour ambulatory blood pressure monitoring. I should also mention
that part of the protocol specified that weight loss be minimized. They
actually had dieticians instructing the patients to eat enough so that
the weight loss was minimized. The idea behind that was to try to
isolate the effect of the drug and not have the confounding effect of
weight loss.

Now, again, we heard this earlier. Aside from the difference in the
gender distribution, the two groups were fairly well matched to
baseline. The mean age was 50 years. Half the subjects were
African-American. This was a bit different from the standard studies
we\'ve heard about. It did not include this number of African-Americans.
As far as weight loss, this slide illustrates a change in body weight
from baseline to week eight. Again, as specified in the protocol, there
was a small amount of weight loss in the sibutramine group. This was not
statistically significantly different from placebo.

Now, this slide represents the baseline values, or day zero values prior
to drug administration for 24 hour ambulatory diastolic blood pressure.
At this point, let me explain how these numbers were derived. From the
hours of 6:00 a.m. to 10:00 p.m., during the daytime blood pressure was
taken every 15 minutes. From the hours of 10:00 p.m. to 6:00 a.m., the
nocturnal readings, a pressure was taken every 30 minutes. From those
values, hourly means were calculated and then a single mean was
calculated for the daytime value and a single value for the nocturnal
time period. What you can see here is that both groups at baseline,
prior to drug administration, had the expected nocturnal reduction in
blood pressure: 86 to 80, 84 to 73. Again, you could argue that these
two groups weren\'t matched ideally and statistically that it wasn\'t
significant. But again, these were not perfectly matched.

Now, following this procedure they were randomized to drug or placebo
and the patients had repeat ambulatory measurements on day three and at
the end of week four and the end of week eight. I\'d like to show you
the results on the next slide. Again, these represent the mean change
from baseline in ambulatory diastolic blood pressure.

I\'d like to direct your attention to the nocturnal readings in yellow.
You can see as early as day three, the placebo group had a reduction
from baseline in nocturnal blood pressure, while the sibutramine group
had an increase of one millimeter. This was significant. This pattern
becomes more exaggerated as time goes on. At week four, the placebo
group has a 12 millimeter reduction in blood pressure while the
sibutramine group has a four millimeter increase from baseline. Again,
significant. The same pattern was seen at week eight.

Now, this overall pattern was mimicked with mean arterial pressure. It
was not seen with systolic blood pressure. And as the sponsor mentioned,
the manually measured blood pressures or the cuffed blood pressures were
not significantly different between the two groups. So, there was a
discrepancy.

Conclusions from this study: 24 hour ambulatory blood pressure
monitoring indicated clinically significant increases in blood pressure
associated with the use of 20 milligrams a day of sibutramine compared
to placebo. In addition, sibutramine eliminated the expected nocturnal
reduction in blood pressure. In some sense, it reversed it.

So, if I were to summarize the effects of sibutramine on blood pressure,
I would say that sibutramine increases mean systolic and diastolic blood
pressure by two to three millimeters relative to placebo. I think we all
agree on that. I\'ve shown some data that indicates sibutramine does,
indeed, induce large increases in blood pressure in a subset of
patients. This is worrisome. We need to be able to screen these people
adequately to lower their risk. The final study suggests that
sibutramine may eliminate the expected nocturnal reduction in blood
pressure. Again, we\'ve heard about the problems with the technology and
so forth. It was a small study and I certainly agree that you can not
make any definitive comments about this but it does raise some
questions.

Now, at this point, I\'d like to move on to lipids. There were a lot of
studies in this NDA that measured lipids, however, they were not primary
or secondary or even tertiary objectives. There was only one study, one
study that had as its primary objective, to measure lipid levels
following sibutramine treatment in patients with hypercholesterolemia.
This is important to keep in mind. This is the only study that was
prospectively designed to look at lipids.

I\'m going to review this study. This was a 16 week study conducted in
Spain. It involved 182 patients. Half the patients received ten
milligrams a day of sibutramine and half received placebo. The entry
criteria included a total cholesterol of 200 to 300 and/or a TG level of
200 to 400. Now again, both groups were well matched for baseline
characteristics. The mean age was 46. They were primarily female, all
Caucasian. They were quite heavy \-- mean BMI was 35 kilograms per meter
squared. This next slide illustrates the baseline lipid levels. This
demonstrates that, indeed, the two groups had comparable baseline lipid
values. They might be considered to have mild to moderate
hypercholesterolemia.

Now, as far as weight loss, this slide illustrates the change from
baseline to week 16. As you can see, there was an impressive weight loss
in the sibutramine group. A mean weight loss of over eight kilograms or
nearly 18 pounds. The placebo group lost 5.7 kilograms. The difference
between the two was statistically significant.

How did this weight loss translate into lipid effects? This slide
illustrates the mean changes in lipids, mean values with standard
deviations in parentheses. Again, despite greater weight loss in the
sibutramine treated patients, there were no significant differences
between any of the lipid parameters. It\'s also interesting to note that
despite a mean weight loss of nearly 18 pounds, the mean HDL level
didn\'t budge.

In conclusion from this study, despite greater weight loss, obese
hypercholesterolemic patients treated with 10 milligrams a day of
sibutramine had no significant improvements in lipid levels when
compared to subjects treated with placebo.

Now, again, the lipid question has become somewhat cloudy. I mentioned
that a lot of studies in the NDA had measured lipids. They weren\'t
primary or secondary objectives of the study. Some post hoc analyses
have been done. I\'ve listed here on the left side, the studies in which
a favorable or significant improvement in lipids were noted in the
sibutramine group. On this side, there are studies where no significant
improvement was noted. Again, these studies are very heterogenous. They
range anywhere from eight to 12 weeks up to one year. Some have multiple
doses. Some were done in the US. Some were done in the UK. One was done
in Spain. It\'s difficult to make a general conclusion from the variety
of data.

In any event, the two largest studies, the two primary or pivotal
studies, BPI 852 and SB 1047 \-- I think it\'s important to show you the
actual lipid data from these two studies. Again, this was a six month
dose ranging study. This shows the mean percent change from baseline to
month six in mean lipid parameters. Now, the sponsor has mentioned they
are going to drop the 30 milligram dose. When you do that, you see some
sporadic improvements in some of the lipid parameters, primarily
triglyceride. You don\'t see a dose response here. There was a dose
response with body weight, but there doesn\'t appear to be a dose
response with lipids. It\'s also interesting to note that LDL,
numerically it looked as though the drug was beneficial. But
statistically, nothing showed up for LDL.

Now, turning to SB 1047, again, this was a year long study. This study
only measured total cholesterol in TG. HDL and LDL were not measured.
It\'s interesting to note that in this study, total cholesterol actually
increased from baseline in all three groups. TG was reduced in all three
groups. None of these differences were statistically significant.

Now we heard the sponsor present a meta-analysis of the lipid data.
Unfortunately, I can\'t comment on that meta-analysis simply because no
details of that study have been submitted to the Agency for review. So,
I am left reviewing the data in the NDA. Simply my conclusion from
looking at the data is the data are inconsistent regarding lipids. I
think I\'ve shown that.

Now, finally, I\'d like to finish up with a brief discussion of two
studies that studied the effect of sibutramine in patients with
non-insulin dependent diabetes.

This was a small study, a pilot study. I guess we didn\'t hear about
this study. This is a 13 week study. It involved 18 obese patients with
Type II diabetes. It had somewhat of an interesting study design. For
the first four days, 12 patients were randomized to 30 milligrams a day
of sibutramine and then placed on 20 milligrams a day for the remaining
12 weeks. Six patients were on placebo for the entire 13 weeks. Now,
aside from the placebo group having a higher fasting c-peptide level \--
which was 40 nanograms per ml versus 24 in the sibutramine group \--
both groups were fairly well matched for baseline characteristics.

To save time, I\'m just going to show you the results of the study in
one slide. This shows the mean change from baseline in body weight,
hemoglobin A1C, fasting glucose, and the two hour glucose concentration
after an all glucose tolerance test. There was a modest mean reduction
in body weight in the sibutramine group. This was not significantly
different from the placebo weight loss. As you can see, there were no
significant improvements in any of the metabolic parameters. Not only
were these differences not significant when compared to placebo, but
within group comparisons, were also non-significant.

Now, the larger study was a 12 week study. It involved 91 patients. Half
were randomized to 15 milligrams a day on sibutramine, half to placebo.
Again, these groups were fairly well matched to baseline. In the
interest of time, I\'ll show you the results. Again, this shows the mean
change from baseline to the end of the study in body weight, hemoglobin
A1C, fasting glucose. This represents the change in the glucose area
under the curve following a test meal. The test meal was a standard
breakfast, 520 kcals. This is the change in fasting insulin and the
change in the insulin area under the curve following a test meal. Once
again, there\'s a modest reduction in body weight in the sibutramine
group. In this case, it was statistically significant. Yet again, there
were no significant improvements in any of the measures of glycemic
control.

To conclude, the treatment of obese diabetic patients with sibutramine
had minimal effect on body weight and no significant effect on glycemic
control.

As an overall summary, I have two slides to conclude with. Regarding
efficacy, the five percent responder analysis: compared to placebo, a
significantly larger proportion of subjects who took five through 30
milligrams a day of sibutramine lost at least five percent of initial
body weight. In general, there\'s consistent evidence that sibutramine
has a pressor effect. More importantly, it appears that this pressor
effect is independent of the change in body weight. Also, in general,
there\'s a lack of consistent evidence that sibutramine improves lipid
levels. Finally, there\'s no evidence that sibutramine significantly
improved glycemic control on patients with Type II diabetes.

Thank you.

CHAIRMAN BONE: Thank you, Dr. Colman.

Are there any questions now from the Committee to Dr. Colman concerning
his presentation?

Dr. New?

DR. NEW: Dr. Colman, how do you know that in the illegible graph that
had the quadrants \-- how did you know that in the right lower quadrant,
those who had lost weight but yet were hypertensive, how did you know
that they were different individuals?

DR. COLMAN: How did I know they were different individuals?

DR. NEW: How do you know they weren\'t the same person? Since you said
they are single blood pressure measurements, how do you know that
they\'re different people?

DR. COLMAN: Because it only represented the people \--

DR. NEW: Once?

DR. COLMAN: \-- once, yes.

DR. NEW: In other words, the data as submitted was by individual?

DR. COLMAN: Yes. There was a plot for each individual, the change in
their body weight versus the change in their blood pressure. They came
out as one point.

DR. NEW: So, what point did you select to plot?

DR. COLMAN: Well, we took the arbitrary \-- we made two measurements. We
said if someone lost five kilograms of body weight, we consider that a
reasonable amount of weight. We decided that ten millimeters of blood
pressure was significant clinically, and that\'s how we came up with
that quadrant. Simply to illustrate that there appears to be a subset of
patients who lose weight on the drug, yet have a substantial increase in
blood pressure.

DR. NEW: But supposing I asked you what was the blood pressure of those
who lost significant amounts of weight at night? Because there is an
ambulatory record which you showed.

DR. COLMAN: Yes.

DR. NEW: So, could you have plotted a different hour of the day? Because
these are single individual blood pressure measurements. How about if
you plotted the mean blood pressure for those people?

DR. COLMAN: Well, we could ask the company to do ambulatory blood
pressure monitoring in 1,000 patients, but I don\'t think they\'d
probably go for that.

DR. NEW: Okay. Could you have given me a mean blood pressure of those
patients in that right lower quadrant?

DR. COLMAN: A mean blood pressure?

DR. NEW: Rather than an individual blood pressure.

DR. COLMAN: A mean of over what time period?

DR. NEW: Twenty days.

DR. COLMAN: Oh, I\'m sure we could do all those things. I don\'t have
the data set to do it. And again, my point was to show that there
clearly is a subset of patients who lose a substantial amount of weight,
yet at that time point, they had an increase in blood pressure.

DR. NEW: And what confidence have you that that time point represents
the blood pressure of that person, in general, on this drug?

DR. COLMAN: Well, also, the point is that there was only one placebo
patient in that quadrant and there were 20 or so sibutramine. So,
there\'s an issue of comparing groups.

CHAIRMAN BONE: Those were the endpoint changes in blood pressure and
endpoint changes in weight, is that correct?

