UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

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CENTER FOR DRUG EVALUATION AND RESEARCH

GASTROINTESTINAL DRUGS ADVISORY COMMITTEE

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THURSDAY,

MARCH 6, 2003

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The meeting was convened in the Ballroom of the Holiday Inn
Gaithersburg, 2 Montgomery Village Avenue, Gaithersburg, Maryland, at
8:30 a.m., Michael Camilleri, M.D., Acting Chair, presiding.

[PRESENT]{.underline}:

MICHAEL CAMILLERI, M.D. Acting Chair

TOM PEREZ, M.P.H. Executive Secretary

SUSAN COHEN Consumer Representative

BYRON CRYER, M.D. Member

RONALD P. FOGEL, M.D. Member

JOHN T. LaMONT, M.D. Member

ROBERT A. LEVINE, M.D. Member

DAVID C. METZ, M.D. Member

MARIA H. SJOGREN, M.D. Member

[CONSULTANTS (VOTING)]{.underline}:

HOWARD McLEOD, PHARM.D.

RUTH HOFFMAN

MICHAEL PROSCHAN, Ph.D.

ZERUESENAY DESTA, Ph.D.

[MEMBERS OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE
(VOTING)]{.underline}:

DAVID KELSEN, M.D.

OTIS BRAWLEY, M.D.

[FDA]{.underline}:

GARY DELLA\'ZANNA, D.O., M.Sc.

FLORENCE HOUN, M.D.

VENKHAT JARUGULA, Ph.D.

ROBERT JUSTICE, M.D.

JOYCE KORBICK, M.D.

NARAYAN NAIR, M.D.

HUGO GALLO TORRES, M.D., Ph.D.

I‑N‑D‑E‑X

[AGENDA ITEM]{.underline} [PAGE]{.underline}

Call to Order, Introductions: 5

Michael Camilleri, M.D., Acting Chair

Meeting Statement: 8

Thomas H. Perez, M.P.H., Executive

Secretary

Opening Comments: 11

Robert Justice, M.D., Director

Division of Gastrointestinal and Coagulation

Drug Products

Merck Pharmaceuticals Presentation 14

Introduction 14

Dennis M. Erb, Ph.D.

Background and Rationale and Clinical 20

Pharmacology

Kevin J. Petty, M.D., Ph.D.

Clinical Efficacy 42

Kevin J. Horgan, M.D.

Clinical Safety 71

Scott Reines, M.D., Ph.D.

Summary and Conclusions 87

Scott Reines, M.D., Ph.D.

Questions and Presentations 92

FDA Presentation 132

Clinical Summary 132

Gary Della\'Zanna, D.O., M.Sc., Division

of Gastrointestinal and Coagulation Drug

Products

Biopharmacology Summary 149

Venkat Jarugula, Ph.D., Clinical

Pharmacology and Biopharmaceutics

Reviewer

Questions on Presentations 158

Open Public Hearing 182

I‑N‑D‑E‑X

[AGENDA ITEM]{.underline} [PAGE]{.underline}

Charge to the Committee 182

Robert Justice, M.D., Director, Division

of Gastrointestinal and Coagulation

Drug Products

Discussion of Questions 184

P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

(8:34 a.m.)

[CALL TO ORDER, INTRODUCTIONS]{.underline}

CHAIRPERSON CAMILLERI: My name is Michael Camilleri. I am the Acting
Chairperson for this Gastrointestinal Drugs Advisory Committee meeting.
We are going to be discussing today the new drug application, NDA
21‑549, on EMEND, which is aprepitant.

I want to remind the board members, please, to speak directly into the
microphone and to remember to switch the microphone off when you are
done with your deliberations.

The next item of business, really, is to invite the board members to
introduce themselves. So I would like to start.

DR. HOUN: Hello. I\'m Florence Houn. I\'m the Office Director for FDA\'s
Drug Evaluation 3 Office. Thank you.

DR. JUSTICE: Hi. I\'m Robert Justice. I\'m the Director of the Division
of Gastrointestinal and Coagulation Drug Products.

DR. DELLA‑ZANNA: Hi. My name is Gary Della‑Zanna. I\'m a medical officer
in the Division of Gastrointestinal and Coagulation Drug Products.

DR. JARUGULA: Hi. I\'m Venkhat Jarugula, clinical pharmacology and
biopharmaceutics on the NDA.

MS. HOFFMAN: Hi. I\'m Ruth Hoffman, patient advocate, National Director
of Candlelighters Childhood Cancer Foundation.

DR. SJOGREN: Hi. I\'m Maria Sjogren. I\'m a gastroenterologist and
hepatologist. And I work at Walter Reed Army Medical Center in
Washington, D.C.

MS. COHEN: I\'m Susan Cohen. I\'m the consumer member, and I just had a
colonoscopy.

DR. FOGEL: Good morning. I\'m Ron Fogel. I\'m a gastroenterologist,
division head at Henry Ford Health System in Detroit.

DR. CRYER: Good morning. I\'m Byron Cryer, member of the
Gastrointestinal Drug Advisory Committee. I am a gastroenterologist. I
am from the University of Texas, Southwestern Medical School in Dallas.

CHAIRPERSON CAMILLERI: I\'m Michael Camilleri. I\'m a member of the
Gastrointestinal Drugs Advisory Committee. I am a gastroenterologist.
And I practice at Mayo Clinic in Rochester, Minnesota.

SECRETARY PEREZ: Tom Perez, Executive Secretary to this meeting.

DR. METZ: I\'m David Metz. I\'m at the University of Pennsylvania at
Philadelphia and on the advisory committee.

DR. LEVINE: I\'m Bob Levine from Syracuse, New York at the Upstate
Medical University, State University of New York. I\'m a
gastroenterologist and a hepatologist.

DR. LaMONT: My name is Tom LaMont. I am from Beth Israel Deaconess
Medical Center in Boston. And I am a member of the FDA committee.

DR. KELSEN: David Kelsen, medical oncologist. I\'m from Memorial
Sloane‑Kettering in New York.

DR. BRAWLEY: I\'m Otis Brawley. I\'m a medical oncologist at Emory
University.

DR. McLEOD: I am Howard McLeod, a clinical pharmacologist in oncology at
Washington University School of Medicine in St. Louis.

DR. DESTA: Zeruesenay Desta from Indiana University, Division of
Clinical Pharmacology. I am a clinical pharmacologist and member of the
advisory committee.

DR. PROSCHAN: And I\'m Mike Proschan. I am a statistician with the
National Heart, Lung, and Blood Institute.

CHAIRPERSON CAMILLERI: Thank you very much. At this point I would like
to turn the proceedings over to the executive secretary for statements.

SECRETARY PEREZ: Thank you.

[MEETING STATEMENT]{.underline}

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

Dr. Byron Cryer has been granted waivers under 18 USC 208(b)(3) and
under 21 USC 355(n)(4), an amendment of Section 505 of the Food and Drug
Administration\'s Modernization Act for ownership of stock in the
sponsor valued at less than \$5,001 and for unrelated consultant for a
competitor. Dr. Cryer receives less than \$10,001 per year.

Dr. David Kelsen has been granted waivers under 18 USC 208(b)(3) and
under 21 USC 355(n)(4), an amendment of Section 505 of the Food and Drug
Administration\'s Modernization Act for ownership of stock in the
sponsor valued between \$5,001 and \$25,000.

Susan Cohen has been granted waivers under 18 USC 208(b)(3) and under 21
USC 355(n)(4), an amendment of Section 505 of the Food and Drug
Administration Modernization Act for ownership of stock in the sponsor
valued between \$5,001 and \$25,000.

Dr. Camilleri has been granted a waiver under 18 USC 208(b)(3) for
membership on a competitor\'s advisory board through a contract with his
employer. This interest generates less than \$10,001 per year.

Dr. David Metz has been granted a waiver under 18 USC 208(b)(3) for his
membership on the sponsor\'s speakers\' bureau. His lectures generate
income greater than \$10,000 per year.

Dr. Robert Levine has been granted a waiver under 21 USC 355(n)(4), an
amendment of Section 505 of the Food and Drug Administration
Modernization Act for ownership of stock in the sponsor valued at less
than \$5,001. Because this stock interest falls below the de minimis
exemption allowed under 5 CRF 2640.202(a)(2), a waiver under 18 USC 208
is not required. A copy of these waiver statements may be obtained by
submitting a written request to the agency\'s Freedom of Information
Office, Room 12A30 of the Parklawn Building.

In the event the discussions involve any other products or forms 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 product they may wish to comment upon.

Thank you.

CHAIRPERSON CAMILLERI: Thank you, Tom.

I would now like to invite Dr. Robert Justice to make his opening
comments.

[OPENING COMMENTS]{.underline}

DR. JUSTICE: Good morning. On behalf of the division, I would like to
take this opportunity to welcome the committee members and consultants
to today\'s meeting. We appreciate the time that you are taking from
your schedules to provide us with advice.

On today\'s agenda is a new drug application for EMEND or aprepitant
capsules followed by a brief closed session later this afternoon. As you
will hear, the new drug application seeks approval for EMEND for the
indication of EMEND in combination with other \*antiemetic medications.
It is indicated for the prevention of acute and delayed nausea and
vomiting associated with initial and repeat courses of highly emetogenic
cancer chemotherapy, including high‑dose cisplatin.

As you listen to the company\'s and FDA\'s presentations, we would like
you to keep the following questions in mind for discussion this
afternoon.

Go to the first slide. The first one is, has the aprepitant regimen been
demonstrated to be effective in the prevention of nausea and vomiting in
the acute phase and in the delayed phase?

The second question is, is the designation of \"highly emetogenic
chemotherapy\" appropriate given the regimens used in the clinical
studies?

Next question, please. The third question is, can the recommended
regimen be expanded beyond that used in the clinical studies to include
the use of any 5‑HT~3~ antagonist as part of the aprepitant regimen? If
not, what additional studies would you recommend?

The fourth question is probably the most important today. The preamble
to that question is that aprepitant is an inhibitor of the CYP3A4
metabolic pathway. For chemotherapeutic drugs that are metabolized by
this pathway, moderate inhibition of their metabolism could result in
serious or life‑threatening toxicity.

Next slide. The first part of the question is, the applicant has
analyzed the safety data by chemotherapy regimen and a significant
number of patients received etoposide, vinorelbine, or paclitaxel, which
are substrates for CYP3A4, in combination with cisplatin and the
aprepitant regimen.

Is this data sufficient to support the safety of aprepitant in
combination with these drugs? If not, what additional studies would you
recommend and should these studies be done pre‑approval or
post‑approval?

Next slide. The second part of the question is, few or no patients
received docetaxel, vinblastine, vincristine, ifosfamide, irinotecan, or
imatinib, which are also substrates for CYP3A4, in combination with
cisplatin and the aprepitant regimen.

The docetaxel drug‑drug interaction study has accrued only five patients
to date. Is there sufficient data to support the safety of aprepitant in
combination with these drugs? If not, what additional studies would you
recommend, and should these studies be done pre‑approval or
post‑approval?

Next slide. And, finally, does the committee have specific concerns
regarding potential drug‑drug interaction with other chemotherapeutic
agents or other drug classes? If yes, please discuss them and whether
any additional studies are recommended.

So those are the questions to keep in mind. With this introduction, I
think we can hear the company\'s presentation.

CHAIRPERSON CAMILLERI: Thank you.

Would the company like to start?

[MERCK PHARMACEUTICALS PRESENTATION]{.underline}

[INTRODUCTION]{.underline}

DR. ERB: Good morning, Mr. Chairman, members of the advisory committee,
FDA, and ladies and gentlemen. My name is Dennis Erb from the Department
of Regulatory Affairs at Merck Research Laboratories. I am pleased to be
here today to discuss EMEND, Merck\'s trade name for aprepitant, for the
prevention of chemotherapy‑induced nausea and vomiting.

I would like to provide a few introductory remarks before we present the
results from our development program. Over one million cancer patients
receive chemotherapy each year in the United States. Twenty percent are
administered highly emetogenic chemotherapy, the vast majority of which
will experience an emetic episode in the absence of antiemetic
prophylaxis.

Patients consistently report that nausea and vomiting are among the most
distressing side effects of chemotherapy. The disruptive effects of
these symptoms on patients\' daily lives has been well‑documented to the
extent that patients may delay potential curative therapy because of
these symptoms.

No single class of drugs is fully effective in preventing
chemotherapy‑induced nausea and vomiting. Current therapy guidelines
recommend a regimen consisting of a 5‑HT~3~ receptor antagonist plus a
corticosteroid. Despite this use, greater than 50 percent of patients
still experience nausea and vomiting.

Even with the advent of the 5‑HT~3~ receptor antagonist, delayed emesis
remains a serious problem with patients experiencing symptoms that often
last for several days following their chemotherapy.

In light of the need for routine emetogenic use of chemotherapy,
effective prevention of nausea and vomiting remains an important goal of
health care providers and their patients. Thus, there is a need for new
therapies which can improve prevention of nausea and vomiting and
provide protection that lasts for several days.

EMEND represents the first new approach in over a decade to address the
significant unmet medical need. It has a novel mechanism of action by
blocking substance P at the Neurokinin‑1 receptor in the brain.

It has a distinct efficacy profile, providing protection throughout the
period when symptoms may occur, both in the acute and in the delayed
phases.

EMEND also improves the effectiveness of current therapies, resulting in
fewer patients experiencing acute or delayed symptoms. Thus, the
potential exists to alter an enduring perception of cancer chemotherapy.
Nausea and vomiting need not be inevitable.

As you have seen in the advisory committee briefing document and will
hear about today, the development program for EMEND provides compelling
evidence to support the use of EMEND in the prevention of
chemotherapy‑induced nausea and vomiting. Results from the clinical
program show that a regimen of EMEND given concomitantly with standard
therapy is effective in preventing nausea and vomiting due to highly
emetogenic chemotherapy.

Efficacy was superior to that observed with standard therapy alone with
significant benefit in both the acute and delayed phases. This advantage
was maintained in subsequent cycles of chemotherapy.

Additionally, this regimen was also effective in reducing the impact of
these symptoms on patients\' daily lives. EMEND when added to standard
therapy also demonstrated a favorable safety profile that was similar to
standard therapy alone and has a drug interaction profile that is
well‑characterized.

The presentation today will focus on the data supporting our new drug
application for the following indication. EMEND in combination with
other antiemetic agents is indicated for the prevention of acute and
delayed nausea and vomiting associated with initial and repeat courses
of highly emetogenic cancer chemotherapy, including high‑dose cisplatin.

In addition to our speakers, Merck has brought several consultants to
the meeting today. So they are available as a resource to the advisory
committee during discussions and deliberations.

Our pharmacology consultants with us today are Dr. Paul Andrews, the St.
George\'s Hospital and Medical School; Dr. Merrill Egorin of the
University of Pittsburgh Cancer Institute; and Dr. Malcolm Rowland from
the University of Manchester.

Our statistical consultant, unfortunately, could not be with us today
because of a family emergency. Our clinical consultants include Dr.
Ronald De Wit of the Rotterdam Cancer Institute; Dr. Steven Grunberg of
the University of Vermont; Dr. Paul \*Hesketh from Tufts University
School of Medicine; and Dr. Loren Laine from the University of Southern
California.

The advisory committee members have previously received a briefing
document from Merck that provides more detailed information than time
allows us to present this morning.

The outline for today\'s presentation is as follows. First, Dr. Petty
will provide background and rationale for the use of Neurokinin‑1
receptors, antagonists for the prevention of chemotherapy‑induced nausea
and vomiting as well as review the clinical pharmacology data from our
program.

Dr. Horgan will present the clinical efficacy information that supports
the use of EMEND in preventing nausea and vomiting due to highly
emetogenic chemotherapy.

Following Dr. Horgan\'s presentation, Dr. Reines will present the safety
findings from our development program and will summarize the evidence
demonstrating that EMEND represents a major advance in the prevention of
acute and delayed nausea and vomiting associated with highly emetogenic
chemotherapy.

I would now like to turn the podium over to Dr. Petty from the
Department of Clinical Pharmacology.

[BACKGROUND AND RATIONALE AND CLINICAL PHARMACOLOGY]{.underline}

DR. PETTY: Good morning. This morning I will provide an overview of the
pharmacological properties of aprepitant. The key points are summarized
on this slide. I will first present data showing that aprepitant has a
novel antiemetic mechanism of action relative to currently available
antiemetic therapy in that it blocks substance P action via NK~1~
receptors in the brain. In both animals and humans, unlike available
therapies, it is effective in preventing both acute and delayed
chemotherapy‑inducted emesis.

Aprepitant has a favorable pharmacokinetic profile that supports once
daily oral dosing and requires no dose adjustment in special
populations, such as the elderly and patients with renal or hepatic
insufficiency.

The background package provides a comprehensive description of the
pharmacokinetics and biopharmaceutics of aprepitant. It describes
several drug interaction studies with aprepitant that were conducted
during the course of this development program. However, several of those
studies were conducted to support the use of aprepitant for chronic
dosing indications. And due to differences in dose levels or duration of
a dosing of aprepitant, they\'re not relevant to the short‑term dosing
proposed for prevention of chemotherapy‑induced nausea and vomiting.

The studies relevant to administration of aprepitant for the proposed
indication will be presented here. And they indicate that drug
interactions with the aprepitant regimen for CINV are generally modest
and not clinically important. Of particular importance is that
aprepitant has a low potential for interaction with chemotherapy, with
which it would be co‑administered.

This presentation will first provide a brief overview of the mechanisms
of chemotherapy‑induced nausea and vomiting. Next, the pharmacological
properties of aprepitant and its efficacy in nonclinical models of
chemotherapy‑induced emesis will be presented.

Finally, I will review the clinical pharmacokinetics of aprepitant,
which will include a description of relevant drug interaction studies
that were performed.

To place the novel mechanism of action of aprepitant in context, I will
provide a brief overview of the mechanisms of chemotherapy‑induced
nausea and vomiting. There are both central and peripheral mechanisms
that contribute to the emetic reflex.

The peripheral component involves effects of chemotherapy within the
gut, in which chemotherapeutic agents cause enterochromaffin cells to
release serotonin. Acting locally, serotonin stimulates vagal afferent
nerves via 5‑HT~3~ receptors.

It is at this level that 5‑HT~3~ antagonists primarily exert their
antiemetic effect. These afferents feed into the brain stem, triggering
emesis via activation of brain stem loci that control the emetic reflex.

The central component of CINV involves direct stimulation by
chemotherapy of these brain stem loci. Within the brain stem, substance
P facilitates the emetic reflex by activation of NK~1~ receptors. It is
at this level that NK~1~ antagonists, such as aprepitant, exert their
antiemetic effects.

Before describing the antiemetic efficacy of aprepitant in animal
models, I will summarize some of the pharmacological properties of
aprepitant. The properties of aprepitant can be summarized as follows.
First, there\'s an antagonist for the substance P or NK~1~ receptor.
Second, it binds specifically and with high affinity to human NK~1~
receptors. It is greater than \*8,000‑fold selective for NK~1~ receptors
over other receptors that mediate antiemetic activity, specifically
dopamine D~2~, serotonin 5‑HT~3~, corticosteroid, and opiate receptors.

Animal toxicology studies revealed no findings that preclude use of
aprepitant in humans.

In the next few slides, I will present data that clearly demonstrate the
antiemetic effect of aprepitant on cisplatin‑induced emesis in ferrets,
a well‑established model that is used to assess antiemetic efficacy of
various compounds.

The ferret models show pathophysiology of chemotherapy‑induced emesis
that is similar to humans. These models were used in the discovery of
the antiemetic effects of 5‑HT~3~ receptor antagonists. Since nausea
cannot be readily assessed in ferrets, the term \"chemotherapy‑induced
emesis\" is used, as opposed to \"chemotherapy‑induced nausea and
vomiting\" in humans.

The ferret model has been used to characterize compounds or
interventions that induce emesis by either central or peripheral
mechanisms. This slide lists various emetogens according to the primary
site of action, either central or peripheral, and qualitatively
summarizes the effects of either NK~1~ or 5‑HT~3~ antagonists.