DR. COLMAN: Not endpoint, over month 12.

CHAIRMAN BONE: I\'m sorry.

DR. COLMAN: Endpoint, I would \--

CHAIRMAN BONE: So, it was only for completers?

DR. COLMAN: Right.

CHAIRMAN BONE: So, do I understand correctly for the benefit of
everyone, that that analysis was performed on subjects who completed the
full 12 weeks \--

DR. COLMAN: Months.

CHAIRMAN BONE: Twelve months, I\'m sorry. Pardon me, 12 months. Excuse
me. Completed the full 12 months, graphing the change between baseline
and 12 months in body weight and the change between the baseline
measurement and the 12 month visit measurement in blood pressure?

DR. NEW: So, it was the 12 month visit?

CHAIRMAN BONE: Yes.

DR. SHERWIN: But what\'s important is it doesn\'t include those people
who were withdrawn because of hypertension. Is that correct?

DR. COLMAN: Very few people were withdrawn from that study for
hypertension is my belief.

DR. SHERWIN: Okay. Do you have the numbers on that?

DR. COLMAN: I don\'t. The sponsor might want to address that.

CHAIRMAN BONE: Perhaps somebody can be checking that unless they have an
immediate answer.

DR. SPIGELMAN: Well, the incidence \-- that was one of the protocols in
Dr. Seaton\'s curve in which there was no mandatory discontinuation. The
discontinuation in that whole population, as I remember it, was in the
order of about .5 percent, much less than one percent. So, I can\'t tell
you for that one study specifically.

Okay, nobody was withdrawn for high blood pressure in that study.

CHAIRMAN BONE: Thank you very much.

I believe Dr. Flack and then Dr. Kreisberg have questions.

DR. FLACK: I think another important point about that right lower
quadrant is that those were people who had unfavorable blood pressure
changes and lost a fair amount of weight, but it really underestimates
what happens in reality because everybody is not going to lose a fair
amount of weight. That\'s really sort of taking the paradoxical smaller
group and putting it together which is, I think, what that slide is
showing.

CHAIRMAN BONE: Dr. Kreisberg?

DR. KREISBERG: Well, that was, I think, my point as well. I would be
interested in people in the right upper quadrant because those are
people who had blood pressure that went up but didn\'t lose weight. That
looked to be a pretty heavy quadrant as well, is that not right?

DR. COLMAN: Right, yes.

DR. KREISBERG: So, these are people that were maintained on the study
for the 12 months and actually were not getting any benefit from weight
reduction but were presumably deriving some detrimental effect from an
increase in their blood pressure?

CHAIRMAN BONE: Dr. Critchlow?

DR. CRITCHLOW: Do you know if blood pressure tended to increase right
away and plateau, or did it steadily go up among those whose blood
pressure increased?

DR. COLMAN: Specifically with this data, I don\'t know. My impression
from the NDA is that \-- well, first of all, I don\'t think the blood
pressure has been well characterized as far as questions like this. In
general, I\'ve seen statements from the NDA such as the peak blood
pressure effect may not be seen for six to eight weeks. At that point,
it may plateau.

CHAIRMAN BONE: Other questions or comments?

Dr. Sherwin?

DR. SHERWIN: I just want to get it straight in terms of the right upper
quadrant. I couldn\'t see \-- you didn\'t point out stars and \--

DR. COLMAN: Do you want to go back to that?

DR. SHERWIN: Well, in other words, stars versus whatever they were,
crosses?

DR. COLMAN: I don\'t know what number slide that is.

DR. SHERWIN: Because it looked like both groups were in that quadrant. I
just don\'t know \--

DR. COLMAN: Keep in mind, again, another way to look at this is to look
just simply at who increased, who decreased from zero. You know, the
zero here and then zero here. We thought it was more clinically relevant
to pick a point where people would be attracted to the drug because they
did lose at least five kilograms. That\'s over ten pounds. Then we
arbitrarily chose ten millimeters as saying this is significant. Some
people may argue this is not significant. And again, it\'s only a single
measurement.

The point is, there\'s only one placebo patient here and there are
roughly 20. Quite a difference in the proportion. But you\'re right,
people are scattered all over the place. Again, that gets back to the
point that there doesn\'t appear to be a correlation between the change
in body weight and the change in blood pressure.

DR. SHERWIN: Were these evenly divided groups? I can\'t tell from this.
There were more people on drug originally?

DR. COLMAN: Well, yes, there were \--

DR. SHERWIN: You don\'t want to skew it too much.

DR. COLMAN: No. There were roughly 166 sibutramine patients who
completed and approximately 71 placebo. But again, if you look at the
proportion, it was significantly different.

CHAIRMAN BONE: Thank you.

Dr. Colman, one of the questions I asked earlier based on some of the
tables that were prepared for us had to do with what the estimated
magnitude of this increase in blood pressure might be for patients on
doses that are likely to be clinically effective. You said that,
particularly with regard to the study 1047, you thought the estimate of
two to three millimeters was a realistic estimate. That does fit with
the \-- I think it\'s the 15 milligram dose in that study.

DR. COLMAN: Yes.

CHAIRMAN BONE: But looking at the other large study 582 \-- I mentioned
earlier that looking at the table, it looked as though to me, the
magnitude of the increase in blood pressure was somewhat greater for
those doses that were likely to be clinically effective.

DR. COLMAN: Right.

CHAIRMAN BONE: And it seemed to be higher yet if anything with chronic
exposure \-- which gets to this question about acuity of the effect. Was
your comment about the two to three millimeter estimate pertinent only
to the 1047 study or to taking all the data together?

DR. COLMAN: That is an overall estimate taking all the data altogether.

CHAIRMAN BONE: Are you confining that to the doses of 10, 15, and 20
milligrams, or to what extent is that influenced by the one and five
milligram doses?

DR. COLMAN: No, and again \-- yes, again, this would probably be better
addressed by the sponsor because the sponsor has \-- actually, that\'s a
quote from the sponsor and I tended to agree with it. I don\'t know all
the specifics of it and they might be able to better address that.

CHAIRMAN BONE: Well, all right. We\'ve heard the sponsor\'s description,
so I guess we\'re just agreeing with it, or not disputing it.

Are there any additional questions or comments concerning Dr. Colman\'s
presentation from the Committee?

Thank you, Dr. Colman.

I guess the next speaker will be Dr. Bruce Stadel.

DR. STADEL: I got drawn into this in early August because some of the
discussions about possible effects of blood pressure were brought
forward in the forms of epidemiologic models and I was asked to look at
those. Then this has progressed. So, I tried to put together some of the
information on the big picture of where we are with appetite suppressive
drugs because I think it does have some relevance to some of the issues
for this drug in particular.

These figures are from IMS America which is a database used by industry
and by the Agency for measuring drug use nationally. The left-hand
column shows numbers of prescriptions and the right-hand column is a
demographics column drawn from a file that asks physicians about
patients they\'ve seen and what drugs have been discussed and so on.

I put up the years that I have because the current episode of interest
in anti-suppressant drugs really got its impetus in 1992, the
publication of the paper by Weintraub and colleagues on long-term weight
control NHLBI had sponsored. There were 62 patients on drug in that
study. It was a long study, but small. Sixty-two patients on study and
59 originally randomized to placebo. This was on a combined
fenfluramine/phenteramine regimen. Now, that was in 1992.

Well, you can see that what\'s happened here with the prescribing of the
two drugs that are used in that regimen for phenteramine \-- there\'s
lots of brands. But it has gone from two million prescriptions written
in 1992 to just under 10 projected for this year on the basis of the
first few months\' return. And for fenfluramine from 69,000 up to 6.3
million prescribed. Now, these aren\'t always used together but I think
they probably are a lot even though there really isn\'t a marketed and
labeled regimen of that kind. But I wanted to show this because I think
it provides some background for what\'s happening in the world of
appetite suppressant drugs.

Then, of course, in April of this year, the redux dexfenfluramine was
approved. We anticipate \-- I mean, my expectation is that it will
supplant fenfluramine which is only one brand, pondimin, and continue
rapid growth.

I have some personal opinions about this growth and what I\'ve been able
to learn about the appetite suppressant market and that is that I think
it is somewhat unlikely to represent a very, very narrowly selected
prescribing to individuals with clearly labeled obesity indications over
comorbidities. I see more reason to believe that this rapid growth
involves a wider prescribing to people with varying degrees of obesity,
many of whom do not have any comorbidity that is going with the obesity.

So, that\'s just sort of a little bit of background information.

Now, the second topic I\'d like to talk about is what do we know about
intentional weight loss and its effects on mortality? There\'s only one
large published study that I\'ve been able to find. It\'s cited in the
NDA, but it\'s not discussed. It\'s a study by Williamson and
colleagues, a perspective study of intentional weight loss in mortality
in never smoking, overweight, US White women, aged 40 to 64 years. It
was restricted to never smoking women to separate out the confounding
effects of smoking from the others in the data.

This is based on the Cancer Prevention Study Number 1 of the American
Cancer Society. It\'s a follow-up study of 43,400-plus women who had a
BMI over 27. They were never smokers, aged 40 to 64 years, who in 1959
to \'60 filled out a detailed baseline questionnaire about their medical
history, personal health practices and so on, including a history of
weight loss practices. Vital records status for 91 percent of the
population was determined through 1972. The mortality outcomes were all
cause cardiovascular, all cancer, obesity-related cancer and diabetes
related.

The questionnaire about weight at baseline included current weight and
height, and a series of questions about weight change recently. Whether
there had been a weight change, whether there had been a gain or a loss.
If it had been a loss, had it been an intentional or unintentional, and
what length of period of time it had occurred over. Analyses were then
grouped by intentional weight loss in one to 19 pounds and 20 pounds
plus. Their potential confounding by pre-existing elements was
controlled primarily by stratifying on the baseline history.

Now, this that I put up here refers to women who at baseline, reported
obesity related health conditions. That is, they had at baseline heart
disease, stroke, diabetes, high blood pressure, or a history of severe
shortness of breath or chest pain. Persons with prevalent cancer were
not included in this group. Now, the group with no pre-existing illness
which we\'ll get to in a moment after I talk about these was no to all
disease and severe complaint categories, and said they felt well at
baseline.

Now, what this shows you is the all cause mortality rate. About a third
of the patients, you see, 15 out of 43,000, reported that at baseline
they had obesity related health conditions. This shows you their all
cause relative risk of dying during the subsequent many years of
follow-up through 1972. I draw your attention to the column \-- let me
find my little pointer \-- labeled \"fully adjusted\". Now, the no
change means they had no change in weight and that\'s used as the
reference group. The unknown weight loss, unintentional loss,
unintentional gain, and then intentional loss. So, what you see here is
for people with clear obesity related comorbidity, there was about a 20
percent reduction in mortality over the subsequent year.

Now, this doesn\'t look very different by the amount of weight loss but
this is a pretty wide interval. And remember, this is questionnaire
based so I think it\'s more important simply to note here that there is
in these data, for this group, with clear comorbidity \-- now, these are
not necessarily all the people who are taking appetite suppressants.
This is a portion clearly needing medical treatment for various problems
and obesity may be one of them. In further analyses, this is clearly
accounted for by a reduction in the mortality from obesity related
cancers. They were mentioned earlier: breast, endometrium, ovary, gall
bladder, primary sites, and in diabetes related deaths. So, it made
sense. Obesity related cancer, especially breast cancer, is well known
in relationship with obesity and with endocrine alterations that are
produced \--

Let\'s go then to the next slide, next transparency, which has to do
with the people who did not have any pre-existing baseline illness,
okay? Now, they didn\'t report any baseline. That\'s two-thirds of the
people. These people had uncomplicated obesity as most of the people in
the large sibutramine trials had where people with NIDDM and
hypertension and so on were excluded. They didn\'t have histories of
heart disease and so on because serious illness \-- and this, I think,
is probably a large part of the appetite suppressant using population.
So, I just think there\'s a need to get down to earth about like what
modeling means and so on with regard to large mortality savings.

I don\'t think that an appetite suppressant drug necessarily has to
accomplish those things to be worthwhile, but I did just want to bring
some perspective on some of the things that have been said. There was no
effect of intentional weight loss on subsequent mortality in people who
didn\'t have obesity related health problems at baseline. Now it may
have done them a lot of good in other ways, but it did not reduce their
subsequent all cause mortality in this study.

Now, some of the strengths and weaknesses \-- I think the study is
strong in terms of controlling for potential confounding by variation in
baseline health. They had a very good questionnaire on health status and
I think they did a good job of controlling for that. I think it\'s
strong in terms of having large numbers and having full ascertainment of
mortality and having an endpoint of mortality that is quite firm.

However, on the other side, one of the problems with big studies like
this is that it\'s a questionnaire based. You don\'t have a lot of
measurements on people. You do have a certain amount of problems with
coding data from questionnaires with unknowns and so on. So, you could
have missed some small effect here in this intentional loss group here,
I suppose.

But I just draw your attention to the difference in findings here versus
those on the preceding transparency where there was a clear association
for people with obesity related conditions. And that\'s the only study I
know of in the literature that looks in the large numbers at the
consequences of intentional weight loss. I emphasize intentional because
the models that have been discussed \-- the Framingham study is a
wonderful study, but it\'s looking at naturally occurring variations.
It\'s not looking at drug induced variations.

Likewise, of the Nurses Health Study which has been \-- not talked about
much here today but has been talked about a lot in terms of obesity. It
looks at over 100,000 women who in 1976 were enrolled and followed for
16 years. It classifies them by their weight at baseline and looks at
their later mortality. Well, that\'s the relation of naturally occurring
variations in body weight and mass with weight or mortality. I have no
reason to question the data from that. But naturally occurring
variations are not the same thing as intentional weight loss, whether
it\'s by dieting or by drugs and so forth. The preponderance of evidence
is that intentional weight loss does not produce large changes in
mortality \-- large savings. That\'s going to be important when we\'re
talking about counterbalancing the pressor effect of this drug. The
argument is that the effects of weight loss as reflected through their
effects on lipids in your model \-- but the argument is that the effects
of weight loss are counterbalancing any risk related to pressor effect.
I submit that that argument is not strong.

Before I go on to talk about the model \-- just on the Nurses Health
Study, I\'d like to make a quote from them. They had a small amount of
data about weight change in addition to looking at the variations. They
said that they examined the role of weight change during adulthood in
relation to the overall and cost specific mortality which was later.
Women who had lost weight did not have significant changes.

Now, in the sibutramine modeling that\'s been done, we\'re looking at
\-- I\'ll look at the one at the right. These are referred to as
scenarios having been developed for coronary heart disease using the
actual mean change of scene in the sibutramine studies. Now we tend to
agree that there is a two to three millimeter mean change in both
systolic and diastolic. Now this, of course, refers to eight years of
follow-up which is kind of a long time I think to be talking about in
terms of drugs that have been studied for one year. But in any case, I
think that as a standard for trying to look at benefit/risk tradeoff,
it\'s reasonable.

I agree with this. I have no question about the Framingham data
themselves. I think we\'re all in agreement that there\'s a two to three
millimeter mean increase in blood pressure. So, that would say \"well,
if you took the drug for eight years and it sustained that level, then
you would expect these kinds of risks per million.\" This change from
here in the before drug to the three millimeter here would come out \--
it\'s hard to get that on a yearly basis because this would change with
the age of the women. But if I do it just dividing by eight, basically,
we\'d come out into an increase in risk of about one in 6,000. You\'d
have an increase in coronary heart risk. And you\'d have added on to
that, whatever other vascular disease risk beyond coronary that was
related to that. We\'ll try to get an order of magnitude of what this
means down to numbers that are easy to think about.

So, our big question is, okay, well that\'s what happens when the blood
pressure goes up from 80 to 83. Now, is the weight change, as reflected
through its lipid effects as shown up here \-- are we really confident
that that counterbalances this blood pressure risk? I submit that I am
not. The reason I am not is two-fold. One is, I don\'t see the other
evidence on intentional weight loss supporting the idea that intentional
weight loss, as it might be reflected in lipids and so on, really
produces these changes in mortality. That\'s not what the other evidence
says to me.

The other is that I don\'t see in the NDA data, and reviewing Dr.
Colman\'s review \-- now I\'ve seen the later submitted material but,
again, it has not been submitted in detail for review under the NDA. I
don\'t think the evidence for the lipid effect has the kind of
consistent and pervasive nature here. I think there clearly is a lipid
effect in people who lose a lot of weight. They\'re a relatively small
fraction of the total exposed population but all of the population gets
blood pressure effect. So, one \-- weigh two different categories of
information. Whereas here, they\'re entered into the regression models
if they have the same weight. That\'s my understanding. That if this
effect were counterbalanced by an effect the magnitude of which
pervasiveness and statistical significance that these were the same, why
then that\'s true in Framingham. But I don\'t think that there is a
pervasive effect shown up through lipids that\'s really a weight loss
effect that is in studies of people without prior comorbidity. I don\'t
think the preponderance of evidence supports the concept that this
counterbalances this, so I\'m left with this. And saying, \"well, we
could be talking about an increase in risk that would have a denominator
in the tens of thousands as opposed to the kind of increase in risk the
other drugs have been approved and have had a denominator in the
hundreds of thousands.\" So, I remain concerned about the issue of the
blood pressure effect in terms of the mean, but I think it\'s a
potentially solvable problem.

If we could go on to the next transparency? Whoops \-- let\'s skip that.
This is the calculations that were made from the Nurses Health Study
based upon the naturally occurring variations in weight. What would
happen if intentional weight loss using the drug produced those changes
and was maintained over the 16 years of follow-up in the study? I just
don\'t feel that there\'s a need to go into detail about that.

Okay, if we could go to the next slide? Yes \-- well, you\'ve seen this
before. We obviously have a certain enthusiasm for these data. And there
has been some questions about them. Maybe I can give my opinions on them
anyway.

Why are we focusing on this group? Well, because they lost a lot of
weight and they would therefore be likely to stay on the drug, okay?
These people \-- yes, they had changes in systolic, but they didn\'t
lose weight so, they\'re not going to stay on the drug. They\'d have a
short-term risk related to the blood pressure but it wouldn\'t go on for
a long time. That\'s why we focused on this group. The point here is
that it almost seems like to be a dynamic relationship between the
weight loss and the blood pressure increase, at least in this one cut.
Now that\'s not entirely true. There\'s quite a few stars over here and
only \-- a few more crosses, but not too many more.

The point in pointing this out is not to draw some ironclad end of the
road conclusion. In my opinion, what it says is that there needs to be
more work done on screening criteria with regard to the issue of there
being some people that look like they have substantial pressor
responses. There\'s a statement made in the NDA submission that they
didn\'t think there was very many people who had clinically important
blood pressure increases. I don\'t agree with that from what I\'ve seen.

It looks to me like the existing database, large database, could be used
to test blood pressure screening scenario. For example, simple ones that
have potential for being clinically useful: baseline resting blood
pressure, blood pressure at two weeks. Let\'s say if one sets some
scenarios, say a criterion of over five diastolic increase and/or over
10 systolic. If you made that cut and then you look at the residual
population, are you able there to really get out a group of people? You
have enough data to track that group. Say if you made that screening
cut, would that strand out a group of people who really are having a
clinically relevant pressor response?

Remember, you know, in blood pressure epidemiology, as I understand it,
it\'s just as important what your rise is from baseline here to here as
it is from here to here, in terms of the overall analyses. So, cut off
the deal with things like diastolic over 90 and systolic over 140.
Represent an older thinking about blood pressure than is currently
state-of-the-art.

So I\'d say if you take the database and you say, \"okay, what\'s your
baseline blood pressure? What\'s your blood pressure at two weeks?\"
Subtract them, run various scenarios that look at tradeoffs. Does that
identify and screen out? It\'s clinically practical. I think there\'s a
reasonable chance that using such data, one could identify a screening
strategy that was practical and that cut a chunk of the blood pressure
response out. That kind of thing then could possibly be tested in a
short, large, simple study that looks simply at the effect at, say,
eight weeks. How effective is that screening scenario? In other words,
generate the hypothesis from the data that are available and test it. I
personally think that sort of thing really needs to be done with this.
That\'s my response to the data.

My last comments I really would like to address \-- Dr. Spigelman and
his colleagues had come and met with us and we had what I felt was an
immensely productive discussion about the potential for a Phase IV trial
were this drug to be approved. I thought the suggestions made were
extremely good and I think that large simple trials have an enormously
valuable role in evaluating therapies including drugs. I do think, of
course, a lot of details would have to be worked out. This discussion
was August 30th, so it\'s really an end principle. But nevertheless, I
think it represents an admirable coming forward in statement and
principle towards a very valuable idea.

I do think myself that this blood pressure issue needs to be sorted
through more before then.

So, that\'s really the essence of my conclusions about this. I think
we\'ve got a rapidly growing marketplace for appetite suppressant drugs.
At present, we\'ve got a more \-- concern about the pressor effect and
its being pervasive than about there being a weight loss lipid effect
that really confidently from a model \-- that\'s enough and that
counterbalances it. I think there is good reason to believe that with
some more work on the existing database that a practical hypothesis
could be developed for blood pressure screening which could be fairly
rapidly assessed in a fairly simple study and might well get this then
into shape to say, \"if you do these things\" and they\'re simple enough
to be done in widespread practice, that the benefit/risk tradeoff would
be considerably improved.

Lastly, were that to occur and then the drug were approved, I would, of
course, greatly support the idea of a large Phase IV trial. Thank you.

CHAIRMAN BONE: Are there questions from the Committee for Dr. Stadel?

Dr. Kreisberg?

DR. KREISBERG: Dr. Stadel, it\'s my understanding that the Williamson
study was an observational study and there was nothing \-- it was a
prospective study but it was not randomized. As a result of that, there
could be confounding factors that lead to the observation that there was
a reduction in mortality in those women with coexistent medical problems
who intentionally lost weight, such as other healthier practices that
they may have had.

I just wonder if you recall from reading that article, were all the
confounding issues excluded as a possible explanation?

DR. STADEL: I thought they were pretty \-- it is an observational
follow-up study. I guess in terms of hierarchy of rigor, I would say
randomized trial first, observational follow-up study second, and
synthetic model third. Yes, it\'s an observational follow-up study.

I think the way that that issue was approached was pretty good. There
are two levels. One was stratification on baseline history with clearly
different results in study using the same methodology for those two
groups. That is, those that had a history of baseline were analyzed.

Baseline obesity related health conditions were analyzed as one group.
Those that did not were analyzed in as a separate group. The results are
different. The study methodology in the two groups was the same. The
finding is specific to obesity related cancers and to diabetes related
death. It\'s not pervasive across all causes of death which is what I
might expect if there were uncontrolled residual confounding.

Also, in addition to the stratification on baseline history, there was a
good deal of covariate data taken in the history that was used for some
fairly extensive regression modeling. It didn\'t change much of the
conclusions. It\'s always kind of comforting when you do these things
\-- if you take these kinds of studies, if you take the crude and you do
regression modeling on possible confounders and it doesn\'t change much.
It\'s always possible, but there\'s some point at which you get tired
and you say, \"well, it looks like that\'s probably true.\"

Lastly, after stratifying on the baseline history, they omitted the
first three years of mortality follow-up precisely to get away from
things that were related to uncontrolled confounding during that period.
So, I think on a big brush stroke, on a big picture thing, I\'m
reasonably comfortable that it\'s a pointer in the right direction. I
think like with all these big observational studies, you trade
generalizability and size for precision. That\'s a tradeoff.

CHAIRMAN BONE: Other questions from the Committee concerning the content
of Dr. Stadel\'s presentation?

The Chair has a question. It\'s a similar question to the one I\'ve
asked a couple of other times. I keep hearing this figure of two or
three millimeters of mercury increase in blood pressure as the estimate
of the pressor effect. But when I look at particularly the larger
studies \-- and particularly the 852 study which is by far the largest
study. It also accounts for the long-term observation in the extension
\-- it looks to me as though the pressor effect may be somewhat larger
if one confines oneself to the doses that are likely to be employed in
clinical practice.

Did you analyze this from that perspective, or has anyone else in the
Agency made any kind of formal estimate of the pressor effect based on
likely clinical dosage?