In these models, NK~1~ antagonists, such as aprepitant, are effective
against a broad spectrum of both central and peripheral emetogens;
whereas, 5‑HT~3~ antagonists show a more limited spectrum of activity
with efficacy mostly for emetogens that exert their effects via
peripheral sites of action.

Among these emetogens, cisplatin is one of the most highly emetogenic
agents known. And it exerts its effect by both central and peripheral
pathways. Thus, cisplatin‑induced emesis in ferrets has often been used
to characterize the efficacy of various compounds against highly
emetogenic chemotherapy.

In this model, ferrets were given a single intraperitoneal dose of
cisplatin at zero hour. And emesis was quantified over the subsequent 72
hours. Vehicle‑treated animals, shown in this graph, display the typical
biphasic emetic response to chemotherapy with an acute phase from 0 to
24 hours followed by a delayed phase beyond 24 hours.

Aprepitant given orally once daily at a dose of one milligram per
kilogram provided significant efficacy in both the acute and delayed
phases of emesis in this model, which was dose‑dependent, as shown by an
even greater effect at a dose of two milligrams per kilogram. These
results demonstrate that aprepitant with once daily oral dosing provides
significant protection against both acute and delayed cisplatin‑induced
emesis in ferrets.

In other ferret experiments that I will not show here but are described
in your background package, it was confirmed that the antiemetic effect
of aprepitant required central NK~1~ receptor antagonism and that
aprepitant demonstrates additive efficacy with established antiemetic
agents, specifically dexamethasone or a 5‑HT~3~ receptor antagonist.

To summarize its nonclinical efficacy, aprepitant is active against both
the acute and delayed phases of cisplatin‑induced emesis. And efficacy
was observed with once daily oral dosing.

In the remainder of this portion of the presentation, I will focus on
the human pharmacology of aprepitant. Clinical pharmacology studies show
that once daily oral dosing provides acceptable plasma concentrations of
aprepitant in humans, which I will show on a subsequent slide.

The pharmacokinetics of aprepitant are not significantly affected by
age, gender, race, or body weight. And dose adjustment is not necessary
in patients with renal insufficiency or mild to moderate hepatic
insufficiency. As I will show subsequently, aprepitant is
brain‑penetrant and binds to NK~1~ receptors in the brain.

Shown here is the plasma concentration profile of aprepitant in healthy
subjects, who receive the aprepitant CINV regimen 125‑milligram loading
dose on day one. Following the day two dose of 80 milligrams, the trough
concentration was similar to that following the day one dose. And the
plasma concentration of aprepitant after the last dose of 80 milligrams
on day three was similar to that on day one.

These data show that the aprepitant three‑day regimen provides
consistent daily plasma exposure of aprepitant. During the development
program, a five‑day regimen was also studied in which the 80‑milligram
doses were additionally administered on days four and five. The five‑day
regimen also provided consistent daily plasma concentrations of
\*aprepitant.

Since aprepitant exerts its effect in the brain, it was important to
determine if aprepitant reaches its intended target in humans. This was
accomplished using positron emission tomography, or PET.

Displayed in the next few slides are the results of PET studies
conducted with aprepitant. For these studies, a specific NK~1~ receptor
binding tracer was developed. And the binding of the tracer in a human
brain is displayed in this PET scan. Note that with this color scale,
the blue color represents low binding of the tracer; whereas, red
represents the highest level of binding to NK~1~ receptors. These red
areas correspond to the corpus striatum, an area known to have a high
concentration of NK~1~ receptors.

When aprepitant was administered for two weeks to healthy volunteers, as
you can see in the lower PET scan, there was a high level of blockade of
brain NK~1~ receptors after aprepitant dosing.

This graph displays the relationship between aprepitant plasma
concentration and brain NK~1~ receptor occupancy determined
approximately 24 hours after the last dose of aprepitant. Each point
represents the result from an individual subject. Note that as plasma
concentrations increase, there is an expected increase in the level of
brain NK~1~ brain receptor blockade.

Superimposed here is a crosshatched area that represents the mean with
standard deviation of plasma trough concentrations of aprepitant that
are achieved with the three‑day CINV regimen. Thus, this regimen is
anticipated to provide a high level of blockade of brain NK~1~
receptors.

In the remainder of my presentation, I will provide an overview of
potential drug interactions with aprepitant. As I mentioned previously,
the potential for drug interactions with aprepitant was
well‑characterized in several clinical drug interaction studies, all of
which are described in your background package.

Studies utilizing the regimen for CINV, which I will describe here,
showed that the aprepitant regimen for CINV generally has at most modest
drug interaction effects and that it has low potential for interaction
with chemotherapy.

*In vitro* experiments indicated that aprepitant is metabolized by
cytochrome P450 3A4, an enzyme that metabolizes more than half of all
drugs. Thus, it was anticipated that drugs that induce or inhibit CYP3A4
activity would affect the pharmacokinetics of aprepitant. And this was
confirmed in clinical studies that I will not discuss here but are
described in your background package.

*In vitro* data also indicated that aprepitant inhibited CYP3A4
activity, raising the possibility that it might affect other drugs
metabolized by CYP3A4. Therefore, it was important to characterize the
potential for aprepitant to inhibit CYP3A4 *in vivo*.

Orally administered midazolam is a well‑characterized sensitive probe
used to assess the effects of drugs on CYP3A4 activity *in vivo*. It is
possible to rank the inhibitory effects of CYP3A4 of various drugs by
their ability to increase plasma concentrations of midazolam defined as
the fold increase in midazolam in plasma AUC.

This slide shows a scale of strength of CYP3A4 inhibition going from
weak on the left to strong on the right. On this scale, ketoconazole,
one of the strongest CYP3A4 inhibitors known, produces a 16‑fold
increase in midazolam AUC. Generally, a two to five‑fold increase is
considered moderate inhibition and less than two‑fold increase is weak
inhibition. Other strong inhibitors are itraconazole and clarithromycin.

Agents considered moderate inhibitors include erythromycin, the calcium
channel blocker diltiazem, and verapamil, and grapefruit juice. The
aprepitant five‑day regimen for CINV on both the first and last day of
dosing results in no more than moderate CYP3A4 inhibition. And, thus, it
produces CYP3A4 inhibition comparable to grapefruit juice and widely
used drugs, such as diltiazem and verapamil.

Although this degree of inhibition of CYP3A4 would not be expected to
produce clinically important interactions with most drugs, it was
important to characterize potential interactions of aprepitant with
drugs with which it might be frequently co‑administered. This includes
other antiemetics, such as the corticosteroids dexamethasone and
methylprednisolone as well as the 5‑HT~3~\* antagonists ondansetron and
granisetron. Note that all of these agents are metabolized to some
extent by CYP3A4.

Also investigated was the potential for aprepitant to affect the
pharmacokinetics of drugs with narrow therapeutic indices, including
docetaxel, a chemotherapeutic agent metabolized by CYP3A4; digoxin; and
warfarin.

Note that digoxin is a drug whose pharmacokinetics are dependent on
P‑glycoprotein, a membrane‑bound transporter that also plays a key role
in the disposition of many chemotherapeutic agents.

Thus, evaluation of the potential effects of aprepitant on the
pharmacokinetic of docetaxel and digoxin provides a reasonable
assessment of its potential to affect the pharmacokinetics of several
chemotherapeutic agents whose clearance is dependent on CYP3A4 or
P‑glycoprotein.

Described first is the effect of aprepitant on dexamethasone, which was
the corticosteroid used in Phase III studies. Shown here are plasma
concentrations of dexamethasone in healthy subjects on day one of a
five‑day regimen in which a 20‑milligram dose of dexamethasone was
orally co‑administered with or without a 125‑milligram dose of
aprepitant. Co‑administration of aprepitant resulted in an approximate
two‑fold increase in the dexamethasone AUC.

On day five of the five‑day regimen, which included oral doses of eight
milligrams per day of dexamethasone and 80 milligrams per day of
aprepitant.

There was also an approximate two‑fold increase in dexamethasone AUC
when co‑administered with aprepitant. This effect of aprepitant on
dexamethasone served as the basis for reduction of the dexamethasone
doses in the aprepitant treatment arms in Phase III studies. This
provided balanced exposure of dexamethasone in the two treatment arms,
which enabled evaluation of antiemetic efficacy, not confounded by
variable dexamethasone exposure.

Methylprednisolone is also used frequently in antiemetic regimens and is
metabolized by CYP3A4. In this study, it was of interest to evaluate the
effect of aprepitant on IV‑administered methylprednisolone since this
route of administration is used frequently. Here methylprednisolone was
administered as a 125‑milligram IV dose with and without the
125‑milligram loading dose of aprepitant.

The results showed a small, approximately 34 percent, increase in
methylprednisolone AUC. This indicates that aprepitant had a weak
inhibitory effect on IV‑administered methylprednisolone. A minimal
effect of aprepitant on another IV‑administered CYP3A4 substrate was
demonstrated in a study using IV ondansetron.

Ondansetron is the 5‑HT~3~ antagonist that was used in Phase III
studies. In this study ondansetron was co‑administered to healthy
subjects at the same dose used in the Phase III studies, as a
32‑milligram IV dose on day one with a 375‑milligram dose of aprepitant,
which is three‑fold higher than the aprepitant dose used in Phase III
studies. As shown here, there was little effect of aprepitant on plasma
concentrations of ondansetron .

Granisetron is a 5‑HT~3~ antagonist also used in the treatment of CINV
and is metabolized by CYP3A4. Since this drug might be co‑administered
with aprepitant to prevent CINV, a separate study was conducted in which
granisetron was administered at a dose of 2 milligrams orally with a
125‑milligram dose of aprepitant on day one.

As shown by the granisetron plasma concentrations in the right graph,
there was no significant effect of aprepitant on granisetron
pharmacokinetics. From these studies, it is concluded that no dose
adjustments of ondansetron or granisetron are required when
co‑administered with aprepitant. These results also indicated that
moderate inhibition of CYP3A4 by aprepitant does not translate into
significant pharmacokinetic effects for some orally administered CYP3A4
substrates, such as granisetron.

As mentioned previously, chemotherapeutic agents with narrow therapeutic
index drugs and, thus, pharmacokinetic interactions with these drugs
could substantially alter their toxicities.

Cisplatin, which was used in the Phase III studies, is not metabolized
by CYP3A4 or other CYPs. The pharmacokinetics of cisplatin are unlikely
to be affected by aprepitant since data indicate that the potential for
aprepitant to interact with chemotherapeutic agents would be via CYP3A4.
Since many chemotherapeutic agents are metabolized by CYP3A4\*, it is
important to evaluate the potential effects of aprepitant on a
CYP3A4‑metabolized chemotherapeutic agent, specifically docetaxel.

In addition, the pharmacokinetics of several chemotherapeutic agents are
modulated by P‑glycoprotein. Thus, it was also important to evaluate
potential effects of aprepitant on P‑glycoprotein activity using
digoxin, which is a P‑glycoprotein substrate.

Finally, warfarin is occasionally administered to cancer patients
receiving chemotherapy. And, therefore, the effect of aprepitant on
warfarin pharmacokinetics was evaluated.

Docetaxel is an appropriate agent to assess the potential for aprepitant
to affect the pharmacokinetics of chemotherapeutic agents because it is
metabolized predominantly by CYP3A4 and it is also a P‑glycoprotein
substrate.

In this particular study, which is ongoing, patients receive the same IV
dose of docetaxel in each of two consecutive cycles given at least three
weeks apart. The pharmacokinetics of docetaxel are assessed in each
cycle.

In one of the two cycles, the patients also receive the aprepitant
regimen for CINV in which the first dose of aprepitant is given one hour
prior to docetaxel infusion. In the other cycle, patients do not receive
aprepitant.

This slide summarizes the data from the first five patients who have
completed the study. Shown on the left is a plot of the mean plasma
concentration profiles of docetaxel with and without aprepitant. And on
the right are the docetaxel AUC values for each patient in both
treatment cycles.

Note that these curves are virtually superimposable and that the
individual AUC values are similar between treatment periods for each
patient. This indicates that there was little, if any, effect of
aprepitant on docetaxel pharmacokinetics in these five patients.

To assess the potential for aprepitant to affect P‑glycoprotein, healthy
subjects were doses to steady state with digoxin and were then
administered the aprepitant five‑day regimen for CINV.

Shown here are plasma concentrations of digoxin with and without
aprepitant on the first day of the CINV regimen. There was no
significant effect of aprepitant on digoxin pharmacokinetics on day one
or at any other time point examined. It is concluded that no clinically
meaningful interactions with P‑glycoprotein substrates are expected with
the aprepitant regimen and that no dose adjustment of digoxin is
required when it is co‑administered with aprepitant.

To summarize, the potential for aprepitant to affect the
pharmacokinetics of chemotherapeutic agents, it has been demonstrated
that CYP3A4 and P‑glycoprotein are common pathways that affect the
pharmacokinetics of chemotherapeutic agents.

We have demonstrated that there is weak to no effect of aprepitant on
IV‑administered CYP3A4 substrates, including methylprednisolone,
ondansetron, and the chemotherapeutic agent docetaxel. We have also
demonstrated that there is no effect of aprepitant on a P‑glycoprotein
substrate.

Therefore, we conclude that aprepitant has low potential to produce
clinically meaningful effects on the pharmacokinetics of IV
chemotherapeutic agents. This conclusion is supported by safety data
from the Phase III studies that will be presented by Dr. Reines.

To evaluate the effect of aprepitant on warfarin, a study was conducted
in which healthy subjects were titrated to constant low doses of
warfarin followed by administration of either the aprepitant three‑day
regimen for CINV or placebo.

Shown here are the ratios of changes from baseline in trough plasma
concentrations of the two warfarin isomers: R warfarin and S warfarin.
These were measured during and for several days after administration of
aprepitant. And they reflect the effect of aprepitant relative to
placebo. There was a modest 34 percent reduction in S warfarin
concentrations five days after completion of the regimen with no
meaningful effect on R warfarin.

The decrease in S warfarin, which is metabolized by CYP2C9, was
accompanied by a small decrease in the international normalized ratio of
the prothrombin time, or INR. This is consistent with modest induction
by aprepitant of CYP2C9 activity, which was confirmed in a separate
study using tolbutamide as a CYP2C9 probe substrate. In that study,
which is not shown here, a modest CYP2C9 induction was returning to
baseline by day 15, which is one week beyond the last time point shown
on this slide. This small inductive effect on warfarin warrants closer
monitoring of the INR in patients taking warfarin.

In summary, aprepitant has a novel antiemetic mechanism of action
relative to currently available antiemetic therapy by blocking substance
P action via NK~1~ receptors in the brain. It is effective in preventing
both acute and delayed chemotherapy‑induced emesis in ferrets.

Aprepitant has a favorable pharmacokinetic profile that supports once
daily oral dosing and requires no dose adjustment in special
populations, such as the elderly and patients with renal or hepatic
insufficiency.

The potential for drug interactions with aprepitant has been
well‑characterized. And drug interactions with the aprepitant regimen
for CINV are generally modest and not of clinical significance for most
drugs with which it would be co‑administered.

Pharmacokinetic data as well as safety data from the clinical studies in
patients receiving chemotherapy indicate that aprepitant has a low
potential for interaction with chemotherapy with which it would be
co‑administered.

In conclusion, the pharmacokinetics of aprepitant and the potential for
clinically meaningful drug interactions with aprepitant have been
well‑characterized. Appropriate guidance can be provided for safe and
effective use in the intended patient population.

I will now turn the podium over to Dr. Horgan, who will present the
efficacy data from studies of patients with chemotherapy‑induced nausea
and vomiting.

Thank you.

[CLINICAL EFFICACY]{.underline}

DR. HORGAN: Good morning. Chemotherapy characterized as highly
emetogenic evokes symptoms in the vast majority of patients in the
absence of preventive therapy.

Current therapy to prevent symptoms consists of a combination of two
agents: a 5‑HT~3~ receptor antagonist and a corticosteroid. Despite this
therapy, at least 50 percent of patients still have symptoms of nausea
and vomiting when they receive highly emetogenic chemotherapy. Hence,
there is an unmet medical need for improved therapy. The clinical data
we will present demonstrates that aprepitant will help meet this medical
need.

Nausea and vomiting typically continue for several days following the
administration of emetogenic chemotherapy. A convention is involved to
delineate the time course of these symptoms. Early symptoms are referred
to as acute and later symptoms as delayed. In the literature and in
previous antiemetic programs, 24 hours after the administration of
chemotherapy has been the transition between the acute and the delayed
phases.

All clinical studies that we conducted assessed efficacy in both phases
with acute, consistently defined as zero to 24 hours. In more recent
studies, particularly Phase III, we emphasized an overall time frame,
which is a merger of the acute and delayed phases, because of its
greater clinical relevance.

This slide summarizes the basis for current therapy for prevention of
symptoms associated with highly emetogenic chemotherapy. 5‑HT~3~
receptor antagonists prevent symptoms, acute symptoms, in approximately
50 percent of patients, though they have equivocal efficacy in the
prevention of delayed symptoms and are only approved for prevention of
acute symptoms.

Corticosteroids augment the acute efficacy of 5‑HT~3~ receptor
antagonists and also have efficacy as monotherapy in the prevention of
delayed symptoms. Though corticosteroids are recommended in consensus
treatment guidelines by the American Society of Clinical Oncology and
are extensively used in clinical practice, they are not approved for use
as antiemetics in the United States.

The program objective was to define the potential role of aprepitant in
the prevention of nausea and vomiting associated with highly emetogenic
chemotherapy. The program followed the development paradigm of agents
previously approved for the prevention of the symptoms of
chemotherapy‑induced nausea and vomiting, notably the 5‑HT~3~ receptor
antagonists.

The program addressed three questions sequentially. The first question,
does aprepitant work alone as an antiemetic, as implied by the
preclinical data from the ferret model? A monotherapy study was done to
answer this question.

Next we asked, is a regimen containing aprepitant more effective than
current standard therapy? Three studies were done to answer this
question. We will present data from one of these studies, the one that
provided the most pivotal information. The data from the other two
studies are in your background.

Our last question was, what was the optimum dose? This was addressed by
a single dose‑binding study.

Finally, two studies were done to confirm that the Phase III regimen is
effective and safe. Before addressing these questions specifically, I am
going to spend a few moments providing a framework for understanding the
approach we took.

All studies enrolled patients receiving cisplatin. There were several
compelling reasons why we focused on this patient population. Cisplatin
is a cornerstone of current therapy for common cancers, such as lung and
ovarian. Cisplatin is the most emetogenic chemotherapeutic agent and has
a predictable and well‑characterized pattern of emesis lasting several
days.

A dose of cisplatin greater than or equal to 50 milligrams per meter^2^
is regarded as being highly emetogenic. Cisplatin has been the benchmark
chemotherapy for evaluation and approval of novel antiemetic agents,
notably the 5‑HT~3~ receptor antagonists ondansetron, granisetron, and
dolasetron; and also the dopamine receptor antagonist metoclopramide.

Efficacy in the prevention of nausea and vomiting associated with
cisplatin has generally been predictive of efficacy in the prevention of
symptoms associated with other chemotherapeutic agents, such as
carboplatin, doxorubicin, and cyclophosphamide.

Some important elements of the clinical trials we did included the
following. All studies were double blind versus an appropriate control.
All patients enrolled were cisplatin‑naive.

All patients received high‑dose cisplatin infused over less than three
hours on day one. The cisplatin dose for enrollment was greater than 70
milligrams per meter^2^ in all studies except the initial study, when it
was greater than 50 milligrams per meter^2^. Additional chemotherapy was
permitted, though additional emetogenic chemotherapy was only allowed on
day one.

Randomization was stratified for gender and additional emetogenic
chemotherapy. Rescue therapy was allowed to treat established nausea or
vomiting.

A daily patient diary was used to collect efficacy data. This included
all emetic events, all use of rescue therapy, and nausea assessments.
The primary efficacy analyses were focused on the first cycle of
chemotherapy and modified intention‑to‑treat populations.

Several endpoints were assessed in order to comprehensively understand
the efficacy profile of aprepitant. The primary endpoint in the majority
of the studies and in both Phase III studies was complete response. And
the efficacy data in this presentation emphasize this endpoint.

A patient has a complete response if they have both no emetic episodes
and also do not take rescue therapy. Since rescue therapy is permitted
for emesis and nausea, this endpoint reflects control of both emesis and
nausea.

Complete response was the primary endpoint for the 5‑HT~3~ receptor
antagonists ondansetron and dolasetron, which were both approved for the
prevention of chemotherapy‑induced nausea and vomiting.

Other endpoints focused on emetic episodes, use of rescue therapy, and
the impact of nausea and vomiting on daily life.

And so back to our questions. The first one, does aprepitant work alone
as an antiemetic? This question was answered in a monotherapy study
which used the intravenous prodrug formulation of aprepitant, as
explained in your background.

There were two treatment groups. One received a single dose of
aprepitant intravenously and the other a single dose of ondansetron, 32
milligrams, intravenously. Both aprepitant and ondansetron were
administered only on day one prior to the administration of cisplatin.

A placebo‑controlled group could not be included for ethical reasons. As
based on historical data from the literature, almost all patients
receiving this dose of cisplatin will be predicted to have emesis in the
absence of therapy.

The data during the acute phase and the delayed phase are shown. The
vertical axis shows the percent of patients with a complete response.
During the acute phase, both aprepitant and ondansetron had similar
efficacy. During the delayed phase, the aprepitant‑treated patients had
a much better outcome than those treated with ondansetron. Forty‑eight
percent had a complete response versus 17 percent. And this difference
was statistically significant.

To provide context, the dotted lines illustrate the anticipated response
in the absence of treatment based on historical data. So this study
provided very useful information. It showed that aprepitant is an
effective antiemetic clinically showing both the acute and the delayed
phases. It also showed that aprepitant has a distinctive efficacy
profile relative to a 5‑HT~3~ receptor antagonist with significantly
superior efficacy in the prevention of delayed symptoms.

The distinctive efficacy profile of aprepitant implied that better
efficacy might be obtained by combining it with other antiemetics, such
as a 5‑HT~3~ receptor antagonist. This possibility provided the
rationale for the next question we asked. Is a regimen with aprepitant
more effective than current standard therapy?

We did three studies to answer this question and will present data from
one of these that was particularly helpful in establishing a rationale
for subsequent studies in the Phase III regimen. The data from the other
two are in your background.

I would like to emphasize some important design features of this study.
An aprepitant loading dose strategy was used with a tablet formulation.

Patients received aprepitant, 400 milligrams, on day one. And if treated
on subsequent days, they received 300 milligrams of aprepitant daily.
This day one loading dose was particularly high relative to the day one
dose ultimately selected for Phase III.

The control group received a regimen that was consistent with standard
clinical practice at the time of the initiation of the study. This
control regimen consisted of therapy on day one only with both a single
dose of a representative 5‑HT~3~ receptor antagonist, granisetron, and a
single dose of a corticosteroid. Granisetron was administered
intravenously and dexamethasone orally.

The design of the study is shown, the control regimen granisetron and
dexamethasone on day one only, placebo for aprepitant on day one and
days two to five. Patients in the other two treatment groups also
received the components of the control regimen on day one with the
addition of aprepitant, 400 milligrams, on day one in both. One group
received aprepitant on day one only. The other group received aprepitant
on day one and also on days two to five.

In summary, three treatment groups, the control group receiving standard
therapy, one day aprepitant regimen, and a five‑day aprepitant regimen.

The data during the acute and delayed phases are shown. The vertical
axis again shows the percentage of patients with a complete response.
During the acute phase, both aprepitant treatment groups were
significantly more effective than the control group. During the delayed
phase, both aprepitant treatment groups were also significantly more
effective than the control regimen. Also, the five‑day aprepitant
regimen was numerically more effective than the one‑day regimen in the
prevention of delayed symptoms.

We concluded that aprepitant enhances the efficacy of a standard therapy
regimen during both the acute and delayed phases. We also concluded that
aprepitant is more effective when administered for multiple days in the
prevention of delayed symptoms, even when a very high dose of
aprepitant, 400 milligrams, is administered on day one.

Hinting that continued dosing is more effective in the prevention of
delayed symptoms was also shown in the second study, the details of
which are in your background.

Based on these conclusions and the data from the other studies that
evaluated different aprepitant regimens presented in your background, we
then did a dose finding study.

There were several noteworthy design features of this study. The primary
hypothesis related to overall prevention of symptoms, \"overall\"
meaning the entire five days following the initiation of cisplatin
therapy. As mentioned before, the overall phase is affusion of the acute
and delayed phases and is favored because it is the most clinically
relevant time frame for the primary assessment of efficacy.

The control group received a standard therapy regimen that consisted of
therapy on day one with both a 5‑HT~3~ receptor antagonist and a
corticosteroid followed by continued therapy with a corticosteroid,
dexamethasone, on subsequent days.

Instead of chronicitron, a study previously, the 5‑HT~3~ receptor
antagonist selected was ondansetron. Based on the very similar efficacy
profiles of the various 5‑HT~3~ receptor antagonists, this change was
not predicted to significantly alter the efficacy profile of the
aprepitant regimen.

There was a transition to an aprepitant capsule formulation with
improved bioavailability. The aprepitant capsule was used in all
subsequent studies and is the formulation proposed for market.

The dose finding study was initiated with two aprepitant regimens. The
first was 375 milligrams on day one followed by 250 milligrams on days 2
to 5. The second was 125 milligrams on day one followed by 80 milligrams
on days 2 to 5.

After initiation of the study, new data became available which
demonstrated that the aprepitant capsule formulation had even better
bioavailability than anticipated.

As a result of this new information, it was predicted that both
aprepitant regimens would have similar clinical efficacy. So in light of
this, in order to adequately explore the aprepitant dose response, the
study was modified.

The 375/250 milligram regimen was discontinued after enrollment of 35
patients. The study was then resumed with a new allocation schedule and
new drug supplies and the addition of a 40/25 milligram aprepitant
regimen. This slide shows the design of the second part of the study
after the modification of the aprepitant treatment groups.

The control regimen received ondansetron, the control standard therapy
regimen, ondansetron and dexamethasone on day one followed by
dexamethasone on days two to five. Patients in the other two treatment
groups received this standard therapy regimen, and both also received a
five‑day aprepitant regimen. The first was aprepitant, 40 milligrams, on
day one followed by 25 milligrams on days 2 to 5. And the other was 125
milligrams on day one followed by 80 milligrams on subsequent days. The
objective of the study was to assess the aprepitant dose response.

The data for the primary hypothesis overall complete response are shown.
The vertical axis shows the percentage of patients with a complete
response. Both aprepitant regimens were significantly more effective
than the control regimen.

A formal dose response analysis was done, which demonstrated that the
125/80 milligram regimen was significantly superior to the 40/25
milligram regimen. The data during the acute phase and the delayed phase
are shown separately. The 125/80 milligram aprepitant regimen was
significantly more effective than the control regimen during both the
acute and the delayed phase; whereas, the 40/25 milligram aprepitant
treatment regimen was significantly more effective than the control
regimen during the delayed phase only.

This Kaplan‑Meier curve illustrates the time to first emetic episode or
rescue over the five‑day evaluation period for the control group. The
horizontal axis shows time over the evaluation period of 120 hours. The
vertical axis, truncated at 40 percent, shows the percentage of patients
with no emesis or rescue. At time zero, the time of initiation of
cisplatin, 100 percent of the patients have had no emetic episodes and
have not taken rescue. At 120 hours, less than 50 percent of patients in
the control group have had no emetic episodes and have not taken rescue.

Few patients are having more emesis or are taking rescue in the first
few hours. However, after approximately 18 hours, a substantial portion
of the patients are having symptoms. Initial emetic episodes and use of
rescue are concentrated in the first 72 hours.

The benefit of addition of both dose regimens of aprepitant is clearly
seen with the 125/80 milligram regimen superior to the 40/25 milligram
regimen.

Initial emetic episodes and use of rescue are also concentrated within
the first 72 hours with the addition of aprepitant. This display shows
the data from the 375/250 milligram regimen superimposed. As predicted,
the outcome in the patients in the 375/250 milligram regimen and the
125/80 milligram regimen was very similar.

The conclusions from the dose finding study were that the aprepitant
125/80 milligram regimen is effective. The 40/25 milligram aprepitant
regimen was less effective. And the 375/250 milligram aprepitant regimen
added little or no benefit relative to the 125/80 milligram regimen.

Almost all initial therapy failures occurred within 72 hours, implying
that 3‑day dosing with aprepitant would provide full benefit. Based on
these conclusions, we proceeded to Phase III in order to confirm the
effectiveness and safety of a 3‑day aprepitant regimen, 125 milligrams
administered on day one followed by 80 milligrams administered on days 2
and 3.

The Phase III hypothesis was compared to standard therapy, the
aprepitant regimen will provide superior control of nausea and vomiting
as measured by the proportion of patients with an overall complete
response. That is, no emesis and no rescue in the 120 hours following
the initiation of cisplatin.

In order to rigorously assess this hypothesis, two Phase III
multinational studies were done with multiple‑cycle extensions. These
studies enrolled over 1,000 patients and were 2 of the largest
antiemetic trials with multiple‑cycle extensions ever done in this
patient population: cancer patients treated with high‑dose cisplatin.

The aprepitant regimen was refined for Phase III. Aprepitant was dosed
for three days, as I mentioned previously. The dexamethasone dose was
reduced in the aprepitant treatment group. So the plasma dexamethasone
levels would be similar in both treatment groups.

The Phase III study design. Two treatment groups; the control therapy
regimen, ondansetron and dexamethasone on day one followed by
dexamethasone on days two to four.

Patients in the aprepitant treatment group received this standard
therapy regimen with the refinement that the dexamethasone dose was
reduced relative to the control group. On day one, the control group
received 20 milligrams dexamethasone; whereas, the aprepitant group
received 12 milligrams. On days two to four, the control group received
16 milligrams of dexamethasone daily; whereas, the aprepitant group
received 8 milligrams daily.

The key inclusion criteria were administration of high‑dose cisplatin,
greater than 70 milligrams per meter^2^ on day one. Exclusion criteria
included significant elevations of liver function tests, AST, ALT, and
bilirubin, reduced renal function, and reduced neutrophil and white
blood cell counts, as shown. The concomitant or very recent use of
strong CYP3A4 inhibitors or CYP3A4 inducers were also precluded.

The treatment groups were similar in terms of gender, age, and
additional emetogenic chemotherapy, as seen in the data combined from
both studies. These are all risk factors for the development of nausea
and vomiting.

The primary cancer diagnoses were similarly distributed between the
treatment groups, data combined from both studies. The vast majority of
patients in the studies, around 95 percent, received concomitant
chemotherapy in addition to cisplatin.

The frequency of concomitant therapy with specific chemotherapeutic
agents was similar in both treatment groups. The efficacy data for the
primary endpoint of overall complete response are shown for the first
Phase III study, protocol 052.

Fifty‑two percent of the patients in the control group had a complete
response versus 73 percent in the aprepitant group, an increment of 21
percentage points, which was highly significant, *p* less than .001.

The outcome in the second Phase III study, protocol 054, was strikingly
similar. Forty‑three percent of patients had a complete response in the
control group versus 63 percent in the aprepitant group, an increment of
20 percentage points, which was also highly significant, *p* less than
.001.

Thus, the primary analysis in both studies showed a consistent advantage
for the aprepitant regimen in the overall prevention of nausea and
vomiting associated with highly emetogenic chemotherapy, which was
highly significant.

The efficacy data for the key secondary endpoints of complete response
during the acute and delayed phases in both of the Phase III studies are
shown. Both studies showed a consistent advantage for the patients
treated with the aprepitant regimen during both the acute and the
delayed phases when analyzed separately. The differences were also of
similar significance in both studies with *p* values consistently less
than .001.

These Kaplan‑Meier curves illustrate the time to first emetic episode or
rescue for the treatment groups over the five‑day evaluation period in
both Phase III studies. The advantage provided by the addition of
aprepitant throughout the acute and delayed phases was clearly
replicated in both studies and was statistically significant.

The efficacy data for the endpoints of no emesis and no rescue overall
are shown for both studies. These endpoints are the individual
components of the primary endpoint of complete response.

Both studies show a consistent advantage for the patients treated with
the aprepitant regimen for both the no emesis and no use of rescue
therapy endpoints. The efficacy of the aprepitant regimen is, thus,
supported by both components of the primary endpoint. The greater use of
rescue therapy in the control group is particularly important to bear in
mind in the context of the assessment of the control of nausea, which I
will now discuss.

Nausea is a particularly important symptom for patients, which
frequently occurs in conjunction with vomiting. Though our primarily
assessment of the efficacy of aprepitant was in the prevention of the
syndrome of chemotherapy‑induced nausea and vomiting, we also carefully
assess nausea prevention independently.

The assessment of nausea is more complex than either the assessment of
emetic events or use of rescue therapy because of its subjective nature.
Nausea was assessed daily by patients using a validated 100‑millimeter
visual analog scale. The scale was anchored by zero millimeters
representing no nausea and 100 millimeters representing nausea as bad as
it could be.

Patients placed a vertical mark daily on the scale corresponding to
their level of nausea in response to the diary question, \"How much
nausea have you had over the past 24 hours?\"

Two pre‑specified nausea endpoints were analyzed with data from the
daily visual analog scale readings: no nausea and no significant nausea.
No nausea was defined as a maximum rating of less than five millimeters
on each day during the overall five‑day assessment period.

This definition of no nausea was also used by the most recently approved
5‑HT~3~ receptor antagonist, dolasetron. No significant nausea was
defined as a maximum rating of less than 25 millimeters each\* day
during the overall 5‑day assessment period. This definition of no
significant nausea correlates with nausea that does not interfere with
daily activities. The efficacy data for the pre‑specified secondary
endpoints of no nausea and no significant nausea are shown for both
studies.

Both studies showed a consistent numerical advantage for the aprepitant
regimen for both nausea endpoints, though, as I mentioned before, it is
important to bear in mind that rescue therapy was most frequently used
in the control group.

Statistical significance was achieved for the no nausea endpoint in
protocol 054. To explore further the control of nausea, the data from
both studies were merged in post hoc analyses of both nausea endpoints
and are shown.

Statistically significant advantages for the aprepitant‑treated patients
for both endpoints were seen in these merged post hoc analyses. These
data show that the addition of aprepitant consistently improves the
control of nausea associated with highly emetogenic chemotherapy.

Other pre‑specified endpoints were also studied. These included the
composite endpoints, complete protection, and total control. Complete
protection is defined as complete responses plus no significant nausea;
that is, no emesis, no rescue, plus no significant nausea.

Aprepitant was significantly superior to control in both Phase III
studies in terms of complete protection. And the data is in your
background. Total control is defined as complete responses plus no
nausea; that is, no emesis, no rescue, plus no significant nausea.

Aprepitant was significantly superior to control in protocol 054 in
terms of total control and numerically better in protocol 052. The data
for total control are in your background.

Symptom relief alone may not fully describe the benefits of effective
antiemetic therapy to patients because it does not assess the impact of
nausea and vomiting on patients\' daily lives. So we assessed the impact
of nausea and vomiting on daily life using a validated nausea and
vomiting‑specified questionnaire.

The questionnaire has two domains: an emesis‑specific domain and a
nausea‑specific domain. Using the overall score derived from the
questionnaire is a pre‑specified analysis, aprepitant was significantly
superior to control in both Phase III studies in terms of impact on
daily life, as detailed in your background.

The data derived from the individual emesis and nausea domains, which
are not present in your background, were also supportive of
aprepitant\'s benefit to patients. In order to assess the benefit of
aprepitant in patients receiving a particular emetic regimen, we did a
post hoc efficacy analysis in the subset of patients treated with both
cisplatin and additional emetogenic chemotherapy, specifically
cyclophosphamide and/or doxorubicin.

Predictably, the complete response was very low in the control group
because of the more intense emetic stimulus, only 26 percent of patients
having a complete response. The advantage provided by addition of
aprepitant was 33 percentage points, more than twice the response in the
control group, and a very substantial therapeutic effect in these
patients that was highly significant.

I would like to briefly summarize the aprepitant cycle 1 efficacy data.
The aprepitant regimen was effective in two replicate clinical trials.
Overall, 20 percent fewer patients vomited or required rescue
medications for established nausea or emesis, a *p* less than .001, in
both studies.

The superiority of aprepitant was evident in both the acute and delayed
phases for both components of the primary endpoint: emesis and the use
of rescue medications. The superiority of aprepitant was also evident in
patients taking cisplatin plus other emetogenic chemotherapy. There was
a consistent advantage to the aprepitant regimen on both nausea
endpoints, and it\'s important to bear in mind in considering the nausea
data that more rescue medications were used in the control group in both
\*studies.

All of the efficacy data we have presented has related to cycle 1 of
chemotherapy. Since cancer patients typically receive multiple cycles of
chemotherapy treatment, the assessment of antiemetic efficacy during
those multiple cycles is important.

The vast majority of antiemetic studies have only collected cycle 1
data. And those that have collected multiple‑cycle data have frequently
been open label studies.

The interpretation of data from multiple‑cycle extensions is complicated
because of the high attrition rate in this patient population and the
potential for bias when observing a subset of the cycle 1 patients. Both
Phase III studies incorporated multiple‑cycle extensions.

Patients could receive the same blinded therapy they received in cycle 1
in up to five additional cycles. Sixty‑eight out of 71 study sites
participated in the optional multiple‑cycle extension.

Data collection was streamlined, and patients were simply asked to
provide \"Yes\" or \"No\" responses to two questions posed at the day
six to eight clinic visit, \"Have you had any episodes of vomiting or
retching since your chemotherapy started in this cycle?\" and \"Have you
had any nausea since your chemotherapy started in this cycle that
interfered with normal daily life?\"

The observed proportion of patients without emesis and significant
nausea are shown during each of the multiple cycles two to six. Data was
combined from both Phase III studies. A consistent advantage is seen for
the patients receiving the aprepitant regimen, which appears to be
maintained throughout repeat cycles for those patients continuing in
each of the multiple cycles.

Another way to evaluate the multiple‑cycle data is the time to first
emesis and the time to first significant nausea during the extensions.
Data from both studies are combined and are shown using a Kaplan‑Meier
approach.

A consistent advantage for the patients receiving the aprepitant regimen
in terms of emesis‑free time and significant nausea‑free time appears to
be maintained throughout repeat cycles for those patients continuing in
the extension, though the advantage is not as pronounced for the no
significant nausea endpoint compared to the no emesis endpoint.

In summary, we performed two large Phase III studies to demonstrate that
the addition of aprepitant to a regimen of a 5‑HT~3~ receptor antagonist
and a corticosteroid is beneficial in the prevention of nausea and
vomiting due to highly emetogenic chemotherapy.

The benefit is clinically important, is evident during both the acute
and the delayed phases, and appears to be sustained during multiple
cycles of chemotherapy.

My colleague Dr. Scott Reines will now present the safety profile of
receptor antagonist and complete our presentation. Thank you.

[CLINICAL SAFETY]{.underline}

DR. REINES: Good morning. I would like to review with you the key safety
findings from the aprepitant clinical development program, which
included over 3,000 subjects and patients treated with aprepitant. Over
1,400 of these patients received aprepitant for the prevention of nausea
and vomiting associated with highly emetogenic chemotherapy.

The background document summarizes the safety of aprepitant across these
populations. Of note is the low inherent toxicity of the drug documented
in studies in non‑cancer patients in which aprepitant, even at very high
doses for up to eight weeks, was associated with few adverse events.

My presentation this morning will focus on the safety of aprepitant in
the Phase III clinical trials in cancer patients, protocols 052 and 054,
which utilize the 3‑day antiemetic regimen for which approval is being
sought.

Initially I will discuss cycle 1 of chemotherapy and then briefly review
safety during administration of aprepitant over multiple chemotherapy
cycles.

Based on its pharmacokinetic profile and our previous clinical
experience, we predicted that aprepitant would be very well‑tolerated in
the antiemetic regimen host for marketing. The Phase III clinical trials
confirm that prediction.

This slide provides an overall summary of clinical adverse experiences
during cycle 1 of the Phase III clinical trials. The incidences of all
clinical adverse experiences, those defined as drug‑related are serious,
discontinuations due to clinical adverse experiences, and death, in the
aprepitant and control groups are displayed.