DR. STADEL: I think that the answer is I didn\'t. My focus here has been
on \-- you have a mean increase. It could be three millimeters. It could
be four millimeters. It\'s more important to me to say is there a
meaningful path towards a screening procedure that gets out of group.
Then if you subtract them out and recompute the mean, you can play that
against your model on the mean.

So, my focus in the time I\'ve had available has been to try to say what
can be done here to separate \-- it looked pretty clear to me that there
is a blood pressure responding group with all \-- some people don\'t
agree with that and that\'s what I see. So, that\'s where I put the
focus of the attention. I guess I\'d want to say if the mean in that
study was four or five, again, the question to me becomes if you take
those data and you run some screening scenarios, and you look at what if
I strip out this response group? \-- and there\'s still a group in which
the drug is working well and it\'s a matter of, like with so many
things, of screening out some people for whom a particular treatment
isn\'t necessarily the right thing and saying for the residual group,
are you getting that mean down somewhat? That is the direction I went.

So, I have not looked study-by-study to say was there significant
variation in the mean because I personally think the more important
issue is the other end.

CHAIRMAN BONE: It does have an impact on the magnitude of effect
predicted in these models though.

DR. STADEL: I agree with that.

CHAIRMAN BONE: Thank you.

DR. STADEL: And it makes quite a bit difference if you go from two to
four and you don\'t have any counterbalance. Then you\'re talking
instead of one in 6,000 in here, you\'re talking one in 3,000. It\'s a
big absolute risk \-- I don\'t want you to think that I\'m diminishing
the point, I\'m just trying to answer \--

CHAIRMAN BONE: But you haven\'t addressed that systematically?

DR. STADEL: \-- what I focused on.

CHAIRMAN BONE: Right. Thank you.

Okay, other questions from members of the Committee?

Fine. Then we\'ll go ahead. In addition to having presentations \--

Thank you very much, Dr. Stadel.

In addition to having presentations by members of the Agency staff, we
also have a guest member and consultant. Dr. John Flack, who is sitting
here, as I mentioned, as a guest member and consultant with the
Committee will make a presentation on the hypertension aspects of this
problem as well.

DR. FLACK: Can you hear me in the back? Okay.

Can I have the first slide, please?

I want to clear up one thing before I start and that is, I\'m not a
surgeon. I\'m not a person who goes in and tucks stomachs out and makes
people lose weight or stuff like that. I\'m actually an internal
medicine doctor, cardiovascular epidemiologist and hypertension
specialist. My perspective is going to be, really, taking one foot on
the more global approach, thinking about the entire group of patients
and risk in an overall group of people who have received this drug, as
well as more high risk approach. Can you screen out individuals who
might be harmed or might not receive benefit from the more clinical
approach. I\'ll have a foot in both camps.

This is a tremendous problem. My talk today is really not to go back and
rehash a lot of numbers. I\'m going to really synthesize what\'s been
said because virtually everything that you need to have seen to
understand what I\'m going to tell you, you\'ve seen, maybe with the
exception of one slide which I apologize for not having made.

I live in a region of the country where obesity is rampant. Seventy-two
percent of African-American women in the Southeastern part of the United
States in the stroke belt are overweight. I live in a state, North
Carolina, where physical activity ranks last in the country. We\'re
actually 49th. The only reason we weren\'t 50th is because Rhode Island
didn\'t report. We\'re also maybe the vice capital of the world outside
of Las Vegas too, because we make a lot of cigarettes.

So, I am very familiar with the clinical problem as well as the
epidemiologic problems with obesity. Clearly, obesity influences
hypertension and influences blood pressure, and affects certain
populations more-so than others. As a clinician, I am very, very
interested in the ability to treat obesity with safe and effective
therapies with more than just behavioral modification, which does work
but is tough to actually implement over the long-term.

Well, there\'s some major questions that got in my review of this
extensive amount of data that was supplied to me. I actually consider it
a privilege to have had the opportunity to do it because it was very \--
it was a lot of information and it was, I think, a very important task.

The first question is, is the pressor effect of sibutramine clinically
relevant? Certainly not for everyone. In a population, even a two or
three millimeter mercury shift may be significant. In a clinical
setting, that\'s not going to be relevant for all the patients. But for
a subset of patients, people who are not necessarily at the central
tendency of blood pressure change but are in the outliers, it may be
very important.

If so, in what patient subgroups would you wish to avoid this effect?
Some of what I\'m going to say today really is predicated on the
assumption that if the drug were to be approved, how would I like to see
it used and labeled, and what I think is reasonable based on what we\'ve
seen. Because some of the decisions we\'re going to have to make, we
simply don\'t have information at this point in time on certain
subgroups.

There\'s several manifestations of the pressor effect that you can
demonstrate with sibutramine. The first is increased resting blood
pressure, clearly a dose related phenomenon. Both systolic and diastolic
pressure tend to go up. Now, there\'s been a lot of talk about the
ambulatory blood pressure, problems with the machine, random error and
problems with dependability of the machine that was used in the very
small ambulatory blood pressure studies.

I would agree with Dr. Bone that random variability should simply affect
both groups and not one group preferentially over the other. Therefore,
it shouldn\'t really create systematic differences between groups. In
fact, random variability in a study usually kills study power and blurs
differences. And so, the differences that we saw in ambulatory blood
pressure which in some hours of the day were in the double digits,
higher on sibutramine, are a cause for concern and further study.

The amelioration or the attenuation of the nocturnal fall in blood
pressure is as well an issue that was surfaced in the ambulatory blood
pressure monitor studies, again, with the stated problems and with the
device and the study design. Again, this is something that did come out.
When we\'re treating high blood pressure, certainly one of the things we
want to do is control the pressure throughout the 24 hour period of
time.

Now, there\'s data discussed by the sponsor \-- are the blood pressure
change distributions by the sponsor discussed and there\'s a talk that
it\'s a shift of the distribution, a blood pressure change to the right,
which would give you a small average increase. Certainly that does
occur, but there\'s something else that happens with the drug that\'s
going to have direct clinical and practical implications. And that is,
not only is the distribution shifted but there\'s a dose dependent
flattening of the distribution with an increasing size of the right
tail. Basically meaning that if the distribution of the blood pressure
change looks like this and this is a zero change and it\'s shifted over
a couple millimeters of mercury, what we\'re basically seeing is that
with giving the drug, the right part of the curve gets fatter and you
get more outliers along with that, giving it a central tendency.

That gets you to the more high risk strategy that makes that important,
and how do you identify these patients who are likely to have sizeable
increases in blood pressure who you clearly up front, wouldn\'t even
want to be exposed to the drug. People who it might be worth taking that
risk, how do you identify them and monitor them once they\'re on
therapy?

What are the implications of this right tail shift in the blood pressure
change distribution? To me, what it really means is that the random
variability of the blood pressure is occurring at a higher absolute
level. That\'s not terribly exciting, but true. The variation in blood
pressure from looking at the distribution curves or the change curves
really is still random. But it actually is more often in an upward than
in a downward direction, particularly as you push the dose up and
flatten the central tendency and make the increase a part of the curve
fatter.

In the material, the editors talk about outliers at three standard
deviations \--

CHAIRMAN BONE: Just a short intermission while we\'re correcting the
microphone.

DR. FLACK: There\'s talk about three standard deviations. Probably a
more routine definition of an outlier is two standard deviations. Two
standard deviations away from the central tendency, you\'re pretty much
sure that that kind of change \-- whether it be an increase or a
decrease \-- is not random and does not belong to what we call the zero
change distribution. Those are people who are true outliers.

If you took everyone in here as they walked out of the room, measured
their blood pressure today, brought you back a week, a month later and
measured your blood pressure again, we would see a change distribution
that would be bell shaped, okay? It would be greatest around zero, the
zero change distribution. But if you were two standard deviations or
more away from that zero change distribution from the central tendency
of that, then we would call you an outlier. Certainly, this is an
epidemiologic and statistical principle that the frequency of true
outliers is related to the central tendency. There\'s also an
exaggeration of the effect out in the tails where there\'s smaller
numbers of people that are having larger changes that we would be
concerned about.

The epidemiologic risk/benefit of the analyses, I think the models
themselves, the Framingham data, is a very valid data set. The analysis
is fine and is certainly the appropriate methodology to look at the
overall impact. Not to identify high risk people, but to look at the
overall impact. One shortcoming of the Framingham data is obviously
they\'re not meaning minorities. The risk functions are likely to be
different, but still, I believe it\'s a valid population to make
estimates from.

I do though think that the information included in these models with the
improvement in the lipid profile with weight loss, really, across the
studies is not consistently observed. So, I would agree with the
previous speaker than Framingham estimates really should be redone
without the favorable changes in lipids included. Because there\'s
clearly not a demonstrable benefit across the studies in the lipid
profile. That will change some of the tradeoff risk estimates that were
made.

Now, here\'s what I\'m going to extrapolate because there\'s really not
a lot of data based on the clinical trials to make these firm \-- you
can\'t go to the bank with this, but you can know from your experience
as a clinician in understanding the pathophysiology of disease or people
who are likely to not do well with a pressor effect from a drug or from
activation of the sympathetic nervous system. You could really come
across several disease categories that you\'d be concerned about.

One, I would be definitely concerned about poorly controlled
hypertension. The sponsor mentioned this and it\'s very appropriate. I
would suggest that anyone with a systolic pressure over 160 or a
diastolic over 100 or both who fit what we call stage two hypertension
\-- have anything above stage one hypertension \-- this drug really
should not be used in them. Patients with known coronary artery disease,
angina pectoris. Certainly a lot of patients have a calcoronary disease.
You\'re more likely to have it the older you get. But if you have known
coronary artery disease, I believe that that is a very clear marker for
caution, or perhaps even a contraindication.

Congestive heart failure is very prevalent amongst the elderly. So is
obesity. Congestive heart failure is clearly a disease state where
activation of the sympathetic nervous system is problematic. Mortality
reduction in many studies is related to the sympathetic nervous system
suppression. Does that mean that sympathetic nervous system suppression
is causing it? No. But we do know that the more uncompensated congestive
heart failure is, the higher the activation of sympathetic nervous
system is. So, it would make sense in those patients not to overload the
ventricle with the pressor response and/or an increase in sympathetic
nervous system activity which is already high in this group.

Patients who have had stroke or TIA \-- again, I think would be a
cautionary group. I\'m not suggesting that every condition up here is an
absolute contraindication, but I think these are the conditions that
should be in the discussion when contraindications are derived and
labelling is being decided. Cardiac tachyarrhythmias clearly are a group
of people \-- perhaps even atrial tachyarrhythmias as well as
ventricular arrhythmias \-- the drugs should either be avoided or used
with extreme caution.

Now, diabetes \-- said earlier didn\'t appear to be any specific harm
with the drug in diabetic patients, but what was evident to me in the
studies that were provided was that the efficacy appeared to be less in
the diabetic population. Dr. Sherwin pointed out this morning to me that
in diabetic patients, there\'s already a concern about sympathetic
nervous system activation. So, you would not want to necessarily
undertake the use of this drug if there\'s not a proven efficacy there.
A select few patients with hyperthyroidism as well, you would not want
to activate the sympathetic nervous system.

My final slide, in conclusion \-- I maybe even going to go a little bit
further and try to tie all this together. I think that the total daily
dose of sibutramine should be 20 milligrams per day or less and 15
milligrams per day or less would be ideal or preferable to that. Because
a lot of the things that you see with the blood pressure are dose
related. There\'s a dose related flattening of the curve \-- more
extreme values are going to be seen at the higher doses. And yes, there
is an increase in efficacy but it\'s a tradeoff. It\'s a balancing of
making the drug available for people who have a very important problem.
I\'m not trying to say that all of the benefits have got to be
cardiovascular, but trying to prevent harm from certain people who might
experience cardiovascular problems.

The number of conditions for which this drug is contraindicated should
really be expanded, in my view, based on what I\'ve seen in the NDA
submission. More investigation into the effects of this drug on
ambulatory blood pressure should be performed. Future studies really
should standardize blood pressure medication dosing, look at peak trough
ratios, which are very important we believe in evaluating the efficacy
of anti-hypertensive agents. I would echo the comment made earlier about
studying African-Americans, Hispanics, and if possible American Indians
because each one of those populations is disproportionately affected by
disease. This is not about being politically correct or anything. This
is about really providing clinicians with the kind of information
that\'s needed for subgroups when these drugs come to market.