The incidences of all categories of adverse experiences are generally
similar between the treatment groups with the exception of adverse
experiences defined by the investigator as drug‑related, which were
somewhat more frequent in the aprepitant treatment group. The difference
was primarily attributable to small increases in drug‑related hiccups,
anesthenia, and fatigue, which were generally mild and trangient.

The incidences of the most common serious clinical adverse experiences
in the aprepitant and control groups are displayed in this slide. Of
note, the overall incidence of serious clinical adverse experiences
during cycle 1 is essentially identical in the two treatment groups,
13.4 versus 13.6 percent. No specific adverse experience occurred in
more than 2.2 percent of patients. And the incidences of specific events
were similar between groups.

Febrile neutropenia occurred as a serious AE in 1.3 percent of patients
in either group. The spectrum of adverse events is typical of cancer
patients receiving chemotherapy.

My next slide summarizes the Phase III chemotherapy cycle 1 laboratory
adverse experiences. The overall incidences of all laboratory adverse
experiences as well as those defined as serious or drug‑related and
discontinuations due to laboratory adverse experiences were generally
similar between the treatment groups during cycle 1 of the Phase III
trials.

When used in clinical practice, aprepitant will be administered with a
variety of concomitant therapies. During Phase III, we sought to confirm
the prediction based on clinical pharmacology data that aprepitant would
not have clinically important interactions with these other medications.

We approached the question in several ways, as illustrated here. Since
all patients receive cisplatin, potential renal and neurological
effects, which are the dose‑limiting toxicities with this agent, were
carefully monitored. Cisplatin‑induced renal effects were evaluated by
analysis of serum creatinine. And particular attention was paid to
nervous system and ototoxicity.

Toxicities of other types of chemotherapy, which were frequently
administered in addition to cisplatin, were evaluated by changes in
neutropenia and other hematological parameters as myelosuppression is
the dose‑limiting toxicity for the majority of these chemotherapies.

Other common chemotherapy‑induced effects include fever, infection
febrile neutropenia, and dehydration. These hematological parameters and
clinical adverse experiences as well as those indicative of potential
glucocorticoid toxicity; that is, hypertension, hyperglycemia, and
hypokalemia, were pre‑specified as worthy of special attention during
Phase III.

In addition, patients receiving chemotherapy metabolized, at least in
part, by CYP3A4, the enzyme responsible for aprepitant metabolism, were
identified and evaluated, both as part of the entire patient cohort and
as separate subgroups.

Before discussing the data on this slide, I would like to describe the
way we collected and evaluated adverse laboratory findings during Phase
III. Laboratory data were to be collected for analysis by a central
laboratory during two clinically important time windows. The first was
day six to eight following chemotherapy, when patients returned for
clinical assessments, including antiemetic efficacy.

At this time, early toxic effects of chemotherapy may be identified. A
later assessment was obtained between days 19 and 29, when patients are
typically evaluated prior to a second round of chemotherapy and when
toxic effects, such as prolonged myelosuppression, can be identified.

These protocol‑mandated assessments were supplemented as needed by
additional measures that could be sent to local laboratories or to the
central lab. The investigator was responsible for assessing all
laboratory data and recording as clinical or laboratory adverse
experiences any clinically significant findings.

Adverse changes in laboratory and clinical parameters may be ranked
according to National Cancer Institute; that is, NCI, common toxicity
criteria based on their severity. The criteria established four levels
of increasing toxicity, grades 1 through 4.

All of our data collected through the central laboratory were evaluated
according to NCI criteria. However, the local laboratory data were not
included in the NCI assessments.

This slide depicts the incidences of any elevation of any serum
creatinine in the first line of the table followed by categorization of
these elevations according to the four NCI severity grades indicated in
the left‑hand column. The incidences of patients with any elevation in
serum creatinine were very similar between groups, both at the earlier
and the later time points.

More than half of the early elevations had resolved my the later
assessment. The NCI severity profile of changes was also very similar
between the groups at both time points. And no findings ranked in the
most severe category.

In summary, there were no apparent differences in the nephrotoxicity of
cisplatin due to aprepitant as evidenced by the findings with serum
creatinine. In addition, there were few neurological adverse experiences
and no differences between groups in terms of neurotoxicity or
ototoxicity.

As discussed earlier, potential changes in the toxicity of non‑cisplatin
chemotherapies were assessed by evaluation of adverse reaction profiles
typical of these agents. For example, this slide displays the occurrence
of neutropenia in the aprepitant and control groups overall and
according to NCI toxicity criteria during cycle 1 of chemotherapy.

As with creatinine and other laboratory parameters, blood counts for NCI
assessments were obtained during the day 6 to 8 and 19 to 29 time
frames. Again, laboratory adverse experiences could, nevertheless, be
reported at any time in patients for whom additional local laboratory
studies were performed.

There were no clinically important differences between the aprepitant
and control groups with respect both to overall incidences of
neutropenia shown in the first line of the table or to the incidences
within each NCI severity grade. There was slightly more neutropenia in
the control group at the day 19 to 29 assessment, but the incidences of
grades 3 and 4 neutropenia were essentially the same.

Unlike the findings with creatinine, neutropenia was more common during
this later assessment period, reflecting the expected time course of
changes in hematological parameters following bone marrow suppression by
chemotherapy.

The data provided no evidence of differential chemotherapy‑induced
toxicity in the aprepitant group based on the similarities in neutrophil
counts. A further assessment of the effects of aprepitant on the
toxicity of concomitantly administered therapies based on occurrence of
the pre‑specified adverse experiences discussed earlier is shown on the
next slide.

This first group of adverse experiences, which includes infections,
dehydration, hematological toxicities, as well as fever and febrile
neutropenia, reflects chemotherapy‑induced adverse effects. There were
no clinically important differences between the aprepitant and the
control regimens.

The second group of adverse experiences, reflecting potential
dexamethasone or corticosteroid‑induced toxicity, also occurred with
very similar frequencies in the two treatment groups.

In summary, assessment of pre‑specified adverse experiences supports a
lack of significant interaction between aprepitant and concomitantly
administered chemotherapies or glucocorticoids.

Earlier, Dr. Petty characterized aprepitant as a moderate inhibitor of
CYP3A4 similar in potency to diltiazem, which should not affect the
toxicity of concomitantly administered chemotherapy agents. We sought to
confirm this by evaluating the safety profile of aprepitant separately
in the subgroup of patients receiving chemotherapies that utilize the
enzyme CYP3A4 as at least one pathway in their metabolism.

The relevant patients in our clinical trials received etoposide; the
vinca alkaloid vinorelbine; taxanes, including paclitaxel and to a
smaller extent the \*\*taxel; and rarely irinotecan and ifosfamide. Data
assessed include clinical and laboratory adverse experiences and
hematological toxicities, in particular.

I will review our neutropenia data in the entire subgroup of patients
and separately in patients receiving etoposide, vinorelbine, and
paclitaxel, the individual CYP3A4 metabolite chemotherapies most
frequently administered during Phase III.

Approximately half of the patients in the Phase III trials received a
concomitant therapy metabolized by CYP3A4, as shown by the N\'s in this
table. During cycle 1, the overall incidences of adverse experiences
were virtually identical, approximately 74 percent, in the aprepitant
and control groups in this subgroup of patients who received, in
addition to cisplatin, any concomitant chemotherapy metabolized by
CYP3A4.

The overall frequencies of pre‑specified adverse experiences indicative
of chemotherapy are glucocorticoid‑induced toxicity or serious adverse
experiences, also showed little difference between groups. There were no
changes characterized as serious laboratory adverse experiences in these
patients.

My next slide displays the occurrence of neutropenia graded according to
NCI toxicity criteria in patients who received chemotherapy metabolized
by CYP3A4. The incidences of neutropenia during the earlier and later
evaluation periods were generally similar in the two treatment groups.
There was a small excess of neutropenia in the control group at the day
19 to 29 assessment, primarily falling into the 2 milder NCI categories
with no differences in the more severe grades.

Based on the incidence and severity of neutropenia at these two time
points, there was no change due to aprepitant in the hematological
toxicity of chemotherapy metabolized by CYP3A4.

This slide depicts the frequencies of neutropenia of grade 2 or greater;
that is, less than 1,500 per millimeter^3^, in all patients who received
CYP3A4 metabolized concomitant chemotherapy, shown on the left, this
being the percent of patients, and in those receiving the 3 most
commonly administered individual chemotherapies metabolized by this
pathway.

Etoposide was the most common. The N\'s are shown at the bottom for each
of these chemotherapies. Substantial numbers of patients receive
vinorelbine, the second most common CYP3A4‑metabolized concomitant
chemotherapy. And paclitaxel was also administered frequently.

During the cycle 1, day 19 to 29 assessment, which is a measure of
prolonged and clinically important myelosuppression, there were no
noteworthy differences in the occurrence of significant neutropenia
among any of these patient subgroups.

As noted, in addition to the NCI gradings of central laboratory data,
investigators were also instructed to record clinically important
laboratory findings as adverse experiences.

This slide depicts all adverse experiences of neutropenia for the
patients described on the previous slides. As with the NCI
characterizations, the incidences of neutropenia adverse experiences
also showed no clinically important differences in the subgroups of
patients receiving any CYP3A4‑metabolized chemotherapy or in the
individual subgroups representing the three most frequently administered
agents.

In summary, during Phase III, we conducted an extensive evaluation of
more than 250 patients per group, who received additional chemotherapy
metabolized by CYP3A4. We saw no pattern of clinically important changes
between the aprepitant and control regimens in these patients based upon
evaluation of overall and subcategories of clinical and laboratory
adverse experiences and of neutropenia, in particular.

In addition to categorizing patients by whether they receive concomitant
therapies, we also evaluated standard patient demographic subgroups
according to age, gender, race, and primary cancer diagnosis. The data,
which are presented in your background package, support the conclusion
that the aprepitant regimen has a consistently favorable safety profile
across these various demographic subgroups.

Thus far I have presented data describing our experience with aprepitant
during an initial cycle of chemotherapy. Cancer patients typically
receive initial followed by repeat cycles of chemotherapy. Therefore,
the Phase III studies evaluated aprepitant over multiple courses of
chemotherapy, up to a total of six cycles per patient.

During multiple‑cycle extensions, patients continued on the same
chemotherapy and antiemetic regimens with which they were treated during
cycle 1. Safety data collection during multiple cycles included the most
critical parameters according to investigators and consultants and by
prior agreement with FDA; that is, clinical adverse experiences defined
as drug‑related or serious, and those causing the patient to discontinue
further participation in the study. In addition, laboratory evaluations
were obtained at the day 19 to 29 visit.

A large number of patients received treatment during multiple cycles.
Over 400 patients in each group continued beyond cycle 1 and
approximately 150 patients were treated for a total of 6 cycles of
chemotherapy in the aprepitant and control arms, as noted in the safety
update to the NDA.

The safety findings over multiple cycles confirm the favorable profile
observed during cycle 1. This slide summarizes the incidences of
drug‑related or serious adverse experiences and those associated with
patient discontinuations as well as serious laboratory adverse
experiences and deaths. None of the numerical differences between the
groups was judged to be clinically significant. And there was no pattern
of clinically important adverse events with the aprepitant compared to
the control regimen.

The next slide illustrates the neutropenia observed during multiple
cycles of chemotherapy. The graph illustrates the potential for
aprepitant to affect the toxicities over time of concomitantly
administered chemotherapies based on the occurrence of neutropenia over
the course of six chemotherapy cycles.

The bars display the percentage of patients with neutropenia of NCI
grade 2 or greater; that is, less than 1,500 per cubic millimeter at
days 19 to 29. During each of the six cycles, the percentages of
patients with neutropenia were remarkably similar, indicating that the
hematological toxicity of concomitant chemotherapies does not change
over multiple‑cycle treatment with aprepitant. Overall, the adverse
experience profiles and laboratory data confirm that the good
tolerability observed during cycle 1 with aprepitant extends over
multiple cycles of chemotherapy.

In summary, the aprepitant regimen was well‑tolerated with incidences of
adverse experiences generally similar to standard therapy control.
Aprepitant did not significantly alter the toxicity of concomitantly
administered cisplatin or other chemotherapy agents, whether or not
metabolized by CYP3A4. And there was no evidence of increased
glucocorticoid toxicity.

There were no clinically important differences in the safety and
tolerability profile of aprepitant based on age, gender, race, or
primary cancer diagnosis. And aprepitant was well‑tolerated during
multiple cycles of chemotherapy.

[SUMMARY AND CONCLUSIONS]{.underline}

DR. REINES: I would like to conclude this presentation to the advisory
committee by sharing our perspective on the role of aprepitant in the
supportive care of cancer patients receiving highly emetogenic
chemotherapy.

When patients are diagnosed with cancer, they are immediately confronted
with the reality of having a life‑threatening disease. Next, they must
begin to consider the prospect of undergoing treatments that may be
debilitating and disruptive to their lives at a time when they may not
be physically impaired by the cancer itself. Clearly, at this time
patients would like to preserve their ability to function normally. The
symptoms of chemotherapy‑induced nausea and vomiting may reduce their
chances of doing that.

Since 1991, symptoms of highly emetogenic chemotherapy have been
partially preventable by use of 5‑HT~3~ receptor antagonists. These
drugs were quickly recognized as important therapeutic advances.
However, despite their use, many patients still experience nausea and
vomiting after emetogenic chemotherapy.

Patients still rank nausea and vomiting among the most distressing
symptoms caused by chemotherapy. In particular, delayed symptoms often
occur when patients are at home following each cycle of chemotherapy.
And they remain difficult to treat.

These Kaplan‑Meier curves, which Dr. Horgan presented earlier today,
illustrate \*\*patients in the control groups of our Phase III clinical
trials. The curves show the percent of patients who remain free of
emesis and the need for rescue medication.

By the end of day one, this proportion has already dropped below 70
percent. And after the five‑day observation period following their
chemotherapy, half or fewer patients in each control group were fully
protected, indicating additional loss of control during the phase of
delayed symptoms.

The graphs clearly illustrate the need for better antiemetic therapy
since all of these control patients were treated with the best currently
available treatment: a combination of a 5‑HT~3~ antagonist and a
corticosteroid.

Aprepitant was developed to address this need. Over the course of seven
years, we studied more than 3,000 patients, including more than 1,400 in
cancer chemotherapy trials. We chose to develop aprepitant as an
essential component of an antiemetic therapy regimen to be used in
conjunction with other antiemetic agents. In that way, we were able to
achieve unprecedented efficacy during both the acute and delayed phases
following highly emetogenic chemotherapy regimens.

The efficacy of aprepitant observed during cycle 1 was sustained over
multiple‑cycle treatment. In all trials, aprepitant was very
well‑tolerated.

Safety was demonstrated across a broad range of aprepitant doses in the
presence of various chemotherapeutic agents, in addition to cisplatin,
and with two different 5‑HT~3~ receptor antagonists. The overall safety
and tolerability of a three‑day aprepitant regimen was confirmed in the
Phase III clinical trials.

Returning to the Kaplan‑Meier curves, which now also illustrate in
yellow the results for the aprepitant regimen, we can clearly see the
marked clinical efficacy observed in the Phase III development program.

More than two‑thirds of the patients who received the aprepitant regimen
were protected from emesis or the need for rescue therapy over the
entire five days following their chemotherapy. This is a marked advance
over the current standard of care, again shown in blue.

The effect of aprepitant begins within 24 hours during the acute phase
of chemotherapy and is especially pronounced in prevention of delayed
symptoms over the next four days.

In conclusion, the aprepitant represents the first of a new class of
therapy, a Substance P antagonist at central NK~1~ receptors that
features a novel mechanism of action with distinct clinical benefits. As
a cornerstone of a regimen for prevention of nausea and vomiting due to
highly emetogenic chemotherapy, aprepitant provides marked symptom
reduction and improves upon the best available antiemetic therapy.

We hope that this new medicine may alter an enduring perception of
cancer chemotherapy by allowing most patients to undergo emetogenic
treatment without the inevitable fear of nausea and vomiting.

We are pleased to have had the opportunity to share our data with you
this morning. In closing, I would like to leave you with our proposed
indication for aprepitant. Thank you.

CHAIRPERSON CAMILLERI: Thank you very much.

[QUESTIONS AND PRESENTATIONS]{.underline}

CHAIRPERSON CAMILLERI: I would like to propose that we spend about ten
minutes now addressing some questions. I would like to thank the company
representatives for their very comprehensive and clear presentations to
us.

And I would like to propose to the committee members that in the first
part of the questions to the company we focus on issues that are not
already entertained in the brief that Dr. Justice provided us. For
example, I am sure we are going to come back later in the presentations
from the agency as well as perhaps questions this afternoon as we
discuss these several issues. We are going to need to address the
specific questions that you proposed pertaining to efficacy in nausea
and also the proportion of patients with other inducers of cytochrome
p450 3A4, which may not have been over‑represented in the patient groups
here.

So I would like the committee members in this first part of the
questioning to focus on specific issues pertaining to the presentations
we have just heard and not the general issues that were entertained in
Dr. Justice\'s opening arguments.

So the other thing I would like to do in the next 10 to 15 minutes
before we adjourn for a break is to try to focus the questions first on
areas pertaining to clinical pharmacology. Then we will have the break.
Then we will come back and deal with clinical efficacy and safety
issues.

So if that is acceptable to \*\*everyone ‑‑ and I am assuming it is ‑‑ I
would like to ask my colleagues on the committee whether you have any
questions pertaining to pharmacology. Perhaps we will address the
questions on 3A4 and numbers, et cetera, later, when we discuss this
with the agency\'s presentation.

Dr. LaMont?

DR. LaMONT: Yes, sir. I have a question about figures 28 and 39. There
seems to be no data provided on figure 28 for aprepitant plasma between
hour 24 and 48. Also, on slide 39, there is no data for days 2, 3, and
4, although you\'re giving the drug on those days. I just wonder why
those data weren\'t included or if they\'re soon to be unrevealing or ‑‑

DR. PETTY: Actually, if I can answer the question, if we could first go
to slide number 28, please? In this particular study, the data actually
weren\'t collected. We did not collect the detailed profile between 24
and 48 hours. So the plasma samples that were collected were from zero
to 24 hours the first day of the regimen and from 48 to 72 hours the
last day of the regime. So there is not a detailed plasma profile in
between day one and day three.

DR. LaMONT: Would you predict it would go up?

DR. PETTY: No. We would ‑‑

DR. LaMONT: Would it exceed the *p* count day one?

DR. PETTY: We think that would be unlikely based on the effect that we
see on day three. We also observe with the longer dosing of the five‑day
regimen that the trough concentrations remain relatively constant.

And if we could go to slide 39, I believe it was?

DR. LaMONT: Thirty‑nine.

DR. PETTY: Yes. And this experiment was conducted in a similar fashion.
The profiles for dexamethasone were collected only on day one and day
five, the first day and the last day of the regimen.

CHAIRPERSON CAMILLERI: Thank you.

Dr. Metz?

DR. METZ: Yes. Thank you.

I noticed in that slide that was just shown right there that you reduced
your dose of the steroid for the therapeutic arm of your trial because
of the induction that occurs. Do you have any data without steroids at
all?

I am interested in whether the effect on your delayed response is
steroid‑mediated because that is the proposed action of the steroids or
whether you are just boosting the effect of the steroids, you are
lowering the dose but you are getting your added effect that way. So do
you have any data at all without the steroids?

I realize your program is designed to add to an existing regimen, but it
seems to me conceivable that you could have a regimen without a steroid,
which in itself has potential side effects.

DR. PETTY: Well, for the effect that we see here with dexamethasone, the
approximate twofold increase, we adjusted downward for the dose of
dexamethasone to provide balanced dexamethasone exposure in the Phase
III studies. And the Phase III studies were conducted with dexamethasone
in both arms.

CHAIRPERSON CAMILLERI: So, to clarify that point, I think what Dr.
Horgan is going to say is that the aprepitant‑treated dose with steroid
dose with the aprepitant group was lower than in the control group. Is
that correct?

DR. PETTY: Correct. They\'re the same level.

DR. HORGAN: Right. And just to clarify the background to your question
and how we approached it philosophically in the program, we did a
monotherapy study first, which clearly showed the efficacy of aprepitant
in the prevention of delayed symptoms without any confounding factors.

Then, when we did a variety of Phase II studies, we studied aprepitant
in the context of concomitant corticosteroid therapy on day one. And we
again consistently showed efficacy in the prevent of delayed symptoms.

Then when we moved into the latter part of the program, when it was
clearly the established standard of care and recommended, for example,
in consensus guidelines that corticosteroids be administered during the
delayed phase, we evaluated aprepitant in the context of addition to a
standard therapy regimen.

Now, it\'s correct. We did not define precisely the relative
contributions in the later part of our program provided by aprepitant
and dexamethasone in the prevention of delayed. However, we clearly
demonstrated prior to that that aprepitant has a substantial effect in
the prevention of delayed symptoms.

DR. METZ: Except that you don\'t have any data without steroids except
for your monotherapy trial.

DR. HORGAN: Right.

CHAIRPERSON CAMILLERI: Dr. Desta?

DR. DESTA: Yes. I have a question of whether you have screened for
CYP2C8 and 2B6 because CYP2C8, even though paclitaxel is metabolized by
3A, there is also a component of 2C8. So at least the *in vitro* data
must be done for this purpose, I guess.

And the other one is CYP2B6. We know that cyclophosphamide and partly
absorbed ifosfamide, these drugs are primarily, including thiotepa also,
metabolized by 2B6. I wonder whether we have some at least *in vitro*
screening data for these isoforms.

The second question I have is, you mentioned address does not affect the
PK of your drug. And I saw in one of the documents that there is a
several‑fold increase in AUC of aprepitant.

So when do you say it is not clinically important in age, the group
with, if I am correct, a 74 percent increase in AUC? Is that correct?

DR. PETTY: You are referring to the effect of other drugs on aprepitant?

DR. DESTA: No, no.

DR. PETTY: I\'m sorry. I didn\'t ‑‑

DR. DESTA: On age.

DR. PETTY: Age? Oh, sorry. Yes.

DR. DESTA: Yes. And my last question is, you talk about the exposure
better, and you have shown PET data in your data analysis. I wonder
whether you did some time course of that because that will guide you
probably to the dosing interval of the drug. After a single dose, did
you do some sort of time course for the PET analysis?

DR. PETTY: If I can answer your first question first?

DR. DESTA: Okay.

DR. PETTY: You asked about effects, potential effects, of aprepitant on
CYP2B6 and CYP2C8.

DR. DESTA: Yes.

DR. PETTY: We have not specifically evaluated those in our *in vitro*
screens of microsomal turnover, although we have evaluated, in addition
to CYP3A4, several other cytochrome p450 enzymes. And there was no
evidence of inhibition of aprepitant of those cytochrome p450 enzymes.
It exclusively had an effect on CYP3A4.

So specifically, no, we have not evaluated CYP2B6 and 2C8 *in vitro*,
although our clinical data would suggest that there doesn\'t appear to
be a significant effect of aprepitant on drugs metabolized by those
enzymes.

For your second question regarding age, we specifically looked at the
potential effects of age on the pharmacokinetics of aprepitant in a
study in elderly subjects as well as a comprehensive analysis of all of
our Phase I data.

We found very slight effects, at most perhaps a 30 percent increase in
the AUC of aprepitant. We have found that in our clinical program,
aprepitant is a rather wide therapeutic index drug. And, as Dr. Reines
pointed out in some of our other studies with higher doses of aprepitant
given for much longer periods of time, we found that plasma
concentrations seven‑fold higher than those achieved with this regimen
have been very well‑tolerated. So we would conclude that a 30 percent
increase in AUC would not be clinically important.

And, to answer your third question, with regard to the PET studies, no,
we have no specifically done single‑dose PET studies. Given the
complexity of those studies, we were essentially only able to measure
the drug concentration and brain occupancy effects at a single time
point 24 hours after the last dose of aprepitant. Based on a
dose‑response, the plasma concentrations clearly correlated very well
with the brain occupancy.

CHAIRPERSON CAMILLERI: Dr. Cryer?

DR. CRYER: Thank you.

This is also for Dr. Petty. So one of the questions which we will be
focusing on is the potential for interaction of aprepitant with
chemotherapy, which is obviously similarly metabolized by CYP3A4. So in
that light, I would like to go back to slide 44, if we could.

The question is, as I understand it, these data are data with aprepitant
with its effects on docetaxel plasma concentrations. And this \*\*issue
is in your application and clinical practice, it is proposed to use
aprepitant as combination therapy with the 5‑HT~3~ antagonists as well
as with the corticosteroids. And so I really can\'t take this data and
generalize it to what we might expect to see in clinical practice.

So do you have any data with the combined therapy of the three, the
corticosteroids, the 5‑HT~3~ antagonists, along with aprepitant, with
regard to its effects on chemotherapeutic agents that would be
metabolized by CYP3A4?

DR. PETTY: Most of our drug interaction studies have been done with
aprepitant by itself to provide as clear a result as possible. We know
that the agents that are co‑administered in the regimen, the 5‑HT~3~
antagonists and the steroids, do not inhibit CYP3A4 activity, for
example. There is no evidence of that.

So we would not anticipate a different type of interaction when the
three agents are used together, but typically the results that we see
with aprepitant used by itself are fairly consistent with that, at most
a moderate effect on CYP3A4.

CHAIRPERSON CAMILLERI: Dr. Fogel?

DR. FOGEL: Thank you.

I have a question about the central binding of aprepitant. The
physiology related to vomiting indicates involvement of the vagal
complex in the area postrema. The PET studies that you showed on slides
29 through 31 show the cortex. And PET scans aren\'t particularly
effective in showing the vagal complex.

Do you have any data regarding blinding studies looking at the effects
of aprepitant on NK~1~ receptors in the dorsal vagal complex and the
area postrema?

DR. PETTY: This particular section, as you point out, is through the
striatum and one area of the cortex. We have examined other areas of the
brain. The PET scans can be examined throughout the entire area of the
brain.

And we find that aprepitant does displace the binding of the tracer and
from the receptor throughout all regions of the brain. And we have
demonstrated that this tracer does bind in the brain stem to the areas
in question.

CHAIRPERSON CAMILLERI: A subsidiary question, I think the brief shows
that there are autoradiographic studies that are more focused on dorsal
motor nucleus of the vagus and nucleus of tractus solitarius.

So can you tell us whether the other nuclei are like ambiguous in dorsal
motor nucleus, rather than the NTS, also have displacence of NK~1~?
Because those would be perhaps more relevant in the context of the
retching and the vomiting.

And a question for you, Dr. Petty. I saw the occipital cortex of the
cerebellum also lights up. So are there any toxicity studies looking at
cerebella or occipital visual cortical functions when you give the NK~1~
antagonist?

DR. HARGREAVES: Sir, I\'m Rich Hargreaves from pharmacology at Merck.

The answer to your question is the PET resolution when we analyzed the
data was for the brain stem only. The resolution is too poor to
distinguish between those nuclei. And so we have a parallel displacement
looking over the general area of the dorsal motor nucleus, but we can\'t
distinguish specific neuronal groups.

CHAIRPERSON CAMILLERI: But, to help the questioner, you do have data in
your profile, I believe, because I read it in the brief, that there are
autoradiographic studies in other animals that show binding to dorsal
motor nucleus of vagas or dorsal vagal complex which would be relevant
in its antiemetic effects.

DR. HARGREAVES: Absolutely. I mean, the NK~1~ receptor is present
throughout those nuclei. And there is a parallel displacement in
certainly the preclinical species, such as the ferret.

CHAIRPERSON CAMILLERI: Thank you.

Question about the occipital cortex or whatever is lighting up in the
back of the brain?

DR. PETTY: Yes. As shown on the PET scans, the tracer binds to NK~1~
receptors within their known distribution, which would include many
cortical areas. Actually, they are a very low concentration of receptors
in the cerebellum. And the tracer actually reflects that as well,
although it is not displayed on that particular slide.

We have not observed, particularly in our clinical studies, again, at
doses much higher and given for much longer duration of time, any
adverse experiences that would be related to potential effects on
vision.

CHAIRPERSON CAMILLERI: Ms. Cohen? Thank you.

MS. COHEN: As you know, I\'m the consumer member. So you have to bear
with me while I ask you some questions.

First of all, I noticed that in your clinical trials, you did four
children. What percentage of the members in your trial were special
populations? I guess I am part of the special population.

And I have a few more questions. Would you like me to give them all at
once? Do you mind?

CHAIRPERSON CAMILLERI: If they are not on clinical pharmacology, can I
suggest that we pick them up later?

MS. COHEN: Well, I do have a curious question. On chemotherapy, on the
drugs that are used in chemotherapy, how many drugs did you test your
aprepitant against?

Also, is there a common denominator within all of the chemotherapy drugs
that do induce the nausea and the vomiting?

CHAIRPERSON CAMILLERI: Thank you.

DR. HORGAN: I will answer your second question first. We used cisplatin
because it is the prototypic drug for evaluating a novel antiemetic. The
precise mechanism of how cisplatin and other chemotherapeutic agents
invoke nausea and vomiting is not completely understood.

As Dr. Petty mentioned, cisplatin and some of the other therapeutic
agents have been shown to invoke the release of serotonin from the
enterochromaffin cells in the gut. And clearly they are likely to elicit
the release of Substance P acting at the NK~1~ receptor in the brain
stem.

Apart from those two mechanisms, it is not really understood what the
precise mechanisms are that are responsible for evoking the symptoms.

Does that answer your question?

MS. COHEN: If I\'m allowed to say something more? To a certain extent.
And that in itself is a puzzle to me in terms of how this all works,
obviously.

I am also interested in how you dealt with the patients who were getting
chemotherapy in the normal controls and how you can simulate the kinds
of things that would happen.

DR. HORGAN: Well, the assessment of efficacy was done in patients
receiving cancer chemotherapy. So all of our assessments of efficacy
were done in that patient population. So we were doing clinical trials
in the context of clinical practice.

MS. COHEN: And the special population, what percentage of that?

DR. HORGAN: In fact, we actually enrolled in the Phase III program a
total of six adolescents. The data are mentioned in the background for
four. Those were I think the only patients that you would describe as
being special that didn\'t conform to the general enrollment criteria of
the general trials.

MS. HOGAN: Well, in the aging population, like me, how many of those did
you have?

DR. HORGAN: Well, that was included in our general population.

MS. HOGAN: Yes, but ‑‑

DR. HORGAN: And that was ‑‑

MS. HOGAN: Thank you.

DR. HORGAN: ‑‑ more than 30 percent of the patients.

MS. HOGAN: At what age? Do you have any idea?

DR. HORGAN: It would be 65. Approximately 30 percent were more than 65.

MS. HOGAN: Thank you very much.

CHAIRPERSON CAMILLERI: Dr. McLeod?

DR. McLEOD: A clinical pharmacology question for Dr. Petty. It\'s two
different questions, each with eight parts.

(Laughter.)

DR. McLEOD: No. There are two specific questions that are interrelated.
And they really go around the area of variability.

First of all, if you could maybe walk us through your selection of a
fixed dose versus milligrams per meter^2^ or other individualized dosing
approaches and also talk a little bit about the linearity of the
pharmacokinetics of this agent across the different doses that were
utilized, recognizing that the starting dose for patients may change as
there is further experience gained with this agent.

DR. PETTY: If I can address your second question first? I believe your
first question is related to the dose of chemotherapies, if I\'m not
mistaken. Sorry.

DR. McLEOD: No. All about the dose of this agent.

DR. PETTY: Of aprepitant?

DR. McLEOD: Yes.

DR. PETTY: I see. In that case, the doses of aprepitant used at
125‑milligram, 80‑milligram are the only doses that we are proposing for
this particular indication. They are not adjusted per meter^2^.

We have demonstrated that for these two doses, there is slight
nonlinearity in the pharmacokinetics of the drug in that there are
slightly higher plasma concentrations as the dose is increased.

We did study other doses as well. And we determined with this particular
regimen with the dose of 120 milligrams on day one and 80 milligrams on
subsequent days that it provides a relatively consistent plasma
concentration across the time interval that we\'re looking.

We did study the kinetics in elderly patients with renal insufficiency,
hepatic insufficiency, found relatively minor effects that would not
necessitate dose adjustment of aprepitant. So we would not recommend
dose adjustment for other situations.

DR. McLEOD: When you look across the more extensive doses that you used
during your Phase II and Phase I programs, when you talk about
nonlinearity, how dramatic is this nonlinearity as you expand the
dosing?

DR. PETTY: Well, for these two doses specifically, which are the only
two doses we\'re proposing for clinical use, if I can refer to one of my
slides here ‑‑ I\'m sorry. It will take just a minute. We\'re getting
there. Just a second. If we could have slide 1324, please?

CHAIRPERSON CAMILLERI: I\'m wondering whether this might be a good time
to have a very brief break, let you find the information you want, and
then come back to the same questions from Dr. McLeod. And then Dr. Cryer
will resume questions as well.

Let\'s take a five to ten‑minute break. And we will be back at 10:50.

(Whereupon, the foregoing matter went off the record at 10:41 a.m. and
went back on the record at 10:53 a.m.)

CHAIRPERSON CAMILLERI: I would like to bring the meeting back to order.

Thank you, Dr. Petty. You are back at the podium.

Dr. McLeod, would you like to remind us of the two questions? And then
Dr. Petty will respond.

DR. McLEOD: The questions really are posed around trying to understand
the degree of variability in pharmacokinetics across the doses that have
been evaluated, including the doses which you have put forward for the
indication. So understanding the linearity across those doses and then
within that will help answer the question of a fixed dosing versus
dosing individualized to something like body weight or body surface
area.

DR. PETTY: Sure. If I can have slide 1332, please? This was a study
actually designed to assess the dose proportionality of aprepitant. In
this case, it was given as a colloidal dispersion.

What was done was in healthy subjects, doses as low as 10 milligrams up
to as high as 600 milligrams, which spans the dose range that we are
proposing ‑‑ as you can see, this was the AUC in those subjects.

And it was fairly linear throughout the entire range here. So, at least
with respect to the area under the curve and the drug, it is fairly
linear over this particular dose range.

DR. McLEOD: So the nonlinearity referred to earlier, was that looking at
intra‑patient differences in pharmacokinetics when they got the loading
dose versus the subsequent doses or is it just a population mean at the
‑‑

DR. PETTY: No. That was only comparing two doses in a healthy
population, a pharmacokinetic study.

CHAIRPERSON CAMILLERI: Dr. Cryer?

DR. CRYER: I just wanted to briefly come back to this issue of
pharmacokinetics with the combined antiemetic regimen. So from your
clinical trial experience of patients who received the combined
antiemetic regimen, there are no pharmacokinetic evaluations of the
chemotherapy regimen. Was that correct?

DR. PETTY: Correct. In cancer patients, in the Phase III studies,
pharmacokinetic data were not collected, although the safety profile of
patients who were receiving the standard regimen both on ondansetron and
dexamethasone compared to the aprepitant regimen, in which all three
agents were given indicates that the safety profile was similar between
the two groups. And we would conclude that there probably were not
significant pharmacokinetic interactions on that basis.

CHAIRPERSON CAMILLERI: Dr. Kelsen?

DR. KELSEN: Can we ask a nonclinical pharmacology question yet?

CHAIRPERSON CAMILLERI: Are we done with clinical pharmacology? Dr. Houn?

DR. HOUN: Hi. Florence Houn.

I am just interested in Dr. Malcolm Rowland\'s opinion on slide 44 and
his interpretation of what he thinks is happening.

DR. PETTY: Can we have slide 44, please?

DR. ROWLAND: Yes. This is obviously a study and it was indicated an
ongoing study of looking at whether or not the target aprepitant
affected docetaxel. These are obviously gained as you go along in the
clinical study. They\'re not easy to do, and you couldn\'t do these in
normal volunteers.

What this basically is saying is that there is virtually no effect of
the aprepitant on the docetaxel kinetics in this regimen. This is a
clinical dosage of the drug.

So the right‑hand side is basically to look at the issue which does come
up, and that is variability. You can get people high or low. And what
you are seeing is that looking at any one with respect to themselves as
individuals, there are no real changes that you can observe.

DR. HOUN: Is this expected?

DR. ROWLAND: Yes. The issue was a lot of the chemotherapeutic agents are
given intravenously. And I think the data, the body of data, coming out
is that aprepitant doesn\'t have a strong effect on inhibition
systemically. Its main effect appears to be at the inner wall level. I
think that is what we are seeing with the data in general.

CHAIRPERSON CAMILLERI: Dr. Levine?

DR. LEVINE: Just had a question about the rescue medications, whether it
was a variety of benzothiazides, whether it was up to the discretion of
the individual investigators, or if they all were limited to one,
compazine or something else.

DR. HORGAN: The choice of a rescue medication was entirely left to the
discretion of the investigator. We did provide a list of recommended
medications, but the specific agent chosen was based entirely at the
discretion of the investigator.

And a wide variety were used. More than 40 percent of the patients who
received rescue received metoclopramide, and then the other specific
agents were all used in less than 10 percent of patients. There was a
wide variety.

What we were really meticulous about was the instructions about when
patients could take rescue. And that\'s where we really focused the
precision of our instructions.

CHAIRPERSON CAMILLERI: I think we should ask Dr. Horgan to stay there
now because we are going to open the questions for clinical efficacy.
Dr. Kelsen, you had the first question.

DR. KELSEN: So this touches a little bit on the point of oral and
intravenous drugs. You have indicated that this agent has effects on
some drugs and not on others in the clinical pharmacology. And we talked
a lot about toxicity. And it looks like it doesn\'t affect chemotherapy
toxicity that much.

Do you have data on chemotherapy effectiveness? About 40 percent of your
patients had lung cancer. I assume a number of those regimens were the
lung cancer regimens. Do you have data on outcome to indicate that it
doesn\'t affect therapeutic efficacy of the treatment of the disease?

DR. HORGAN: We did not formally assess the efficacy of chemotherapy in
these clinical trials. We followed the paradigm of the 5‑HT~3~ receptor
antagonists.

As you mentioned, many of the patients had lung cancer, but they also
had a wide spectrum of cancers. It\'s not possible in the context of a
trial like this to formally assess the efficacy of chemotherapy.

In general, the toxicities that we saw that would be predictably
associated with chemotherapy were well‑balanced between the treatment
groups, indicating that there was unlikely to be any pharmacokinetic
explanation as to why the efficacy of chemotherapy should be altered.

DR. KELSEN: There are about 200 patients in each group who had lung
cancer, right? We don\'t have data on response rate or survival or
anything?

DR. HORGAN: No. It wasn\'t possible given the heterogeneity of the
patient populations, their specific diagnoses, their specific regimens.
That has been the practice in these trials. It\'s not, as you know, to
actually formally evaluate the efficacy.

DR. KELSEN: I guess my interest was the concern that there is an
interaction with some pharmacokinetic interactions, but you have
answered my question. Thank you.

MS. HOFFMAN: In terms of the pediatric population and clinical efficacy,
one thing that I would like to say, I guess, is that you mentioned that
you didn\'t do a study arm without the use of steroids.

From the pediatric population, the impact of steroids can sometimes be
as difficult to deal with as the nausea and vomiting from a parent
perspective, the mood swings, the moon face, that sort of thing. So a
study arm spanning the pediatric population without the use of steroids
might be something to look at and to see the effectiveness of your study
drug without steroids.

CHAIRPERSON CAMILLERI: Thank you for the comments.

Dr. Proschan?

DR. PROSCHAN: Yes. I was wondering. You measured nausea on a visual
analog scale, but you presented results in terms of nausea less than
five yes or no. I am wondering whether you did any kind of analysis of
it in a continuous way.

DR. HORGAN: Yes. We have looked at nausea very comprehensively. And the
bottom line is that, whatever way we look at it, we consistently see an
advantage for the aprepitant regimen.

And, actually, if I could have slide 203? The reason we used the visual
analog scale was because of its greater sensitivity. And if I can just
walk you through this slide, which shows the data for both protocols
combined? And it shows the distribution of maximum visual analog scale
ratings over each of the five days, the maximum reading over each of the
five days in which patients gave recordings.