Because if you come to my practice in Winston-Salem, North Carolina, a
lot of the people who are going to be asking for this drug \-- yes,
there will be White women and maybe a few White men, but a lot of
African-American patients. I live in a town that\'s 40 percent
African-American. I think we can make the same kind of statements for
Hispanics and American Indians. I think for the sponsor, it was a very
important market for them as well. So, I\'d like to see that data and
not just referred to, but actually presented to us where we can look at
dose response cards and look at efficacy.

You know, for blood pressure drugs, there may be differences in dose
response curves. It doesn\'t mean the drugs don\'t work across different
groups, but there may be differences in dose response curves as well as
modifying factors that influence dose response.

Finally, I\'d like to make a strong pitch for more work to be done in
older people. Older people are going to have a lot of conditions which I
would believe that may cause us to at least use a drug with caution. And
as well, older people in this society are becoming increasingly obese.
There\'s a lot of overweight older people. Less than one percent of the
available database in the submission that I saw was from people, I
believe, over 65 years of age. I think beefing up the database there
would be important.

So, what I tried to do was to really give you an overview as a clinician
as well as a clinical researcher with one foot in both camps, and
provide you a balanced view of what I really thought should happen with
this drug. My impression of this drug was that it clearly lowers \--
reduces weight. There are some issues though with blood pressure that
are going to be much more magnified in subsets of patients. But it
doesn\'t negate the fact that yes, even in the overall population, the
two to three millimeter mercury shift will be an issue but it\'s not the
immediate clinical issue that it is in subgroups of patients that I
described. I think we should focus there.

Thank you very much for your attention.

CHAIRMAN BONE: Are there questions from members of the Committee for Dr.
Flack concerning his presentation?

Dr. Illingsworth?

DR. ILLINGSWORTH: Would you also potentially add peripheral vascular
disease, recognizing that patients with coronary disease often have
peripheral vascular disease?

DR. FLACK: Yes. Yes, your point is well taken. That was inadvertently
left off. People with peripheral vascular disease could potentially be
harmed by the pressor effect as well as by raised blood pressure.

CHAIRMAN BONE: Dr. Kreisberg and then Dr. Marcus.

DR. KREISBERG: John, you mentioned it but you passed over it pretty
quickly. It seems to me that you\'ve identified obvious cardiovascular
risk factors but there are many people who are asymptomatic who actually
are at very high risk for events because of multiple risk factors \--

DR. FLACK: Right.

DR. KREISBERG: \-- sort of on the threshold of an event, but not yet
there. I just wonder whether you thought that you should expand your
recommendation to include those?

DR. FLACK: Well, certainly you can say that the people who have these
conditions and peripheral vascular disease are patients you\'d want to
avoid the pressor or the SNS effects of the drug. There are clearly
people who have these problems that we don\'t really know in clinical
practice.

I guess that\'s what you\'re getting at, people who maybe have multiple
risk factors or high risk for vascular disease but yet have never
declared themselves clinically. I think you have to use the drug there
with more caution. I\'m not saying you don\'t use it in those patients
who haven\'t really declared themselves because ruling out something is
probably one of the hardest things to do in medicine because there\'s
always one more task you can do in a widespread, even a clinic
population. Watch for screening of people, say, with echoes to make sure
they don\'t have heart failure is probably not going to be feasible to
do.

So, I think that\'s where clinical judgment is really going to come in
and I\'m not sure that that can be well proscribed from here but should
be discussed.

DR. KREISBERG: Well, it seems almost like a paradox that the people who
are at the least risk are the best candidates and the patients who are
at the greatest risk who might derive the most benefit, if there is
health benefit of weight reduction, are the ones that you\'re less
inclined to use it on.

DR. FLACK: Yes. There is a paradox. I guess the main benefit of the drug
is weight loss. For all the psychological and feelings of well being and
all that that brings \-- produces discrimination and things like that.
We focus on the cardiovascular effects but the cardiovascular effects
are probably limiting the use of the drug in some of the higher risk
people.

But you\'re right, the primary benefit for weight loss and where you\'re
going to use the drug where the competing risk and benefits of the drug
are going to get you into least trouble are those who are at the lowest
risk.

DR. KREISBERG: Thank you.

CHAIRMAN BONE: Dr. Marcus had a question.

DR. MARCUS: I didn\'t notice in the NDA materials. Has anybody looked at
an interaction between smoking and the hypertensive effect? Do we know
anything about that?

DR. FLACK: I don\'t know. I think you\'d have to ask the sponsor about
that. I honestly don\'t know the result on that.

Kind of as a follow-up to that, there also may be differences in blood
pressure drugs which influence sympathetic nervous system activity in
one direction or the other versus those that don\'t. Again, I don\'t
know that information. Maybe the sponsor does.

CHAIRMAN BONE: I\'m just going to ask Dr. Spigelman to specifically
answer, if he has the information, on interaction with smoking. If you
don\'t, you don\'t.

DR. SHERWIN: Or caffeine.

CHAIRMAN BONE: And what about with caffeine?

DR. SPIGELMAN: No.

CHAIRMAN BONE: The sponsor states that they have not looked at those
interactions specifically.

Are there other questions for Dr. Flack from the Committee?

Thank you very much.

DR. FLACK: I\'d like to make one final comment.

CHAIRMAN BONE: Oh, yes, please.

DR. FLACK: I don\'t know if I said this or not but clearly, in addition
to the subgroups I\'ve proposed that ought to be looked at in further
detail, the ambulatory blood pressure monitor studies definitely need to
be reconstituted and redone as well because I think there are some
issues that were raised that we\'re in limbo about.

CHAIRMAN BONE: Thank you.

Dr. Colman, can you tell us when \-- or perhaps the sponsor can \-- when
was the ambulatory blood pressure monitoring study completed? When was
that completed? All I need to know is the date.

DR. SEATON: 1991 it was done.

CHAIRMAN BONE: Thank you.

Oh, Dr. Sherwin?

DR. SHERWIN: Time, let\'s get to that, yes.

CHAIRMAN BONE: Okay, the time has come for discussion for discussion
amongst the Committee. Just to clarify one point, Dr. Flack and Dr.
Zawadzki are both here to participate in the discussion but are not
members of the Committee as it stands, so will not vote. But they are
invited to participate in the discussion with the regular Committee
members.

I\'m going to just briefly summarize the four questions that the
Committee will be asked to vote on. We\'re going to discuss for however
long it takes amongst the Committee. Then we will vote on each of these
questions in turn. The Committee members will be asked to vote yes or no
on each of these questions based on the data in the NDA, based on the
data that have actually been submitted and reviewed. The Committee
members may wish to add additional comments about what additional data
they would need or what might modify their position if the data became
available but we will be voting the established data.

The four questions are firstly, does sibutramine meet the guidance
criteria of effectiveness for weight loss? Secondly, is the pressor
effect of sibutramine clinically important? Thirdly, do the benefits of
sibutramine outweigh the risks? Fourthly, if sibutramine were to be
approved for marketing, should there be a Phase IV study? And I presume
that people will be asked to briefly comment on what they thought the
elements might be in light of prior discussion.

I\'m now going to open the floor for discussion and comments on any of
these issues by members of the Committee. It seems that there is not a
dispute about whether there is a pressor effect. That seems to be
established through some discussion about the other implications here
that we have before us.

Perhaps what we might do if the Committee is agreeable is just go around
the table for comments to get the discussion going. Perhaps we\'ll start
with Mr. Molitch.

DR. MOLITCH: You mean on question one?

CHAIRMAN BONE: No, you\'re not confined to the structure of the
question. This is a general discussion at this point. You\'re certainly
welcome to discuss any points that have occurred to you or you can pass
if you want to and talk later.

DR. MOLITCH: I don\'t think there\'s any question, at least in my mind,
about the effectiveness of the drug for a substantial portion of the
population. I think the pressor effect is of concern. Actually, one
thing that did occur to me as I was listening to this on one area that
was really not addressed very much today but in some of the materials
that we were sent were some of the comparison studies with
dexfenfluramine. Looking at the weight loss studies, I was actually
interested to know what happened to blood pressure in those studies in
the placebo versus the sibutramine studies, versus the dexfenfluramine
studies? Did the blood pressure rise in the dexfenfluramine treated
studies in those comparison studies? Do we have that information?

CHAIRMAN BONE: That\'s a specific question for the sponsor which we\'ll
ask them to answer very concisely.

Do you have the data and what was the result?

DR. KELLY: I don\'t have any data to show you but I can tell you that
the blood pressure changes on sibutramine and the two dexfenfluramine
studies were consistent with the overall blood pressure changes in the
overall database. The patients on dexfenfluramine had small decreases in
both systolic and diastolic blood pressure and in heart rate.

CHAIRMAN BONE: Thank you. Very concise.

Let\'s see, Dr. Zawadzki, perhaps you\'d like to comment in general at
this point? Do you have anything that you\'d like to introduce into the
discussion?

DR. ZAWADZKI: I have a question I\'ve been wondering about as we\'ve
been discussing here. This is a drug that potentially would be approved
for chronic use, but we know that most people do not take medication
indefinitely. One set of data that I have not seen is what happens to
blood pressure after discontinuation of the drug, specifically to those
individuals in whom blood pressure becomes elevated during the use of
the drug?

CHAIRMAN BONE: I think it\'s a very interesting question. Can the
sponsor specifically answer that exact question? In patients who
experience an increase in blood pressure on drug, what happens to the
blood pressure when it stops?

DR. SPIGELMAN: It goes down.

CHAIRMAN BONE: Thank you.

Does it go back to baseline?

DR. SPIGELMAN: We have variable periods of follow-up. By three months,
certainly it\'s back to baseline. By one month, it was almost there.
We\'d have to go through the data to give you the details.

CHAIRMAN BONE: Thank you.

Dr. Kreisberg?

DR. KREISBERG: Well, I don\'t know how much of the comments will
actually relate to the questions or not.

CHAIRMAN BONE: It doesn\'t matter.

DR. KREISBERG: I have a question for the sponsor. That is, do we have
any data on plasma catecholamines during the course of the
administration of sibutramine acutely to patients to get a sense of the
magnitude of the change, if any? Or urinary metabolites?

DR. SPIGELMAN: Could I just introduce Dr. Danforth whom we\'ve asked to
look at that specific question, or to look at that area and some of the
diabetic related questions?

DR. DANFORTH: This is an interesting question. One might expect that a
drug that causes a reuptake block of norepinephrine might actually
produce an elevation of circulating concentrations of norepinephrine
depending on the degree of the block. The company has done five studies
to look at this issue. If I could have the red carousel number 17?

CHAIRMAN BONE: Okay, please be extremely concise.

DR. DANFORTH: Well, the bottom line is, in the five studies \--
concentrations of norepinephrine, epinephrine, dopamine were measured
and were not different from placebo. And there were two studies in which
urinary event mandelic acid was measured and in both of those studies
the actual values were lower in the drug treated versus the placebo.

CHAIRMAN BONE: All right, thank you.

Urinary, epi and norepi as well, were they also measured?

DR. DANFORTH: They weren\'t measured.

CHAIRMAN BONE: Thank you.

DR. KREISBERG: I\'d like to just modify the presentation of the sponsor.
I think they used the modifying word \"very effective\" in talking about
medication. I think it\'s mildly effective. I think it is comparable in
its effect to dexfenfluramine which is also mildly effective contrary to
what the press seems to think about dexfenfluramine.

I\'m concerned about the issue of the Phase IV study. I think you said
we could have the opportunity of commenting on what we think it ought to
include. I think I can tell you what it should not include and I don\'t
think it should include the study as proposed by the sponsor. I have a
great of difficulty with there comparing their drug to another mildly
effective drug that is by no means the goal standard for promoting
weight loss. That drug has never been demonstrated to have any effect on
the clinical endpoints. It seems to me that that\'s more of a marketing
strategy than it is a real interest in determining whether there\'s a
difference or a benefit from weight reduction on cardiovascular
endpoints.

CHAIRMAN BONE: Thank you.

Dr. Stadel, did you have something short to add to that?

DR. STADEL: Yes, I\'d like to make a short comment in response to the
evolving thing here. The only pressor that I\'ve been involved with is
the Phase IV trial of metformen where the comparison is the standard of
care. You either add metformen randomized or you manage the patient as
you would otherwise. To some degree, I think one can see this as along
dose-wise. That is, what is required of a company in using a Phase IV
trial to compare their drug to the safety \-- I think there is an
argument \-- to the safety of currently approved therapies.

DR. KREISBERG: I thought we were looking at efficacy. And the question
was whether lowering body weight would reduce clinical endpoints?
Therefore, we need a control group, don\'t we?

DR. STADEL: That\'s not the question for which the study was proposed to
me. It was proposed to me in response to our ongoing concern about
pressor effects and about whether this would convey a greater net risk
in the population than existing proposed therapy. It was a response to
that concept.

CHAIRMAN BONE: So, there\'s really two different objectives here. Dr.
Kreisberg is really addressing the objective of the effect of on
comorbid conditions and the overall health impact, and the other
addresses, let\'s say, a more circumscribed issue.

Dr. Critchlow, did you have a comment at this point?

DR. CRITCHLOW: Just at this point, I wanted to concur with Drs. Flack
and Stadel with respect to their analysis of the epidemiologic model.

Another quick question, given the titration schedule which I think is
good in keeping patients on the lowest dose possible, is there any data
to suggest that the approximately third of the patients who do not
respond to the ten milligram dose in losing four pounds in four weeks,
do they have the same probability of responding when they go up to 15 as
those initially put on the 15 and then 20?

CHAIRMAN BONE: That\'s an interesting question. Comments from the
sponsor were somewhat contradictory in the morning. One suggestion was
that patients who were started on the drug and didn\'t lose four pounds
in the first month should be discontinued. The other suggested that the
dose should be increased. Now, do we have specific information \--
specific information \-- on the likelihood of a response as a result of
dose escalation after four weeks?

DR. SPIGELMAN: I think the fact that I didn\'t come across clearly is a
problem that I really would like to clarify just to make sure that the
Committee understands what the position is, if I could?

CHAIRMAN BONE: Please.

DR. SPIGELMAN: The dose titration is geared both toward safety and
efficacy. It probably wasn\'t picked up but one of the overheads that
Dr. Seaton showed was that, in fact, if you look at elevation of blood
pressure as measured by a rise of ten millimeters or more in two
consecutive visits \-- which is perhaps arbitrary, but we feel more
clinically relevant than a single visit \-- the vast majority of those
are detected within four weeks of starting therapy. Seventy-five percent
of those patients who ultimately will have, during the course of the
total therapy, two consecutive visits where blood pressure rises either
systolic or diastolic by ten millimeters of mercury or more, can be
detected within the first eight weeks of therapy. Over 50 percent within
the first four. That was the overhead that Dr. Seaton showed.

The titration schedule is geared around enhancing both efficacy and
safety. So that, in fact, if a patient is noted to have an increased
elevation that is clinically not acceptable to the treating physician
\-- and in the vast majority of cases, those will be detected early. Not
at 12 months \-- then that patient should be discontinued.

CHAIRMAN BONE: I don\'t think that was Dr. Critchlow\'s question though.
Thank you for that information.

Dr. Critchlow\'s question was we\'ve had two proposals about what to do
with a person who doesn\'t lose at least four pounds in one month. One
is to discontinue the patient and the other is to increase the dose. The
information suggesting discontinuation seems to be clearer. The response
rate, we were very convincingly shown, was very poor if patients don\'t
lose four pounds in the first four weeks.

Is there any evidence that increasing the dose at that point is likely
to result in a response?

DR. SPIGELMAN: The evidence comes from the response curves in the
prospective study by subtracting what patients respond at ten versus
five, at 15 versus 10. We do not have a titration study in which we have
studied those patients who do go from 10 to 15, but we have no reason to
think that the data that gives subtracted differences \-- there is a
population who do not respond at 10. There is a population who do not
respond at 15, similarly at any dose.

CHAIRMAN BONE: So, your assumption is that the response rate at 15 minus
the response rate at 10 would be the incremental response rate?

DR. SPIGELMAN: That\'s correct.

CHAIRMAN BONE: But there\'s no actual trial of any kind to test that so
far?

DR. SPIGELMAN: That\'s correct. It comes from the data that we
presented.

CHAIRMAN BONE: Thank you.

Dr. Marcus, do you have questions or comments?

DR. MARCUS: Yes. Once again, it\'s on the issue of blood pressure. I
think that I\'m sufficiently concerned about that that I think a formal
and good study of blood pressure as a primary endpoint needs to be
undertaken. And I think it should be undertaken in a way that the usual
sorts of anti-hypertensive big trials would endorse. It should have
readings of supine sitting standing blood pressure. I don\'t know what
the current status is of what they call random zero readings to get out
\-- ways to get out the bias of the interpreter in reading the results.
To go into it in a formal and established method that the hypertension
community would accept.

Furthermore, there\'s many questions about interactions of this drug
with such every day events such as alcohol, anti-hypertensive medication
of various sorts, diuretics, caffeine, tobacco, probably a zillion
others that simply have not been addressed and need to be. The final
issue, once again, is to explore the interactions with blood pressure
and efficacy in an ethnically representative population.

Finally, I remember maybe a year-and-a-half ago when we had the first
meeting to discuss guidelines. I remember Dr. Bray saying, \"listen,
folks, if you\'re looking for these markers of cardiovascular risk,
that\'s not where the action is in the drugs we\'re asking you to
consider for these patients.\" That if the patients we\'re talking about
with profound obesity had those risk factors, they would have died.
We\'re talking about a completely different set of risks. We\'re talking
about sleep apnea. We\'re talking about the need to lose 40 pounds so
that a patient can undergo surgery.

Dr. Bray made a very eloquent and powerful presentation to focus this
Committee on that particular aspect of obesity. I haven\'t heard a
single word about that aspect of it in the entire presentation ever
since that meeting. It\'s kind of like that was it, you know? It\'s got
my vote. Then ever since then, it was completely ignored. I would make a
plea that we should consider also some of the aspects that were
contained therein.

CHAIRMAN BONE: Dr. New, do you have comments or further questions?

DR. NEW: Perhaps my comments will seem like being perseverant or perhaps
reflecting the fact that I take care of very young subjects in which
blood pressure is extremely variable. It really depends on whether the
child or adolescent is sitting, standing, supine, has rested for five
minutes, has had an anxious episode because blood has been taken, the
size of the cuff that\'s being used when the blood pressure is taken,
whether the child is screaming, performing a Valsalva maneuver and other
things.

I looked at the methodology for the measuring of blood pressure here and
it says that they used the Krackoff sound disappearance as the diastolic
and that the patient was seated for five minutes. I think that\'s a
better description than I read in most adult literature but \-- and
because I work in hypertension all the time, these factors are extremely
important.

Secondly, when I addressed Dr. Colman \-- and I seem to have lost my
mind because I wanted something in sleep \-- the fact of the matter is
that the way I would plot this data if I were doing this study is I
would plot the blood pressure and the several blood pressures at every
monthly period or visit to show the variability and the tracking of that
blood pressure. I don\'t know, for instance, whether the blood pressure
was lower at ten months than at 12 months. You really have to check
every individual in the blood pressure and to show the centiles that
he\'s in, and whether the centile comes up. Only then can you tell if
you have a blood pressure effect of this drug which is consistent.

I said it before. I think we need some sort of indication of the
standard deviation of the measurement and I don\'t see that.

CHAIRMAN BONE: Dr. Illingsworth?

DR. ILLINGSWORTH: I just echo the comments made concerning the proposed
Phase IV trial, that I would also have reservations about a comparison
with another drug, particularly if morbidity is going to be one of the
endpoints. Because I don\'t think in two years in a patient without
coronary artery disease, you\'ll get any difference in morbidity or
mortality. I think although you could make a case for doing it with an
active control, I think I would certainly endorse the need to do a
placebo controlled trial and to see what happens long-term. That\'s the
only way we\'ll find out what\'s the incidence of hypertension going up
substantially in subsets of patients or provide this kind of a study.

CHAIRMAN BONE: Thank you, Dr. Illingsworth.

Dr. Colley?

DR. COLLEY: I would echo Dr. Marcus\' comments as well in obtaining data
with patients using other substances that would increase blood pressure,
capping, smoking, other risk factors like smoking that will increase the
rate of hypertension that we don\'t have data on. Again, although the
subset may be proportionately small that people who have significant
increases in blood pressure, it\'s clearly a definite subset that does.
This is a drug that\'s likely to be used in much larger population than
simply the BMI greater than 27 as is indicated. For that reason, I think
the need to be vigilant as to the adverse effects is especially
important.

CHAIRMAN BONE: Dr. Sherwin?

DR. SHERWIN: I think one of the comments earlier I liked because it
really is \-- I think it was Bob who said it\'s a paradox that the
people who this drug probably would be best for, the people have the
least problems. The people with the most comorbidity perhaps, are the
poorest risk for this drug.

One of the problems with the people who have very few problems and have
obesity is \-- and the reason we think that they have higher risks of
hypertension and diabetes and dyslipidemia relates to resistance. This
is the underlying factor, we believe, that contributes to all these
other complications. I haven\'t heard anything yet about insulin
resistance, insulin action except for one study in some ob/ob mice which
clearly don\'t relate to human problems. So, this is a unique animal
model of obesity which probably doesn\'t relate to human disease at all,
which is a disease of leptin deficiency.

So, my feeling is, number one, I was struck by that absence of
information for me to assess people who were healthy and looking at
long-term problems. With respect to people who do have problems
currently, so far I haven\'t heard anything that diabetes has benefitted
and I\'m not sure that hypertension is benefitted. It seems to be
equivocal about lipids, although I\'m impressed that my gut feeling is
that there may be some tendency in that direction. Those are just
rambling comments.

The final point I\'d like to make is if we\'re going to have a long-term
trial, I do believe you need a control group.

CHAIRMAN BONE: What kind of control group?

DR. SHERWIN: I mean a control group with placebo.

CHAIRMAN BONE: Thank you.

DR. SPIGELMAN: Dr. Bone, if you do want, we do have some glucose insulin
data that addresses the issue. Obviously, we can\'t present everything
within the time allotted.

CHAIRMAN BONE: Is this human data?

DR. SPIGELMAN: Yes, this is from the clinical trial in the study
submitted in the NDA.

CHAIRMAN BONE: Okay, why don\'t you get that up very quickly while I\'m
making some additional comments \--

DR. SPIGELMAN: Yes, okay.

CHAIRMAN BONE: \-- and we can then respond to Dr. Sherwin\'s question or
comment.

I have, I think, the same concern as everyone else about balancing risk
and benefit here. Clearly, the drug does have a sufficient anorectic
effect to result in a reduction in body weight. But I think we have
uncertainties about the magnitude of the risk and the magnitude of the
potential benefits. I think the model system that was presented on
behalf of the sponsor took the most optimistic case on both sides.

It looks to me as though the magnitude of the risk, just based on the
blood pressure measurements from the trials, is at least two to three
millimeters of mercury and I don\'t think this has been systematically
analyzed. But when one looks at the largest trial and the longest term
experience, it appears that for the doses likely to be used clinically,
the magnitude of blood pressure increased maybe as much as twice as that
used in the assumptions which would substantially increase their risk
from hypertension.

One worrisome aspect of this is, it\'s extremely difficult in the clinic
to make much out of a five millimeter increase in blood pressure
measurement when we know you\'ve got a ten millimeter or so variability
on an individual measurement. This is the sort of thing that you can\'t
detect easily in an individual patient unless the magnitude is really
larger than that. At the same time, the evidence is that changes of this
magnitude do influence risk over time.

The other question has to do with the assumed favorable effect on
comorbidities. I think the problem here is that there was no sufficient
attention to the effect on these comorbid conditions as defined
endpoints in the clinical trials. That data were not collected in a
prospective and rigorous way and that may be part of the explanation for
the fact that there\'s some considerable variability and uncertainty
about that. Because we\'d like to think that weight loss would
consistently improve some of these things, although the data are not
consistent.