So on the horizontal axis, you see the peak nausea score. And then on
the vertical axis, you see the percentage of patients. So, for example,
if you look at a peak nausea rating of 40 and you look at the vertical
there, what you are seeing is this represents the percentage of patients
who have a peak nausea score of 40 or less. And you can see that there
are more patients in the aprepitant group who have a peak score of 40 or
less.

Now, where we drew our lines for our two pre‑specified endpoints were at
5 and at 25. You see at those cutoffs, we had an advantage in the
aprepitant group.

Now, we could have drawn those vertical lines right across the spectrum
of peak nausea scores. And we would ultimately have gotten the same
outcome.

We pre‑specified those for the reasons that I gave because there were
prior precedents. And they correlated with impact on daily life. And
this difference for the analysis of the continuous data was
statistically significant.

CHAIRPERSON CAMILLERI: Dr. Metz?

DR. METZ: Thank you.

I was thinking about what Dr. Kelsen was saying. I don\'t know if it has
been fully addressed. Excuse the naivete of all of this, but I don\'t
know anything about NK~1~ receptors. Does anyone know where in the body
NK~1~ receptors are distributed? Especially are there any NK~1~
receptors on any kind of tumor types at all? Has anyone looked?

DR. HORGAN: There is some data that NK~1~ receptors are expressed by
tumor cell lines, gliomas, some breast cancer lines, and some small cell
line cancer lines.

The significance of those is not definitively known. There is some
suggestion that blockade of those receptors may alter the growth
characteristics, reduce the growth of those tumor cell lines. And that
is basically the extent of the current knowledge with regard to that.

CHAIRPERSON CAMILLERI: Dr. LaMont?

DR. LaMONT: Yes. I have a question relating to emesis and nausea on
slides 107 and 108. I am just trying to reconcile the data given in
slide 107, which says that at week 6, approximately 75 or 80 percent of
the aprepitant patients had no nausea; whereas, if we look in the left
panel of slide 108, it looks like the percentage of patients with emesis
is less than that.

I just don\'t understand. I am trying to reconcile these two slides and
to understand the apparent decline in efficacy. So it\'s a two‑part
question.

DR. HORGAN: Okay. Well, the background to this is this is the assessment
of efficacy during multiple cycles of chemotherapy. And there is a
variety of ways to look at this data to provide insight into the
efficacy profile.

The first one that we showed in 107 is the observed proportion of
patients without emesis and without significant nausea. The information
derived from the two questions that patients were asked at each
chemotherapy cycle.

What we are illustrating here is a snapshot at each cycle of what the
outcome was for those two variables. And it\'s not linked, the outcome
in each cycle is not linked, to what happened in the preceding cycle.
It\'s a snapshot at each cycle. This is the efficacy profile that we
see.

I don\'t think that you can really make an inference so much as to what
is happening, the trend over the cycles, within each treatment group. I
think the key message here is the relative difference between the
treatment groups at each individual cycle.

Then in the next slide, 108, this is a Kaplan‑Meier approach. In this
case, for the time to first emesis, a patient having emesis in the first
cycle is obviously lost, then, in the analysis for subsequent cycles. So
it\'s a different way of looking at the data. And the outcome at each
cycle reflects what is the outcome in previous cycles.

Again, the key message here is not so much the trend within each
treatment group. It is the relative efficacy, the advantage afforded by
aprepitant during each cycle. It is simply a different way of looking at
the data.

CHAIRPERSON CAMILLERI: Dr. Brawley?

DR. BRAWLEY: Do you have any data about dose reduction chemotherapy
cycle to cycle?

DR. HORGAN: Could you clarify?

DR. BRAWLEY: I am wondering if patients were given less chemotherapy in
cycle 2 and cycle 3 versus cycle 1 or perhaps because of less nausea,
maybe even the patients were able to get full doses of cisplatin in
cycle 2 through ‑‑

DR. HORGAN: Right. We didn\'t actually look at the dose that was
administered in subsequent cycles of chemotherapy. We didn\'t
specifically address that question.

CHAIRPERSON CAMILLERI: Dr. Proschan, I will follow you.

DR. PROSCHAN: Okay. Thank you.

You know, in some of your slides, like the last one you show, you have
got both of those protocols, 052 and 054, combined. And in others, you
look at them separately. I don\'t mean to be cynical, but I am guessing
that the combined ones are when you didn\'t have significance of either
one separately.

DR. HORGAN: Well, the displays are really done for combined for reasons
of convenience. We did not do statistical testing on the data for the
multiple cycle. So these are displays of efficacy.

And the bottom line is that a similar picture was seen in the individual
displays.

CHAIRPERSON CAMILLERI: Dr. Horgan, I have a question pertaining to
whether the 40/25 regimen is really less effective. I would like to
refer you to your charts 82 and 83 because there is something there that
I don\'t completely understand.

DR. HORGAN: Here you see the 40/25 regimen has an overall complete
response rate of 59 percent. In 83, next slide, please. Somehow when you
look at the information separately for acute and delayed, it goes up
from 59 to 76 and 64. And here there doesn\'t seem to be a significant
difference.

So my question to you is, is it true that the minimum effective dose
perhaps or the maximum dose here is the 125/80 relative to the 40/25?

DR. HORGAN: Right. Well, the first part of your question, the apparent
discrepancy, there isn\'t a precise correlation between efficacy in the
acute phase and the delayed phase. There is a correlation, but it\'s not
precise.

So some patients here who had controls during the acute phase of the 76
percent of patients would have gone on to have symptoms in the delayed
phase and vice versa, which is why when you merge the two phases below,
that the overall response that you\'re seeing, the 59 percent you
mentioned, is actually lower than what you see in the delayed phase
alone because the correlation is not precise.

And if you go back to slide 82? So what we saw in the data that we
gathered in this study for the spectrum of endpoints that we used, there
was consistently always a numerical advantage for the 125/80 milligram
regimen versus the control regimen.

And then when we did a formal analysis for the primary endpoint of
overall complete response, we saw a statistically significant difference
here, justifying our selection of the 125/80 dose.

CHAIRPERSON CAMILLERI: Ms. Cohen?

MS. COHEN: I want to make sure I understood Dr. Kelsen\'s question and
your answer to him in terms of the effectiveness against medication or
an anti‑chemotherapy. You didn\'t study if there was any relationship to
the efficacy of the drug itself affected by aprepitant?

DR. HORGAN: We did not formally assess whether aprepitant altered the
efficacy of chemotherapy.

MS. COHEN: Well, then would it not be appropriate to tell a patient that
\"We can reduce your nausea and vomiting, but we don\'t know the effect
of the chemotherapy, how it affects the chemotherapy\"? I would want to
know that. I think I am entitled to know that. Wouldn\'t you think so as
a patient?

DR. HORGAN: Well, the data we have on the drug strongly suggest that
there is no interference with the pharmacokinetics of the chemotherapy
that the patient is administered; in other words, the levels of the
chemotherapy.

MS. COHEN: Well, was that specifically studied?

DR. HORGAN: Yes.

MS. COHEN: Go ahead. And I have one other question, then. I didn\'t know
if there were other chemotherapy drugs that you didn\'t test with
aprepitant. That would be my second question.

DR. REINES: Sorry. If I could comment on your question because it is so
critical? If we could have slide 133? Although it is not possible in
studies of this size and duration to formally assess the efficacy of the
chemotherapy regimen on the cancer, as a surrogate of that, we look
carefully at the toxicity due to the chemotherapy because the efficacy
would be expected to be related to how much toxicity the chemotherapy is
causing. This essentially is a measure of the exposure the patient gets
to the chemotherapy at the level of the bone marrow.

As you can see, I emphasized in my presentation that there wasn\'t more
neutropenia in the aprepitant group, but there is not less neutropenia
either, which means that there should not be any less exposure in those
patients.

And so, as a surrogate of efficacy since we couldn\'t measure pure
efficacy of the chemotherapy regimen, we looked very carefully at
parameters like this. And we didn\'t find any evidence that there might
be a reduction in the exposure to the chemotherapy agent.

CHAIRPERSON CAMILLERI: Dr. LaMont and then Dr. McLeod.

DR. LaMONT: Yes. You list a death rate of 6.8 percent in the aprepitant
group out of 413 patients versus 5.3 in the controls. I wonder if any of
those deaths are attributable, in part or in total, to aprepitant.

DR. REINES: During the first cycle of chemotherapy, the death rate was
20 in the aprepitant group and 21 in the control regimen. So it was very
evenly balanced. Over multiple cycles, we observed the death rates that
you described.

If we could go to slide 515, please? Sorry. If we go to 516 first, this
shows the death rate by cycle beyond cycle 1. And, as you can see, there
is no pattern there of an increase, although it does lead up to this
small differential that you mentioned.

If we go to 517, this displays over the multiple‑cycle data the
percentages 6.8 and 5.3 and the primary causes. None of these were
attributed to aprepitant. And they were virtually all attributed to the
underlying disease in the patients.

CHAIRPERSON CAMILLERI: Dr. McLeod?

DR. McLEOD: My question is actually more probably for Dr. Horgan. There
are three main components to chemotherapy‑induced nausea and vomiting.
The acute and the delayed phase you have presented the information on. I
wondered if you had any data on the degree of anticipatory nausea and
vomiting that occurred during cycles 2 and beyond as a way of
understanding the level of control that the two arms evaluated had
during the first cycle of chemotherapy.

DR. HORGAN: Right. Unfortunately, we didn\'t formally assess that
because, as I mentioned, our approach to the collection of efficacy data
during multiple cycles was streamlined and simply reflected the two
questions that patients were asked at the day six to eight clinical
visit. So we didn\'t formally assess the incidence of anticipatory
symptoms.

CHAIRPERSON CAMILLERI: Thank you.

I believe we have had enough questions on the presentation from the
sponsors. I would like to invite the FDA presentation. The first
presentation is on the clinical summary by Dr. Gary Della\'Zanna. He
will be followed by pharmacology by Dr. Jarugula.

[FDA PRESENTATION]{.underline}

[CLINICAL SUMMARY]{.underline}

DR. DELLA\'ZANNA: Good morning. My name is Gary Della\'Zanna. I\'m a
medical officer in the Division of Gastrointestinal and Coagulation Drug
Products at the Food and Drug Administration.

I would like to take the time to introduce the other divisions involved
in this presentation. Dr. Wen‑Jen Chen is a mathematical statistician
from the Division of Biometrics II. And Dr. Venkat Jarugula is a
clinical pharmacology reviewer from the Office of Clinical Pharmacology
and Biopharmaceutics.

During today\'s presentation, I will give a brief background of
aprepitant, touching on a treatment regimen and the proposed indication.
Efficacy results will be presented for the \*\*primary endpoint and some
of the secondary endpoints that are relative to the proposed indication.

I will present the questions the agency has in regard to the dose of
highly emetogenic cisplatin and our safety concerns for potential
drug‑drug interactions. Following my presentation, Dr. Jarugula will
explain the metabolism of aprepitant in detail and the potential for
drug‑drug interactions.

On September 27, 2002, Merck and Company submitted a new drug
application for aprepitant. Aprepitant is a New molecular entity that,
if approved, would be the first in a new therapeutic class, the NK~1~
receptor antagonist. At the time of the submission, the applicant
requested and was granted priority review status.

The proposed treatment regimen is a three‑drug therapy that includes
aprepitant in combination with a 5‑HT~3~ antagonist and a
corticosteroid. The applicant has requested an indication for the
prevention of acute and delayed nausea and vomiting associated with
initial and repeated courses of highly emetogenic chemotherapy.
Aprepitant would be the first drug to be granted an indication that
includes the delayed phase of chemotherapy‑induced nausea and vomiting.

One of the questions the agency has is in regard to the primary endpoint
and whether the submitted data supports the proposed indication. The
primary endpoint for both Phase III studies was defined as complete
response in the overall phase. A patient was considered to have complete
response if they did not vomit and did not require rescue therapy. The
overall phase was from zero hours to 120 hours after the administration
of cisplatin.

The complete response endpoint was evaluated and analyzed for three
distinct time periods, the overall phase being the primary endpoint with
the acute and delayed phases being secondary endpoints.

Since the proposed indication is for nausea and vomiting in the acute
and delayed phases, each were analyzed independently as secondary
endpoints.

The agency reviewed the applicant\'s data and concurs with the results
of the major analysis. The sponsor successfully demonstrated the
aprepitant regimen was superior to standard therapy for the primary
endpoint, complete response in the overall phase, as well as the
secondary endpoints of complete response in the acute and delayed phases
and the no vomiting endpoints in the overall, acute, and delayed phases.

Next slide. Results of the no nausea endpoints, however, were not as
persuasive. This table displays the results of the no nausea endpoints
for the two Phase III studies.

The nausea endpoints were evaluated for three time periods using two
separate criteria that were based on a 100‑millimeter visual analog
scale. The no nausea endpoint was defined as a VAS rating of less than
five millimeters with no significant nausea being less than 25
millimeters.

I would like to draw your attention to the top portion of this chart for
the no nausea endpoint. The no nausea endpoints were only statistically
significant in the overall and delayed phases of study 054. The
aprepitant regimen did not reach statistical significance in the acute
phase of study 054 or any of the three phases in study 052.

Additionally, the no significant nausea endpoint, shown here on the
lower half of this table, was only statistically significant in the
acute phase of study 054 with an unadjusted *p* value of 0.01. Because
several predefined secondary and exploratory endpoints were analyzed,
the nominally significant results cannot be taken at face value due to
multiple comparisons.

The agency agrees with the firm that the results of the nausea endpoints
may have been affected by the use of rescue therapy. Twenty‑eight
percent of the patients in the standard therapy group required rescue
therapy compared to 18 percent in the aprepitant group.

Furthermore, time to analysis showed that the time interval for the use
of rescue therapy was longer in patients in the aprepitant group than
the standard therapy group.

However, since this would be the first time that the agency granted an
indication for chemotherapy‑induced nausea and vomiting in a delayed
phase and the results of the nausea endpoints independently were not
statistically significant, the agency would like the committee\'s
opinion on whether the data supports the applicant\'s proposed
indication.

The agency would also like comment from the committee regarding the dose
of cisplatin considered highly emetogenic. This dose varies in the
medical literature\*\*. In the clinical trials that led to the approval
of ondansetron, a highly emetogenic dose of cisplatin was greater than
100 milligrams per meter^2^. The present ondansetron label describes the
range of 50 to 80 milligrams per meter^2^ as a moderate emetogenic dose.

The aprepitant Phase III protocol clearly defined a highly emetogenic
dose of cisplatin as greater than or equal to 70 milligrams per
meter^2^. In spite of this, approximately 20 percent of the patients in
these studies received less and were still included in the efficacy
analysis.

As part of the submission, the firm included recent literature that
defines a highly emetogenic dose of cisplatin as greater than 50
milligrams per meter^2^.

The agency performed additional analysis excluding patients who received
less than 70 milligrams per meter^2^. And the efficacy was maintained
for the primary endpoint of complete response in the overall phase as
well as the secondary endpoints of complete response in the acute and
delayed phases.

The agency\'s question for the committee is whether any or all of the
patients in the Phase III trials received a highly emetogenic dose of
cisplatin.

Additional concerns the agency has are related to potential drug‑drug
interactions that have not been thoroughly evaluated. Aprepitant has a
complex metabolic pathway. It has been identified as a substrate, a
moderate inhibitor, as well as an inducer of CYP3A4. In addition to
this, aprepitant is also an inducer of 2C9.

The proposed treatment regimen states aprepitant may be used in
combination with any 5‑HT~3~ antagonist and a corticosteroid. The
applicant has exposure and pharmacokinetic data for only ondansetron and
granisetron.

In these drug interaction studies, aprepitant did not have clinically
important effects on the pharmacokinetics of the specific drugs in the
formulations studied. The agency does not have any data for the
intravenous formulation of granisetron or the oral formulation of
ondansetron.

Because of first pass metabolism, the inhibitory effect is greatest in
the oral formulation. Therefore, one cannot extrapolate PK results from
the intravenous ondansetron studies to its oral formulations.

One needs to consider that oral antiemetics may be utilized as rescue
therapy. This could result in higher plasma concentrations of these
drugs.

Additionally, within the class of 5‑HT~3~ antagonists, there are
differences in metabolic pathways. Both ondansetron and granisetron are
predominantly metabolized by CYP3A4. Dolasetron, however, is metabolized
by carbonyl reductase to hydrodolasetron. Further metabolism is then
through CYP2D6, 3A4, and flavin monooxygenase.

The agency presently has no data on the use of the aprepitant regimen
with dolasetron. This is a concern since it is the only 5‑HT~3~
antagonist that has QTc and cardiac warnings in its label.

Since dolasetron utilizes different metabolic pathways than ondansetron
and granisetron and there are no exposure data on the use of the
aprepitant regimen with dolasetron, the agency seeks advice as to
whether the regimen proposed in the label should specify only the
5‑HT~3~ antagonists that have been studied. Additionally, the agency
would like the committee\'s opinion on whether any additional studies
are recommended for dolasetron and/or the oral formulation of
ondansetron.

During the Phase III trials, approximately 95 percent of the patients
received a concomitant chemotherapeutic agent in addition to the
protocol cisplatin. The agency questions whether enough safety data
exists to use aprepitant with all chemotherapeutic agents at highly
emetogenic doses.

Presently there are no completed PK data available regarding drug‑drug
interactions of the aprepitant regimen with other chemotherapeutic
agents.

The applicant does have an ongoing drug interaction study with
docetaxel, which is primarily metabolized through 3A4 pathways. The
available data for the five patients enrolled has been reviewed by the
agency. The data suggest that the aprepitant regimen has no effect on
plasma concentrations of docetaxel.

Aprepitant is a moderate inhibitor of 3A4. The agency would have
anticipated some effect on the metabolism of docetaxel considering the
effect the aprepitant regimen had on other drugs evaluated.

The agency questions whether docetaxel is a sensitive enough probe and
has concerns as to whether the results of the pending docetaxel study
can be used to make generalizations about the safety of the aprepitant
regimen with all oncologic agents metabolized through 3A4 pathways.

One well‑documented drug‑drug interaction was identified during the
development of aprepitant. During the Phase IIb trials, an interaction
with dexamethasone was identified. This ultimately \*\*led to the
sponsor redefining the aprepitant regimen for the Phase III trials and
resulted in a decrease in the dexamethasone dose by 50 percent in the
aprepitant group.

Similar drug‑drug interaction studies have not been completed with
chemotherapeutic agents metabolized through 3A4 pathways. This will be
discussed in further detail during the biopharmaceutical presentation.

During the Phase III trials, in addition to the protocol cisplatin, 517
patients were treated with a concomitant chemotherapy metabolized
through 3A4 pathways. In spite of the number of patients, there is only
limited safety data on most 3A4‑metabolized agents.

Common agents known to be 3A4 substrates are listed here along with the
number of patients that received them. Of these, the applicant has no
safety data for irinotecan or imatinib and has only very limited
information on several others. Although specific PK data is not
available for any of these, there is reasonable exposure data for
paclitaxel, vinorelbine, and etoposide.

Overall, the incidence of adverse events was similar between treatment
groups in patients receiving 3A4‑metabolized chemotherapy. However, when
analysis was performed of serious adverse events by body system, a
higher incidence of hematologic and infection‑related adverse events was
seen in the aprepitant group during cycle 1.

In the aprepitant group, septic shock was reported in three patients,
sepsis in one patient, and a serious upper respiratory infection in one
patient. In the corresponding standard therapy group, there were no
reports of these serious adverse events.

Neutropenia was reported as a serious adverse event in eight patients
receiving the aprepitant regimen compared to only two patients in the
standard therapy group. The incidence of anemia and thrombocytopenia
were similar between treatment groups.

It is worth noting that during the multi‑cycle extension, the incidence
of hematologic serious adverse events appear to be similar between the
treatment groups. The applicant did perform additional safety analysis
broken down by concomitant chemotherapy for the most common agents used
during the Phase III trials.

In order to focus on the primary concerns, the remainder of this
presentation will address serious adverse events in patients who
received concomitant chemotherapy metabolized through 3A4 pathways.