The assumption that was made in the model that was presented was that
the reduction in the total cholesterol would be about ten milligrams per
deciliter. Whereas, in the studies, actually, that is a little higher
than what I read from the sponsor\'s studies. Even small differences may
be important here. All of the comments that were made earlier about the
extrapolation limitations from intentional weight loss \-- and I would
also say that we might very well see a different kind of extrapolation
from weight loss induced by altered dietary practices and increased
exercise and weight loss that was as a result of an anorectic agent \--
to me make the calculation that the benefits would more than offset the
risk of the increased hypertension no more were certain than a
calculation showing that this would be a wash, or conceivably even going
the other direction. It would depend on an equally tenable set of
assumptions to support either case. So, those are the areas I have of
residual concern here.

Is the sponsor ready with their data on glucose and insulin?

DR. WEINSTEIN: Yes.

Dr. Steven Weinstein, Knoll Pharmaceutical.

Dr. Mendel already mentioned this morning that in diabetic patients on
sibutramine who lose weight, their fasting plasma glucose decreases.
This slide shows mean fasting insulin parameters in sibutramine treated
patients who lose greater than or equal to five percent of their initial
body weight. These are in patients who are not taking insulin. I need to
remind you that there were no patients in the placebo group who lost
this amount of weight. Fasting insulin in the sibutramine treated
patients who lost this amount of body weight decreased from a baseline
value of 21.5 milliunits per liter at baseline to 13.5 at week 12. This
is a decrease of eight units.

The fasting glucose, the fasting insulin ratio which may be viewed as an
index of insulin sensitivity \-- and an increase in this ratio would
indicate an increase in insulin sensitivity \-- this parameter increased
from baseline to week 12 by 5.2 units. In contrast, in the all placebo
group, fasting insulin as well as this glucose insulin ratio showed only
a modest increase. These data suggest an increase in insulin
sensitivity.

Can I have the next and last slide, please?

This slide shows mean glucose and insulin kinetic parameters during a
test meal in subjects for this study. These are basically in the same
subjects, sibutramine treated subjects not taking insulin who have lost
this amount of weight. The insulin area under the curve was about 31,000
at baseline. This decreased to 24,000 at week 12. This is a change of
about 7,000, a decrease of 7,000. The area under the curve for glucose
remained about the same, actually with a modest decrease by week 12. The
area under the curve for glucose divided by the area under the curve for
insulin, which is, again, another measure of insulin sensitivity,
actually increased from .18 to .23 at week 12, an increase of .05.

There were very modest changes in the all placebo group in this same
time period so we believe that this does suggest an increase in insulin
sensitivity in the sibutramine treated patients who lose weight.

DR. SHERWIN: Do you have data in non-diabetic individuals?

DR. WEINSTEIN: No.

CHAIRMAN BONE: I notice that you have groups of five and six \--

DR. SHERWIN: Yes, we\'re dealing, obviously, with small numbers of
patients in a selected population who had \-- the weight loss itself
presumably would have this kind of effect. You might have seen a greater
effect, for example, if they hadn\'t been on the drug and lost that same
amount of weight.

DR. WEINSTEIN: Right. I think the point is though, if the patients are
not on the drug, they don\'t lose the weight. There were no patients in
the study who lost that amount of body weight.

DR. SHERWIN: Well, I think that\'s fair.

DR. WEINSTEIN: And indeed, the effect of the drug on the comorbidities
is due to weight loss, not due to the drug itself.

DR. SHERWIN: I think when you look at that data on balance, it\'s really
up in the air at this point.

CHAIRMAN BONE: Did you look at insulin levels in the isocaloric patients
in the other study, where you\'ve maintained weight on drug?

DR. WEINSTEIN: No, not to my knowledge.

CHAIRMAN BONE: Okay, thank you.

Dr. Molitch?

DR. MOLITCH: Yes, can we go back to this last set of data? Did you try
to stratify the placebo patients for the same amount of weight loss as
the diabetes patients to see if there was any particular beneficial
effect of drug or detrimental effect of the drug for the same amount of
weight loss?

DR. WEINSTEIN: I\'m sorry. Can you repeat that again?

DR. MOLITCH: To stratify the placebo patients for the same amount of
weight loss, so that you have equal weight loss for placebo versus drug.

DR. WEINSTEIN: In this study?

DR. MOLITCH: Yes, in these last two slides you just showed us.

DR. WEINSTEIN: Right. There were no placebo patients who lost that
amount of body weight. Twenty percent of the patients on sibutramine
lost five percent of body weight by week 12. There were no patients in
the placebo group who \--

DR. MOLITCH: But you only had six insulin treated patients here \-- six
diabetic patients.

DR. WEINSTEIN: That group was the number of patients treated on
sibutramine who lost that amount of body weight, approximately 20
percent of the entire sibutramine treated group.

CHAIRMAN BONE: Did you match groups with equivalent but lesser degrees
of weight loss and do the same analysis?

DR. WEINSTEIN: We have not done that analysis.

CHAIRMAN BONE: All right.

Dr. Kreisberg and then Dr. Flack.

DR. KREISBERG: Well, I think if I\'m hearing all of this right, what
you\'ve compared here in these slides is patients who lost weight with
patients who did not lose weight. I don\'t think that gets to the
question at all.

CHAIRMAN BONE: Dr. Flack?

DR. FLACK: On the ambulatory blood pressure side \-- I\'d like to shift
gears a little bit \-- I would like to re-echo the comment that was made
earlier today about looking at blood pressures during exercise. Because
if you think about it, these are patients who were talking about losing
weight and they\'ll probably be enrolled in comprehensive programs, or
at least they should be. Exercise will be a valid part of that. Many of
them \-- more than a handful may elect to even go do resistance
training, or may not be cautioned not to do it at the health clubs and
stuff. So, I would certainly want to echo that.

Dr. Kreisberg made a comment earlier and he started me to thinking. In
the higher risk patients, particularly higher risk people with multiple
risk factors for ischemia, it might be worthwhile in some of the future
studies that are done to look at ambulatory ischemia along with
ambulatory blood pressure because actually, there are monitors now that
do both of those simultaneously. One of the major concerns about some of
these patients with multiple risk factors, or even people with coronary
disease, is that the blood pressure burden and the sympathetic nervous
system activity may increase the risk of ischemia. You\'re probably not
going to study enough people to actually count events.

So, ambulatory ischemia, along with the ambulatory pressure where you
can actually even relate the ischemia occurrence to the change in
pressure, whether it\'s followed or not, I think would be a
consideration in the design of future studies.

CHAIRMAN BONE: Other members of the Committee?

Dr. Zawadzki?

DR. ZAWADZKI: I would just like a point of clarification. The guidelines
that we have, granted, were written after submission of this IND, but
there are two points raised here that I would just like to clarify to
what extent we have the data.

One point is the demonstration that the weight loss is actually fat loss
in humans. Number two, that we have data going beyond 12 months.

CHAIRMAN BONE: I think the sponsor did one study with dual energy x-ray
absorptiometry, is that correct? And also, had a number of studies in
which circumference or girth was measured.

DR. SPIGELMAN: That\'s correct. I think the waist/hip ratio data was
presented. There is a DEXA study that is in the briefing packet that
also showed reduction in fat. Again, we can show that data if you would
like. I believe it is in the briefing document. Therefore, the weight
does come off from the appropriate areas.

CHAIRMAN BONE: Actually, I think you showed a reduction in mean body
mass but it was not as great as the reduction in fat mass, isn\'t that
correct?

DR. SPIGELMAN: Yes, I \--

CHAIRMAN BONE: Okay.

DR. SPIGELMAN: No. No, I\'m sorry.

DR. SEATON: One specific measurement in one group showed that in the
gynoid region, there was a slight reduction in lean body mass. Overall,
there\'s really no reduction in lean body mass.

CHAIRMAN BONE: Thank you.

Dr. Zawadzki, you had another part to your question. What was that?

DR. ZAWADZKI: The other point was extension of the data beyond 12
months.

CHAIRMAN BONE: Is there just the one 852 extension that goes longer?

DR. SPIGELMAN: That\'s right. And that 852 extension \-- we have not
discussed in detail. I think there were some misassumptions though that
were made in the earlier discussions about that, however. Specifically,
that the doses that were used in 30 percent of those patients was 30
milligrams. Over 100 patients were at 25 milligrams and that really has
an impact on the interpretation of the vital signs of those patients.
I\'m not sure that was clear from some of the discussion earlier.

CHAIRMAN BONE: Yes, I actually was looking at it by dose in the table
that was provided.

DR. SPIGELMAN: And also, there were breaks in therapy. Practically all
patients stopped because of just the design of the trial. Those were
pure safety trials. Or that was purely a safety trial. This is not
continuous data in terms of even beginning to try to interpret what was
one of seven centers.

CHAIRMAN BONE: All right, thank you.

Dr. Kreisberg?

DR. KREISBERG: I wonder if somebody could clarify for me whether the
Committee is asked to consider this drug for more than 12 months\'
therapy, or are we only considering it for 12 months\' therapy?

CHAIRMAN BONE: Dr. Troendle, would you care to comment on the question
of the duration of exposure?

DR. TROENDLE: Well, we would like to have longer studies but we don\'t
have them to deal with. We\'d like you to tell us what you think would
be suitable.

CHAIRMAN BONE: I guess Dr. Kreisberg\'s question had to do with the
proposed length of duration of use. As it stands, would it be
indefinite?

DR. TROENDLE: No, I don\'t think so.

DR. SPIGELMAN: Our studies clearly have only been done out to 12 months
in a randomized manner, and that\'s the data that we have at this point.

CHAIRMAN BONE: What claim do you plan to ask for?

DR. TROENDLE: And there\'s only one study that went to 12 months.

DR. SPIGELMAN: Two, the SB 1049 and the 1047.

CHAIRMAN BONE: The question I have is, are you pursuing a claim for a
year\'s treatment or for indefinite long-term treatment?

DR. SPIGELMAN: Again, similar to \-- we believe that the data that was
there on the drug dexfenfluramine, there was one study only for one
year. The data obviously can only speak to one year as far as in
labeling where there has been shown efficacy. That would clearly have to
be reflected in the labeling, in my opinion.

CHAIRMAN BONE: Obviously, there\'s no practical control over the
duration of treatment beyond the advice that\'s given in the labeling. A
physician is free to prescribe for any term.

DR. MARCUS: Mr. Chairman, I\'d like to move that we go on to voting. I
don\'t want you to lose your quorum.

CHAIRMAN BONE: Yes, thank you.

I think we\'re ready, unless there are further comments or observations
from the Committee members, to go through the questions. I certainly
appreciate Dr. Marcus\' concern.

We\'ll just go around the table in different directions and I\'ll vote
last, I guess, each time. Perhaps we\'ll start with Dr. Zawadzki on \--
excuse me, Dr. Zawadzki is a participant but not a voter today. So, we
can start with Dr. Kreisberg. As I mentioned earlier, I\'m going to ask
the Committee members to vote yes or no based on the data in hand. Then
to make additional comments briefly if they think it is necessary to do
so.

DR. KREISBERG: Yes.

DR. CRITCHLOW: Yes, based on the responder analysis but not by the other
criteria of greater than five percent difference between placebo and
drug.

CHAIRMAN BONE: Yes, Dr. Critchlow.

This is Dr. Marcus.

DR. MARCUS: Yes.

DR. NEW: Yes.

CHAIRMAN BONE: That was Dr. New and then this is Dr. Illingsworth.

DR. ILLINGSWORTH: Yes.

CHAIRMAN BONE: Dr. Colley?

DR. COLLEY: Yes.

CHAIRMAN BONE: Dr. Sherwin?

DR. SHERWIN: Yes.

CHAIRMAN BONE: Dr. Molitch?

DR. MOLITCH: Yes.

CHAIRMAN BONE: The Chair votes yes.

The second question is, is the pressor effect of sibutramine clinically
important?

Perhaps we\'ll start with Dr. Marcus for that.

DR. MARCUS: Well, I don\'t know the answer but I think I have to give it
the benefit of the doubt and say yes.

CHAIRMAN BONE: Dr. New?

DR. NEW: I can not answer because I don\'t think I have sufficient data.