Going in order by number of patients exposed, the first agent we will
discuss is etoposide, which is a 3A4 substrate. During the Phase III
trials, 197 patients received etoposide in combination with cisplatin.
This breaks down to 106 patients in the aprepitant group and 91 patients
in the standard therapy group.

Overall, the incidence of serious adverse events in this population was
similar between treatment groups, occurring in approximately 15 percent
of the patients.

By analyzing the distribution of these adverse events by body system, it
was noted that three times as many serious hematologic adverse events
occurred in the aprepitant group.

Neutropenia, thrombocytopenia, and anemia were reported as serious
adverse events only in the aprepitant group. When you include both
serious and non‑serious infection‑related adverse events, there were
more than twice as many patients reporting an infection in the
aprepitant group. Eighteen percent of the patients in the aprepitant
group developed an infection compared to nine percent in the standard
therapy group. Furthermore, only patients in the aprepitant group
reported serious infection‑related adverse events.

The agency is concerned over this trend. However, the numbers of
patients are too small to establish any conclusions.

The next most common 3A4‑metabolized agent was vinorelbine. A total of
158 patients were treated with this in combination with cisplatin. The
incidence of serious adverse events was higher in the aprepitant group
than the standard therapy group.

Overall, the incidence of serious hematologic adverse events was similar
in both treatment groups. However, serious infection‑related adverse
events were higher in the aprepitant group. Four patients in the
aprepitant group were described as having a serious infection compared
to two in the standard therapy group. There were three reported cases of
sepsis or septic shock as serious adverse events, and all occurred in
the aprepitant group.

On further analysis, there was a marked difference in the incidence of
serious respiratory‑related adverse events. Six of the 82 patients in
the aprepitant group compared to only one of the 76 patients receiving
standard therapy experienced a respiratory‑related serious adverse
event.

There were no patients in the standard therapy group who experienced
respiratory insufficiency; whereas, four patients receiving the
aprepitant regimen developed a fatal respiratory insufficiency. In
addition to these four fatalities, \*three deaths occurred in this
subpopulation of the aprepitant group. Two patients died from septic
shock and one from cardiopulmonary arrest.

In the corresponding standard therapy group, there were only two
fatalities reported. One patient died as a result of a pulmonary emboli.
And the other patient\'s cause of death was reported as unknown.

Vinorelbine is known to have pulmonary toxicity. The agency has concerns
that the aprepitant regimen may have affected this toxicity since all
fatal cases of respiratory insufficiency occurred in the aprepitant
group. The regimen may also increase the risk of serious infections in
patients receiving vinorelbine. However, the numbers are too small to
draw any definite conclusions.

The next most common 3A4‑metabolized chemotherapeutic agent was
paclitaxel. A total of 110 patients were treated with paclitaxel in
combination with cisplatin. On analyzing the data, there was little
difference between treatment groups for hematologic or infection‑related
adverse events.

The remaining chemotherapeutic agents characterized as 3A4 substrates
either had no or too few patients to permit meaningful analysis. This is
a concern for the agency because of potential drug‑drug interactions.
And the proposed label offers little guidance to the prescribing
physicians.

Under the \"Precautions\" section of the label, the applicant states,
\"EMEND should be used with caution in patients receiving concomitant
medicinal products that are primarily metabolized through CYP3A4. Some
chemotherapy agents are metabolized by CYP3A4.\"

The agency would like the committee\'s opinion on whether the present
safety data is adequate and whether any additional drug‑drug interaction
studies should be performed since several of the chemotherapeutic agents
had too few patients to establish a safety profile.

To better understand the agency\'s concerns, the Office of
Biopharmaceutics will present their findings now. And then we will have
questions.

DR. JARUGULA: Thank you, Dr. Dalle\'Zanna.

[BIOPHARMACOLOGY SUMMARY]{.underline}

DR. JARUGULA: Good morning. I am Venkat Jarugula, clinical pharmacology
and biopharmaceutics reviewer of the nda. Dr. Myong Jin Kim of my
division has also been doing giant review with me of this NDA.

This morning the sponsor has already discussed the pharmacological
properties of aprepitant. So I am not going to repeat this. For the next
20 minutes, I am going to present on drug interactions of aprepitant.

My presentation is divided into the following. First I will give a brief
introduction on the metabolism of aprepitant. Then I will present the
results of key drug interaction studies that demonstrate aprepitant as a
CYP3A4 inhibitor and then discuss the effect of other drugs on
aprepitant followed by drug interactions with 5‑HT~3~ antagonists. Then
I will discuss the most important issue, the potential of aprepitant to
interact with chemotherapy agents that are metabolized by CYP3A4,
followed by my conclusions.

Aprepitant is extensively metabolized in humans, primarily by oxidation
by CYP3A4 isozyme. Based on the *in vitro* and *in vivo* studies,
aprepitant regimen is shown to inhibit CYP3A4 as early as one hour after
drug administration on day one. Aprepitant regimen induces CYP2C9
isozyme.

Upon multiple dose administration for more than two weeks, aprepitant
induces its own metabolism by autoinduction. This phenomenon is not
relevant for the current indication. However, this may be important for
chronic administration of aprepitant.

Next slide. This slide shows the effect of aprepitant on various CYP3A4
substrates. The AUC ratio of the CYP3A4 substrate with and without
concomitant administration of aprepitant is given in this chart. For
comparison, the AUC ratio of control is given as one.

As can be seen here, the aprepitant regimen significantly inhibited the
metabolism of midazolam, which is a sensitive CYP3A4 substrate. As can
be seen here, the aprepitant regimen significantly inhibited the
metabolism of midazolam, a sensitive CYP3A4 substrate, resulting in a
3.34 increase in AUC on day five of aprepitant regimen.

Dexamethasone, as you see, also was increased by 2.24 of this
interaction. Sponsor has reduced the dose of dexamethasone in clinical
studies by half the drug standard regimen for chemotherapy‑induced
nausea and vomiting.

The diltiazem, as you see, also was increased by 1.74.
Methylprednisolone, also a CYP3A4 substrate, when administered after all
administration with aprepitant, diltiazem is a significantly higher AUC
change of 2.54 compared to its IV administration of 1.344. This
interaction suggests that aprepitant as a CYP3A4 inhibitor has less
effect on IV‑administered drugs compared to the oral‑administered drugs.

Based on these interactions, the sponsor has, in fact, recommended in
the proposed package insert that the IV dose of methylprednisolone be
reduced by 25 percent and the oral dose of methylprednisolone be reduced
by 50 percent when co‑administered with aprepitant.

Next slide. This just shows the effect of CYP3A4 inhibitors or inducers
on aprepitant. Again, the AUC ratio of aprepitant with or without
concomitantly administered CYP3A4 drug is shown here.

Ketoconazole, an important CYP3A4 inhibitor, significantly increased AUC
of aprepitant by five‑fold while diltiazem, a moderate CYP3A4 inhibitor,
resulted in an increase of two‑fold change in the AUC of aprepitant.

Dexamethasone resulted in a modest increase of 30 percent in AUC. On the
other hand, rifampin, an important CYP3A4 inducer, resulted in
production of almost an 11‑fold change in AUC of aprepitant.

It should be noted that these drugs are not a part of aprepitant\'s
regimen, and the sponsor included a caution in the label when these
drugs are to be co‑administered.

The other significant drug interactions of aprepitant, aprepitant
regimen reduces the S‑warfarin. And the INR also is reduced by
aprepitant. Therefore, the patients on warfarin need to be monitored
carefully when aprepitant is co‑administered with warfarin.

Upon multiple dosing for two weeks, the aprepitant reduces the level of
ethinyl estradiol by 40 percent and reduces the efficacy of oral
contraceptive. This interaction is relevant for the current application
of aprepitant. However, since the aprepitant regimen for three days is
not studied, sponsor has appropriately recommended in the label to use a
backup contraceptive method for a woman.

Many chemotherapy agents are substrates for P‑glycoprotein transporter.
Aprepitant regimen does not significantly affect the P‑glycoprotein
transporter as there is no effect on the pharmacokinetics of digoxin,
which is a P‑gp substrate. Therefore, aprepitant regimen is not likely
to interact with chemotherapy agents via the P‑gb transporter mechanism.

The drug interactions with 5‑HT~3~ antagonists, two pharmacokinetic drug
interactions were conducted. These studies showed that aprepitant does
not significantly affect the pharmacokinetics of IV ondansetron and oral
granisetron. However, there is no data on PK drug interaction with oral
ondansetron.

In general, the pharmacokinetic interaction with oral administration of
drugs is greater than intravenous administration, mainly because of the
inhibition of the dose effect involved in oral administration. However,
the package insert for ondansetron states that \"This drug is
metabolized by multiple p450 isozymes. Therefore, significant drug
interactions are not likely.\"

Furthermore, there is no PK drug interaction data with dolasetron. It is
reported that dolasetron is metabolized by multiple metabolic pathways
with carbonyl reductase and CYP2D6 being the main pathways. And CYP3A4
plays a minor role.

Therefore, the pharmacokinetic interaction with dolasetron is not
likely. However, as Dr. Della\'Zanna mentioned, there is no clinical
safety data on co‑administration of aprepitant with dolasetron.

Coming to the most important issue today, the potential of aprepitant to
interact with chemotherapy drugs metabolized by CYP3A4. As mentioned
previously, aprepitant is a moderate CYP3A4 inhibitor.

Many chemotherapy drugs are known to be metabolized by CYP3A4. And,
therefore, concomitant administration of aprepitant may increase the
systemic exposure to these chemotherapy agents and may result in serious
or life‑threatening toxicity.

Next slide. The NDA does not consist of any control drug‑drug
interaction studies with these chemotherapy agents except an ongoing
study with IV docetaxel. Although many chemotherapy agents are known to
be metabolized by CYP3A4, there is inadequate information in the
literature regarding the role of CYP3A4 in the metabolism and regarding
the drug‑drug interactions with CYP3A4 inhibitors.

There are two studies reported in the literature with ketoconazole. One
study reported that the ketoconazole increases the exposure of SN‑38,
the active metabolite of irinotecan, by 100 percent.

Another study reported that ketoconazole does not significantly affect
the pharmacokinetics of paclitaxel as this drug is metabolized by
multiple pathways. This result is consistent with the lack of safety
signal noted by Dr. Della\'Zanna in the safety database of the NDA for
patients who are on paclitaxel.

As Dr. Della\'Zanna also discussed, there is some safety data available
in the NDA for patients who are on etoposide, paclitaxel, and
vinorelbine. However, there is minimal or no data available on
co‑administration of aprepitant with irinotecan, ifosfamide, imatinib,
vinblastine, and vincristine, which are also known to be CYP3A4
substrates.

As mentioned previously, there is a drug interaction study ongoing with
IV docetaxel. The primary data on five patients show no interaction with
docetaxel.

Since the docetaxel is known to be metabolized by CYP3A4, it is rather
surprising to see no effect of aprepitant on docetaxel. Therefore, the
interaction results of docetaxel may not be generalized to other
chemotherapy agents.

As mentioned previously, the sponsor\'s proposed package insert in the
\"Precautions\" section states that \"EMEND should be used with caution
in patients receiving concomitant medicinal products that are
metabolized through CYP3A4. Some chemotherapy agents are metabolized by
CYP3A4.\"

However, the label does not list these chemotherapy agents, and the NDA
does not contain any information or data to provide dosage adjustment or
appropriate caution when aprepitant is co‑administered with these
chemotherapy agents.

Conclusions. Aprepitant is extensively metabolized in humans, primarily
by a CYP3A4 isozyme. Potent inhibitors increase the aprepitant exposure
significantly. Potent inducers reduce the aprepitant exposure
significantly. And based on the drug‑drug interaction studies,
aprepitant is known to inhibit the CYP3A4 metabolism of the
co‑administered drugs.

Co‑administration of aprepitant with the chemotherapy agents that are
metabolized by CYP3A4 may increase the exposure to these agents and may
result in serious or life‑threatening toxicity.

Finally, the potential of aprepitant to interact with the chemotherapy
drugs that are metabolized by CYP3A4 has not been characterized
adequately.

This concludes my presentation. Thank you very much for your attention.

CHAIRPERSON CAMILLERI: Thank you, Dr. Della\'Zanna and Dr. Jarugula.
Maybe you should both be at the microphone now to address questions from
the committee members pertaining to your presentations. Dr. Kelsen?

[QUESTIONS ON PRESENTATIONS]{.underline}

DR. KELSEN: Well, I thank you for that review. I think the point we were
discussing a few minutes ago is that, is there a chance that the
antiemetic will affect outcome from the therapy?

I think there are two sides to that. You have discussed toxicity. I
guess I would just make the comment that, unfortunately, there is not a
direct correlation between therapeutic efficacy and toxicity with many
chemotherapeutic agents. That is, not all patients who have serious
toxicity also have an excellent response.

The MTDs are developed because that is the maximum dose that you can
give. But making assumptions that because you don\'t see much more in
the toxicity, you, therefore, will see equal efficacy\*\*, that may not
be a direct correlation.

CHAIRPERSON CAMILLERI: In fact, wasn\'t the analogy that since there
wasn\'t less toxicity, there should be similar therapeutic efficacy?

DR. KELSEN: Yes. I guess what I am trying to say is that I do understand
the hypothesis, but I think that\'s a hypothesis, hasn\'t been proven.

I also am aware that it is not usual to look at therapeutic endpoints
with antiemetics, but the reason I asked that before is that many
antiemetics don\'t apparently have this degree of drug‑drug interaction.
So I think it is a little bit of a different situation.

CHAIRPERSON CAMILLERI: Dr. LaMont?

DR. LaMONT: Yes. I wonder if there was a clustering in the same patients
of infectious adverse events and neutropenia or can you tell if these
are separate or the same patients?

DR. DELLA\'ZANNA: I\'m not sure from the data that I have right now. I
don\'t know if the firm would have any input on that, if that was
clustered together.

DR. REINES: Seven eighty‑seven, please. Okay. So this is the infections
in the total population in Phase III, cycle 1. And, as you can see, most
of the infections are not neutropenic infections, either in the
aprepitant or in the control regimen.

CHAIRPERSON CAMILLERI: Dr. Levine?

DR. LEVINE: Just to follow up that slide and Dr. LaMont\'s question.
It\'s of interest in very large studies in hepatitis, interferon causes
neutropenia, but it doesn\'t seem to be causing a correlation with
infection very often.

There is a disconnect because if one looks at the individual white count
and then go down to neutrophils percentage and then go down to the
absolute neutrophils, there is a much better correlation.

So I wondered perhaps later at a time ‑‑ you probably don\'t have that
data ‑‑ whether the absolute neutrophil count, the percent in the
absolute neutrophil count, was, in fact, a disconnect, as opposed to the
data you showed. But it is interesting that that large data didn\'t seem
to show a very good correlation either.

DR. DELLA\'ZANNA: Well, one of the concerns the agency has wasn\'t
necessarily related specifically to the incidence of serious adverse
events as much as the incidence of serious adverse events for specific
chemotherapeutic agents.

We realize that the numbers that we were talking about were small and
the differences were small. But when you broke them down specifically ‑‑
for example, can you go to slide 16?

Etoposide. Overall, the incidence of serious adverse events was
identical, but when you looked at them specifically for neutropenia,
there were three times as many. The results that the firm has presented
have been serious adverse events overall inclusive of both CYP3A4 and
non‑CYP3A4 or CYP3A4s completely inclusive.

Now, like paclitaxel, we saw no difference at all in either hematologic
or infection‑related adverse events. So I don\'t think we can look at
them as a broad class and say, \"All CYP3A4 chemotherapeutic agents are
going to have the same safety profile.\"

And that was one of the other reasons I emphasized and pointed out that
the docetaxel study may not be something that we can rest a lot of our
faith on because it had absolutely no effect on plasma levels.

I would have anticipated at least a minimal effect, something that we
could have at least seen as a normal comparison. I think we would have
predicted approximately like a 15 percent effect.

CHAIRPERSON CAMILLERI: Dr. Brawley?

DR. BRAWLEY: Out of some ignorance, aren\'t we dealing here not just
with different drugs but also with different polymorphisms of CYP? I
mean, so that is an entirely different variable.

DR. DELLA\'ZANNA: Right.

CHAIRPERSON CAMILLERI: Did you want to expand on the inference from your
comment?

DR. BRAWLEY: Well, I\'m wondering if we need to try to look at I guess
if I were to put it into a simple question, are there perhaps
populations that I would define, not necessarily by race, maybe even
area of geographic origin, but define by the polymorphism of the p450
that they have who might be dosed very differently with this drug or
with some of the other drugs that we are using.

DR. JARUGULA: To address the polymorphism, in general among the CYP 450
isozymes, the isozymes 2B6 and 2C9 are known to have extensive
polymorphisms. They are poor metabolizers and tend to be metabolizers.

There may be some information in the literature coming up recently on
the polymorphisms of various CYP3A components, but we don\'t have a good
handle I think on the polymorphisms of CYP3A, and this drug is mainly
metabolized by CYP3A4.

Among the components that are to be given with the aprepitant which are
corticosteroid, dexamethasone, and 5‑HT~3~ antagonist ondansetron,
these, specifically 5‑HT~3~ antagonists, are less prone to drug‑drug
interactions because they have multiple metabolic pathways.

So I am not sure if there is any more information that can be added to
address the issue of the polymorphism.

CHAIRPERSON CAMILLERI: Dr. Metz?

DR. METZ: Yes. Thank you.

One of the questions that FDA has asked us to look into is whether we
think all 5‑HT~3~ drugs in the class should be considered the same, but
after your presentation, my understanding is that you would be less
concerned with dolasetron than you would with the other two 5‑HT~3~\'s.
Can you confirm that? That is question number one.

Question number two relates to anti‑fungal agents. I think many of these
patients develop thrush, for example, and end up getting anti‑fungals.
Nobody has actually raised this as a specific concern, but I am
wondering if you think that should be something that should be looked at
carefully.

DR. JARUGULA: Regarding the first question, the interaction with
dolasetron, based on its multiple metabolic pathways, we don\'t think
that there will be a significant pharmacokinetic interaction. However,
there could be a pharmacodynamic interaction or there could be a
different safety profile when aprepitant is administered with the
dolasetron, specifically as Dr. Della\'Zanna mentioned. Dolasetron is
known to have QT prolongation and other cardiac side effects.

Regarding the second question about anti‑fungal agents, ketoconazole,
which is an important CYP3A4 inhibitor, actually significantly reduced
the AUC of aprepitant by about five‑fold. That is quite a bit of
significant interaction, and it is a concern that needs to be brought
out properly or adequately in the label.

CHAIRPERSON CAMILLERI: Dr. Metz, is it fair to say that the fungal
infections don\'t usually happen in the first couple of days?

DR. METZ: I have thought about that, but the truth is we have got to
realize these patients are going through multiple cycles of chemotherapy
and are going to be getting repetitive regimens. And you can certainly
pick up your fungal infection in an intervening period and come up for
chemo in due course.

CHAIRPERSON CAMILLERI: Thank you.

Dr. Fogel?

DR. FOGEL: I also have a question related to the ketoconazole. The
ketoconazole is a very potent inhibitor of the 3A4 enzyme, actually much
more potent than aprepitant. Do you have any data on ketoconazole
effects on chemotherapeutic agents?

DR. JARUGULA: As I presented in one of my slides, there are two studies
reported with ketoconazole. One study showed that the ketoconazole
increases the AUC of the irinotecan active metabolite by 100 percent.
And the other study showed that ketoconazole does not affect the PK of
paclitaxel. These are the two studies we have come across with the
chemotherapy agents with ketoconazole.

DR. FOGEL: Can we use ketoconazole as a surrogate for aprepitant
effects?

DR. JARUGULA: The problem in using ketoconazole as a surrogate is that
midazolam is a sensitive CYP3A4 substrate for measuring these
interactions.

If you compare the interaction with midazolam for ketoconazole and the
aprepitant, aprepitant only results in a 3.34 change in AUC. But
ketoconazole can go up to a 16‑fold change in AUC.

But, again, with chemotherapy agents, depending on the sensitivity of
those agents to the CYP3A4 isozyme, a change of two‑fold or even less
than two‑fold could be concerning in terms of its toxicity.