CHAIRMAN BONE: Dr. New abstains.

Dr. Illingsworth?

DR. ILLINGSWORTH: Potentially yes in a subset of patients.

CHAIRMAN BONE: Okay, that\'s a yes?

DR. ILLINGSWORTH: Yes.

CHAIRMAN BONE: Thank you.

Yes, go ahead Dr. Colley?

DR. COLLEY: Yes.

DR. SHERWIN: Potentially yes in a subset of patients. Therefore, yes.

CHAIRMAN BONE: Okay.

Dr. Molitch?

DR. MOLITCH: Yes.

CHAIRMAN BONE: Chair says yes based on the data at hand, just as we were
talking about.

The third question is \--

DR. CRITCHLOW: I vote yes.

CHAIRMAN BONE: Oh, excuse me, Dr. Kreisberg. I am very sorry.

DR. KREISBERG: That\'s okay. It doesn\'t make any difference what I
vote, actually. But it\'s yes.

CHAIRMAN BONE: Dr. Critchlow, I\'m sorry. I confused myself with my
innovative order of voting. It just goes to show you.

Okay, I\'m sorry. So, that\'s a unanimous yes except for one abstention.

The third question is do the benefits of sibutramine outweigh the risks?
We\'ll start with Dr. Molitch answering this question.

DR. MOLITCH: I would have to say yes, barely.

CHAIRMAN BONE: Okay.

Dr. Sherwin?

DR. SHERWIN: Yes and no, because \-- it has on the patients. I would say
no. I don\'t have the data \-- can I just comment because I\'m not happy
about saying that.

My gut feeling is that we\'ve not been dealt a full card and that\'s
making it very hard. You would like, if nothing else, better data on the
ambulatory blood pressure. If I hadn\'t seen that ambulatory blood
pressure readings, I might have weighed the other way. Because I think
we could screen out more effectively, the individuals who might have a
subtle change and I\'m not sure that\'s so significant.

CHAIRMAN BONE: But unfortunately, we have to speculate about that, I
think. It\'s a question of what we have.

Yes, Colleen?

DR. COLLEY: I\'d say no based on the data that we have currently.

CHAIRMAN BONE: Dr. Illingsworth?

DR. ILLINGSWORTH: I\'d say yes, given to appropriate patients with
comorbid conditions. In other words, the patients need to be accepted
appropriately.

CHAIRMAN BONE: Do you have a basis for that selection at this point?

DR. ILLINGSWORTH: I would say the criteria that we have discussed
originally, a BMI of 27 with diabetes or hyperlipidemia who are at risk
\--

CHAIRMAN BONE: Okay, but \-- okay.

I guess we have a question here because that\'s not the indication
that\'s being sought.

DR. ILLINGSWORTH: Correct.

I still would favor yes.

CHAIRMAN BONE: Okay.

Dr. New?

DR. NEW: Yes, barely.

CHAIRMAN BONE: Dr. Marcus?

DR. MARCUS: Barely yes.

CHAIRMAN BONE: Dr. Critchlow?

DR. CRITCHLOW: I\'m going to have to be conservative and say no based on
the pressor effect, the inconsistency in findings with respect to lipid
reduction and weight loss, and the modest weight loss.

CHAIRMAN BONE: Dr. Kreisberg?

DR. KREISBERG: Dr. Bone, I would like to tell you that I have never
enjoyed these questions and I still don\'t enjoy these questions.

CHAIRMAN BONE: I don\'t either.

DR. KREISBERG: I don\'t think they\'re right. I don\'t think these
questions are framed properly. We\'re always stuck at this meeting with
these types of issues about yes and no for the same question. I think we
need to work better on the questions.

I\'ll have to vote no.

CHAIRMAN BONE: Have to vote no.

I take your point. The questions are \-- we\'re sort of to advise the
Agency and these are the questions that the Agency has asked us. Perhaps
we could have some further discussion with the Agency about the
questions perhaps in the future.

On question number three, based on the available data, I would have to
say no.

The fourth question is if sibutramine were to be approved for marketing
\-- now, this supposes at some point that the drug were approved.

I\'m going to add one comment since other people made comments to my
vote on number three. I would say that more information directly on the
subject of comorbidities would be extremely helpful and might result in
a different answer if the data were available.

Number four \-- if sibutramine were to be approved for marketing, should
there be a Phase IV study? And the implicit question is then, very
briefly, what would be your major comments on the character of that
study?

Perhaps we\'ll start with Dr. New.

DR. NEW: I think there should be a Phase IV study and I would like more
precise data on the variability of blood pressure, the comorbidities,
and some idea of compliance.

CHAIRMAN BONE: One of the design issues that came up earlier had to do
with whether this could be an open label study comparing with
dexfenfluramine. There\'s been some discussion of different perspectives
on that. Would you favor, oppose, or have no opinion on that particular
question?

DR. NEW: I don\'t think a comparison is necessary. I think it should
stand on its own.

CHAIRMAN BONE: Thank you.

Dr. Marcus?

DR. MARCUS: I agree that the appropriate comparitor arm would be a true
placebo arm. If the company wanted to go to the expense and have all
three arms, that would certainly be acceptable to me. But I think the
major comparison needs to be the placebo. In addition to the things that
Dr. New asked for, I just reiterate a rigorous attempt to evaluate blood
pressure.

CHAIRMAN BONE: Dr. Critchlow?

DR. REEDY: That\'s a yes?

CHAIRMAN BONE: That\'s a yes.

DR. MARCUS: Oh, yes.

CHAIRMAN BONE: Yes, with editorial comments.

Yes, Dr. Critchlow?

DR. CRITCHLOW: Yes, definitely. I just wanted to reiterate previous
comments on increasing the ethnic diversity in the group, making some
attempt to increase the people who stay on the drug for whatever period
of time because it\'s very difficult to evaluate these data, or the
validity of these data, given the approximate 50 percent completion
rate.

The other concern is \-- and I don\'t know if this is even possible \--
given that probably at least half, if not more, of the patients taking
the drug will be ones for whom are not according to the label. I don\'t
know if it\'s possible to get safety data, for example, in young women
who are not necessarily obese but on contraceptives, but there\'s
certainly a large population of people who will be on it for whom we
will have no other way to get data.

CHAIRMAN BONE: Thank you.

Dr. Kreisberg?

DR. KREISBERG: Well, I\'ve previously spoken to this point and yes, I
think a Phase IV study should be done. I think it should be a placebo
control study. I would certainly accept Dr. Marcus\' suggestion that the
company could add another arm if they wanted to compare it to
dexfenfluramine.

I\'m a little bit concerned, based upon the issues that Dr. Flack
discussed, as to whether or not the projections that the company has
already made on the numbers of patients is likely to give important
differences at two years, particularly if patients that are at high risk
for events are going to be excluded because they are, in fact, risky
patients. It would seem to me that their projections are wrong.

CHAIRMAN BONE: Let\'s see, Dr. Molitch?

DR. MOLITCH: Yes, I certainly agree with the Phase IV study or more than
one Phase IV study that will get at some of these issues, especially the
comorbidity issues. Because the drug, if it does get approved will, in
fact, be used in patients who do have comorbidities. I think we need to
find out that information sooner rather than later.

CHAIRMAN BONE: Let\'s see, Dr. Illingsworth?

DR. ILLINGSWORTH: I would endorse a Phase IV study, ideally placebo
controlled, so you can assess the efficacy, safety and comorbidity. I\'d
also suggest inclusion of patients with significant hypertriglyceridemia
who have most to benefit from treatment of dyslipidemia. Triglycerides
are a risk factor in women and in diabetics particularly, quite
strongly. The population who have been studied with dyslipidemia didn\'t
have significantly high triglycerides. So, it\'s not surprising that the
lipid changes are not very profound because a weight loss doesn\'t
really dramatically change LDL cholesterol.

CHAIRMAN BONE: Thank you.

Dr. Colley?

DR. COLLEY: Yes, and I would agree with the comments made previously
that it should be placebo controlled whether or not it has
dexfenfluramine as a comparison as well. And that it include the groups
that have a higher rate of hypertension in Native Americans, Blacks,
Hispanics, as well as older patients.

CHAIRMAN BONE: I think the need for Phase IV studies is manifest. It may
well be, as Dr. Molitch has suggested, that the large simple trial may
not be the answer to all of the outstanding questions, some of which are
vague by the fact that they weren\'t addressed in the trials done to
date, specifically comorbidities. I think some of the issues that my
colleagues have suggested must be addressed in placebo control trials
\-- could be addressed in placebo controlled trials that were more
narrowly focused and smaller in size. That would not necessarily require
the scope of study that was initially suggested by the sponsor in their
positive control trial.

So, there might be more than one way of getting at these issues. It
might be that the large simple trial, accompanied by a program of more
limited and focused studies, could be satisfactory.

Just a moment, please?

Oh, Dr. Sherwin. I\'m very sorry.

DR. SHERWIN: No, that\'s all right.

CHAIRMAN BONE: I\'m very sorry. I\'ve very sorry, Dr. Sherwin. When I
try to vary the sequence, occasionally, as everyone has noted, I get out
of order. I apologize.

DR. TROENDLE: I would like to ask for opinions from Dr. Flack and Dr.
\--

CHAIRMAN BONE: Can\'t hear you.

DR. TROENDLE: I\'m sorry. I wanted to ask for opinions from Dr. Zawadzki
and Dr. Flack on this last question in particular, even though they\'re
not voting members.

CHAIRMAN BONE: Certainly. Thank you very much. We\'ll do that.

Dr. Sherwin has voted.

DR. SHERWIN: Yes. We\'ve heard enough comment.

CHAIRMAN BONE: Okay. Then Dr. Flack and then Dr. Zawadzki.

DR. FLACK: On the issue of the Phase IV study, yes. What should the
control group be? I would number one, endorse that it be a placebo
control. If the sponsor wants to spend the money to add an active
control, that would be fine but at the very minimum, a two arm study.
One of them needs to placebo versus sibutramine.

Again, I\'d just like to reiterate that there should be sampling
procedures in place, or recruiting procedures up from, to ensure
adequate subgroups of patients, non-White patients in the study. An
additional thing I would do is encourage them to perhaps look at no
higher than 15 milligrams a day, but that\'s up to them.

CHAIRMAN BONE: Thank you, Dr. Flack.

Comments from Dr. Zawadzki?

DR. ZAWADZKI: I agree that a Phase IV study may provide some very useful
data, I think, particularly regarding some of the issues regarding
hypertension induced by the medication. I think the comments that were
previously made regarding careful measurements of blood pressure during
clinical use are very important.

I also agree that unless the studies are very, very carefully designed,
we may not find some of the real final endpoints that we would be
looking for.

CHAIRMAN BONE: Thank you.

Any additional questions from the Agency for the Committee? No?

Thank you.

All right, well, to summarize, in its 64th meeting, the Endocrinologic
and Metabolic Drugs Advisory Committee has reviewed the presentation for
sibutramine for the long-term treatment of obesity. The four questions
were answered by the Committee with all the comments and the Agency has
previously noted on a number of occasions that the comments are often
more important than the vote because of the nature of that process.

On the first question, the Committee voted nine members voting yes, that
the sibutramine met the criteria for effectiveness and none voting no.

On the second question, is the pressor effect of sibutramine clinically
important?, eight members voted yes and one abstained. Several of the
members voting yes commented that that was based on the available
information but that the clinical significance wasn\'t fully explored.

On the third question which was, do the benefits of sibutramine outweigh
the risks?, the Committee was closely divided. Four of the Committee
members voted yes, that the benefits outweighed the risks. Five voted
no, that the benefits did not outweigh the risks and there were a number
of comments to the effect that uncertainty about estimates of both
benefits and risks made this question particularly difficult.

The fourth question was, if sibutramine were to be approved for
marketing, should there be a Phase IV study? All of the Committee
members, nine, voted yes with a variety of comments concerning different
aspects that they felt should be considered.

I want to thank the sponsor for an outstandingly clear and cogent
presentation, and for the timeliness and cooperative way in which this
was handled. We really appreciate that very much.

I would like to thank the Agency for their presentations and close the
meeting at this point.

(Whereupon, the meeting was concluded at 3:18 p.m.)