So there is not adequate information in the literature to say or to rank
these chemotherapy agents in terms of their metabolism by CYP3A4. So
that is a difficulty unless you study with main chemotherapy agents that
are known to be metabolized by CYP3A4. I would think that you may not be
able to credit the interaction.

CHAIRPERSON CAMILLERI: Dr. McLeod?

DR. McLEOD: I\'m trying to solidify opinion on how much we should care
about the drug interactions in terms of the change in blood levels of
the aprepitant and not its effect on other drugs but, rather, its change
in blood levels.

Some of the data that was presented, we tried to get this out from Dr.
Petty during the discussion, but there seems to be a fairly wide index,
a therapeutic index, with this agent.

I wondered, with your review of the data, which is obviously more
extensive than you are able to present during the short presentation
time here, whether you had a feel for whether even a doubling or a
halving of blood level would likely change the place a patient would be
on that sigmoidal affect curve that was demonstrated during the
applicant\'s presentation.

DR. JARUGULA: Yes. Regarding the dose‑response of the aprepitant,
sponsor has investigated three dose regimens, 40/25, 125/85, and
375/250. Based on the trough concentrations that you can expect from
these dose regimens, you don\'t expect a significant improvement in
efficacy, going from 125/85 to 375/250.

The efficacy is almost maxxed out at 125/85 regimen if that is your
question. I can see where you\'re coming from there, but if you are
using rifampin or something like that.

If your blood levels were decreasing, were cut in half, for example, I
don\'t have a feel from reading the data that was provided to us whether
that is likely for the efficacy to fall off the curve at that point. You
know, there was a sigmoidal curve, and there is quite a lot of
variability shown, at least with the standard deviation.

DR. McLEOD: How about in the other direction?

DR. JARUGULA: As far as I know, in the dose‑ranging studies, I think
that\'s the only place where they have tested multiple dosage regimens.
And in the Phase III, only one dosage regimen was tested.

For the lowest dose regimen, 40 milligrams, 25 milligrams, the sponsor
reported that the efficacy was not maximal. However, it was shown to be
efficacious. But it was not at the maximal response that you hope for.

CHAIRPERSON CAMILLERI: Dr. Desta?

DR. JARUGULA: But regarding how much lowering of plasma levels would
interfere with the efficacy, certainly rifampin reduced the \*\*blood
levels by 11‑fold. And that is a lot of change in the blood levels. The
efficacy I think would be affected.

DR. DESTA: In most of the presentations, three of four is mentioned. I
never heard about three of five. And that is polymorphic, actually. It
could also influence the drug interaction profoundly. It could also
influence some of the pharmacokinetics. That is one question for the
company and for you guys.

The second question is you mentioned that dolasetron has multiple
metabolites. And you would not expect any drug interaction with the
aprepitant. Is that correct?

DR. JARUGULA: Yes, that is correct.

DR. DESTA: Yes. If you have, for example, a poor metabolizer which is
not producing any enzyme 2B6 because it seems that 2B6 is the enzyme
which is metabolizing the active modifier by the carbonyl reductase,
then if you put on top of that like aprepitant, wouldn\'t you expect any
significant drug interaction in that respect?

DR. JARUGULA: If that main metabolic pathway is shunted to a different
metabolic pathway, which is 2C8, it is possible that you could see an
interaction with aprepitant. It is possible.

CHAIRPERSON CAMILLERI: Is that a question about 3A5?

DR. JARUGULA: The question regarding 3A5, in the NDA data package, I
haven\'t seen any information on CYP3A5 isozymes specifically. If
sponsor has anything more to add, I don\'t know.

CHAIRPERSON CAMILLERI: Ms. Hoffman?

MS. HOFFMAN: I guess my question was fairly similar. I just wondered if
there was data looking at further downstream mechanism, molecular
mechanisms, and then potential drug‑drug interactions from the
downstream molecular changes as well.

DR. JARUGULA: That\'s a good question. As alluded to in the
presentation, aprepitant on chronic administration induces its own
metabolism. And there is a conclusion in the NDA that aprepitant induces
CYP3A4 isozyme also.

So that could lead to a different scenario of interactions where
aprepitant might induce the metabolism of the co‑administered drugs and
result in lower efficacy if it is administered chronically. So that is a
significant issue when this drug is going to be considered for the
chronic administration.

CHAIRPERSON CAMILLERI: Dr. Proschan?

DR. PROSCHAN: Yes. You mentioned the multiplicity issue with respect to
some of the secondary outcomes, nausea being one of them. It seems to me
that there is a big multiplicity issue with the adverse events as well,
namely you are looking at many different drugs, many different organ
systems. It seems like it would be pretty likely that you would find one
of them with a nine to three difference.

DR. DELLA\'ZANNA: Right. We are not playing that down, and we realize
the numbers that we are talking about and the differences that we are
talking about are small.

However, we are concerned that we don\'t have enough information to draw
a conclusion, and we have to work with the numbers that we have.

CHAIRPERSON CAMILLERI: Dr. Cryer?

DR. CRYER: One of the things that caught my attention from the
sponsor\'s presentation was this difference in adverse event rates in
the multiple‑cycle extension versus just cycle 1. And most of the data
that you showed us with respect to the adverse events were from cycle 1.

I was wondering what sorts of patterns you might have observed with
respect to cycles 2 through 6 with specific regards to the adverse
events.

DR. DELLA\'ZANNA: The serious adverse events balanced out a little more
during the multi‑cycle extension. Okay? But one of the concerns I had
regarding, for example, like vinorelbine, we had a fair number of
pulmonary problems that occurred. And if you removed those patients from
the multi‑cycle extension, then the number of patients exposed is also
smaller.

Overall, most of the things they focused on which were the greatest
differences were during the cycle 1.

DR. CRYER: In follow‑up to that, I would like to follow up with the
sponsor for that specific question. So I believe, Dr. Reines, on the
very last slide which you showed us that had to do with infections
during cycle 1, I don\'t remember the specific number, but it was the
last one that you requested to be shown, that was cycle 1 data. Would
you happen to have similar data for cycles 2 through 6 with respect to
infection?

DR. DELLA\'ZANNA: Can I just clarify one of my concerns, too, which may
not be able to be demonstrated on that slide? The slide that we are
going to see is maybe multi‑cycle extension data, but it is not broken
down specifically to the areas of concern that the agency has, which are
specifically the individual CYP3A4 chemotherapeutic agents.

Overall I tried to include that in my presentation, that overall the
incidence of serious adverse events as a whole was similar between the
two treatment groups. It\'s only when we broke these out and looked at
the specific chemotherapeutic agents that we started seeing some small
but definite differences. These differences are where we are focused on
concerns.

If we see another slide that shows that overall in cycle 2 through 6
that the serious adverse events were the same, I don\'t think it\'s
going to answer the agency\'s concerns.

DR. REINES: I don\'t think I have that same breakdown of infections, but
I can show the serious adverse events that occurred. If I could have
509, please? If we look at serious adverse events over multiple cycles,
the incidences were very similar between the two treatment groups. And
the more common are indicated on this slide.

CHAIRPERSON CAMILLERI: Okay. Perhaps just for clarification, Dr.
Della\'Zanna, can you tell us a little bit more about the vinorelbine
pulmonary toxicity that concerns you? The specific question I have is,
is it just conceivable that there were more people with lung cancer in
the aprepitant group relative to the control arm?

DR. DELLA\'ZANNA: Overall the incidence of cancers was pretty
well‑balanced within each group. So to say that this population had a
higher prevalence of lung cancer that would have resulted in this bias I
don\'t think was what occurred.

CHAIRPERSON CAMILLERI: Can the sponsor specifically answer that
question? Among the people with pulmonary or respiratory problems in the
vinorelbine‑treated group, were there more in the aprepitant group who
happened, for instance, to have been lung cancer patients than in the
other group?

DR. DELLA\'ZANNA: Most of the serious respiratory or fatal respiratory
insufficiencies occurred at the same site. So I am not sure as far as
the numbers specifically for the balance of vinorelbine for lung
cancers.

DR. REINES: Could I talk about those patients, the vinorelbine patients,
for just a moment? I want to emphasize that myelosuppression is the
dose‑limiting toxicity with this agent and that we did not see an excess
there.

In terms of the patients with respiratory insufficiency, these did occur
at one site, as was mentioned. At this site, we specifically spoke with
the investigator. These were all patients with lung cancer, although
there was not an imbalance of lung cancer between the aprepitant and
control groups.

However, these patients did not have the respiratory insufficiency
typical of vinorelbine; that is, the acute dyspnea that occurs within a
day or two. These were chronic patients. And the investigator said they
died of their lung cancer. They did not have any sort of bronchospasm or
acute dyspnea.

CHAIRPERSON CAMILLERI: Dr. Brawley, did you have a question? Go ahead,
Mike.

DR. PROSCHAN: I had a question on a different topic. I don\'t know if it
is appropriate, but it was about the nausea. The rescue medication, is
that something that is given at the time someone is feeling nauseous? Is
it given like if I am nauseous today, I get it and then two days later,
I get it again if I am nauseous again or is it given from then on?

DR. DELLA\'ZANNA: No. The rescue medication was administered upon
complaints of nausea. It wasn\'t something that was scheduled. As a
matter of fact, the firm actually while still blinded analyzed the use
of \"rescue medication\" to make sure that it was appropriately given.
And they did a good job isolating those patients out to make sure that
it wasn\'t just given prophylactically where somebody said, \"Oh, I
might get nauseous.\"

DR. PROSCHAN: It sounds like there are a fair number of people who got
rescue medication and checked or put a mark that is less than five on
that VAS score. I am wondering if they just didn\'t remember. I mean,
they had to be rescued from something. Maybe they didn\'t know that even
if you don\'t vomit, you could be nauseous.

DR. HORGAN: Right. We were very careful about the instructions that we
proffered the patients. I think one of the key issues that one has to
bear in mind and that maybe didn\'t come out in my presentation is
emesis is easy.

The patients had a diary. They recorded the emetic event. When they took
rescue, they recorded the time of the rescue event. Nausea is from
one\'s own personal experience a much different entity. The patients
were taking daily ratings of their nausea experience over the preceding
24 hours. And so the correlation between their actual experience of
nausea on a given day is different than it was for the other efficacy
elements: emesis and rescue.

We did look carefully to corroborate the fact that the patients were
actually taking rescue for nausea. And we saw that the patients that
took rescue did, in fact, have higher nausea ratings than the patients
who did not take rescue. So we are confident that it was an effective
surrogate of the experience of nausea for the patients.

Does that address your question adequately?

DR. PROSCHAN: Yes.

CHAIRPERSON CAMILLERI: Ms. Cohen?

MS. COHEN: Maybe you already presented it, but how often did people in
your clinical trials have to take rescue medication as a percentage?

DR. HORGAN: We presented the data in my presentation that actually
showed the percentage of patients who took rescue at least once. That
was a component of our primary endpoint. So we had approximately 20 to
25 percent of the patients in both of the Phase III trials took rescue
at some point.

MS. COHEN: Did you delineate between one, two, three, or four or just ‑‑

DR. HORGAN: For the purposes of the primary endpoint, we did not, but we
did enumerate all of the occurrences of rescue therapy. And we saw that
consistently the patients in the control group were taking more rescue.
They were taking rescue more frequently than the patients in the
aprepitant treatment group.

CHAIRPERSON CAMILLERI: Do the committee members have any other
questions?

(No response.)

CHAIRPERSON CAMILLERI: If not, this is a good time for us to take a
break. We plan to be here again at 1:10 so that we can start the
proceedings for the afternoon. Thank you very much.

(Whereupon, at 12:15 p.m., the foregoing matter was recessed for lunch,
to reconvene at 1:10 p.m. the same day.)

A‑F‑T‑E‑R‑N‑O‑O‑N S‑E‑S‑S‑I‑O‑N

(1:12 p.m.)

[OPEN PUBLIC HEARING]{.underline}

CHAIRPERSON CAMILLERI: Okay. Good afternoon. We are now at the stage in
the proceedings where we would invite the open public hearing or
presentation. And we have not yet received any notification of such a
presentation. Is there anybody from the public that wishes to make such
a presentation at this time?

(No response.)

CHAIRPERSON CAMILLERI: If not, I think we should move on to the next
item. Really, it is to ask Dr. Justice to address the committee and give
us the charge.

[CHARGE TO THE COMMITTEE]{.underline}

DR. JUSTICE: Well, our charge to the committee really is brief. And, as
I discussed this morning, now that you have heard the presentations, we
would appreciate your discussion and vote on those questions.

As you can tell from the questions and the presentations, we are
particularly concerned about the potential for drug‑drug interactions,
particularly with chemotherapy drugs that are metabolized by CYP3A4.

So that is basically all I want to say. I think we can move to the
committee\'s discussion of the questions and votes.

CHAIRPERSON CAMILLERI: Thank you very much. Are we going to present the
questions or are they on a slide?

DR. JUSTICE: They are on a slide and in your handouts, I think, as well.

CHAIRPERSON CAMILLERI: Okay. Just to remind the committee members, as we
address each question, if there are areas of clarification where we
still wish perhaps the sponsor to give us some further information for
clarification, I think we still have an opportunity to do so.

Also, we will need to go around the table. And each individual member of
the committee will be asked to give a vote yes or no. If I forget to
specify your name before you give your vote, please remember to give
your name so that it is there for the record.

Okay. The first question, has the aprepitant regimen been demonstrated
to be effective in the prevention of nausea and vomiting in the acute
phase and in the delayed phase?

I guess the first thing I need to ask is are members around the
committee wishing to have some further clarification on any of these
issues? Dr. McLeod?

[DISCUSSION OF QUESTIONS]{.underline}

DR. McLEOD: I think one of the issues that has come up is the issue of
effectiveness against vomiting versus effectiveness against nausea.

I would like some further clarification of this because the question
that is going to be posed to us includes both. And so I wouldn\'t want
to have to err on one side or the other without being clear if we can
divide the question or at least understand specifically what is on the
table there.

CHAIRPERSON CAMILLERI: Okay. I think we are going to have some
restricted time for some clarification from the sponsor with regard to
the specific point.

DR. HORGAN: I think it\'s compellingly clear that our data shows that we
have efficacy in the prevention of both nausea and vomiting with our
primary endpoint. I would like to show slide 96, the primary endpoint of
complete response being a patient having no emesis and taking no rescue
therapy and highly significant advantages for the aprepitant regimen
with the primary endpoint ‑‑

DR. HOUN: Okay. I\'m not sure where. The question on the table was how
we should ask the question should be divided. I am not really sure if
people are wanting to go through show us the data again about this
before we vote.

May I ask, Dr. McLeod, is it that you are asking in terms of how you
should vote? You are questioning whether the \"and\" phrase, \"nausea
and vomiting in acute phase,\" \"nausea and vomiting in delayed phase,\"
should it be voted as nausea and vomiting or you were asking whether it
should be separated as nausea in the acute phase, vomiting in the acute
phase? Is that your question?

DR. McLEOD: I guess so, yes. I mean, I don\'t know what the procedure is
in this context, but certainly the data for one of those areas is
dramatically more compelling than the other.

I didn\'t know which way we probably are going to vote; either way you
want it. But I just wanted clarity that if we have to be \*\*100 percent
for both of those indications, then that may sway some of the votes
versus whether we disbelieve that it is a good antiemetic, as opposed to
anti‑nausea, agent.

CHAIRPERSON CAMILLERI: So let me just ask for a clarification from Dr.
McLeod. Would it make it easier if the question were posed, is this
medication effective for vomiting in the acute phase and the delayed
phase? That\'s one question.

Second question, is this medication effective or have the data been
demonstrated that it is effective in the context of nausea in the acute
phase and the chronic phase, or the delayed phase?

DR. McLEOD: Yes. I think that\'s really getting to the gist of what I am
trying to ask because practically speaking, it doesn\'t matter. You
don\'t treat nausea and vomiting separately. You give therapy for them
together.

Going by the data that has been presented, the data is certainly much
stronger for vomiting than it is for nausea.

CHAIRPERSON CAMILLERI: I actually think that I am trying to understand
how that can be clarified further by data that the sponsor may have. I
think there has been ample opportunity to tell us what the primary
endpoint is.

I guess what the people around the table might need to decide for
themselves is whether the complete response in the lack of use of
antiemetic medication safety constitutes a surrogate for the symptom of
nausea.

I think that is what it comes down to ultimately because the nausea, no
significant nausea and no nausea demonstrated by the VAS of ‑25 or up to
5, the data had been presented. And I don\'t think that it will be
useful to present them again.

Is that clear?

DR. ERB: I do think that there is an opportunity here to clarify a
little bit more on the nausea and response, too, to the impact on
patients\' lives, which I think is an equally important measure that has
not been presented so far.

CHAIRPERSON CAMILLERI: Okay. Dr. Horgan, let\'s have two minutes with
one pivotal slide to convince us more than what we have just addressed
here?

DR. HORGAN: Well, I think that the single slide that I would like to
show is slide 203, which just emphasizes that for the data that we
collected, the continuous variable of nausea over the entire spectrum,
maximum nausea ratings, we saw a consistent advantage for aprepitant,
which was statistically significant. The data was similar for both the
individual studies and was statistically significant from one of those
studies.

So, in addition to the data that I have shown for this particularly
troubling symptom, we also had data assessing the impact of nausea and
vomiting on patients\' daily lives.

Now, the committee hasn\'t seen that data, but I think that provides
compelling additional information that illustrates the consistency of
the effect that we saw in the prevention of nausea. And also it provides
information on the clinical significance of the effects that we saw.

So I think that it may be valuable to see for the committee to have an
opportunity to see that data. My colleague can present that.

CHAIRPERSON CAMILLERI: I think that it probably isn\'t necessary at this
stage. Thank you very much.

I think we can go back to Dr. Houn\'s question.

DR. HOUN: I think that if you do want to split them out, you can, but we
would want you to vote also on this question, the combined.

CHAIRPERSON CAMILLERI: That\'s fine. We can certainly address the
question. Are there any specific questions or questions of further
clarification pertinent to question number 1 that the members of the
committee wanted to address? Dr. Metz?

DR. METZ: Yes. I think we need to define the regimen because that comes
up in later questions, but when you say, \"Has their regimen been
demonstrated?\" that is the study drug regimen used in each of these
pivotal trials, one with granisetron, one with ondansetron. Is that
correct?

DR. JUSTICE: That\'s correct.

DR. LaMONT: Yes. I would like to hear from the clinical oncologists
about the separating out of these symptoms because it seems to me that
they are virtually inseparable.

DR. JUSTICE: I think there is not a significant difference.

DR. BRAWLEY: I see perhaps some more of a difference than Dr. Kelsen,
but I read this really as more of a quality of life question. I would
just say, has the regimen been demonstrated to be effective in improving
the quality of life in the acute phase and in the delayed phase?

CHAIRPERSON CAMILLERI: So I think that the consensus is that we put
these back together again. And that is the question the agency really
wants us to answer.

Are there any other issues of clarification before we start to take
votes? Ms. Cohen?

MS. COHEN: I think that you said that less than 25 percent of rescue
therapy was used; is that correct, when I asked before?

DR. HORGAN: Yes. Approximately 25 percent of patients used rescue
therapy.

MS. COHEN: Can I say something? You know, a lot of you are delivering
physicians. And you have to deal with the anguish of people having
nausea and having vomiting.

As a consumer member, I think there is another dimension that we need to
be protected also. And I think since you have to deal with the end
result of very sick people, your compassion is very strong. I would like
to know that there is a balance here in the drug‑drug reaction. And not
studying it, to me, I am very concerned.

And that is my speech.

CHAIRPERSON CAMILLERI: Thank you.

Other issues related to question number 1 or are we prepared to go
around the table and answer the question? Michael?

DR. PROSCHAN: So the decision was to do two things, the combined and
then the nausea separately or just the one thing combined?

CHAIRPERSON CAMILLERI: I think the decision is that we go back to the
original question as posed by the agency and address it separately for
the acute phase and the delayed phase.

DR. PROSCHAN: So it is just nausea, then? That is the ‑‑

CHAIRPERSON CAMILLERI: No. It is the combined package of prevention of
nausea and vomiting.

Okay. I think not seeing any other hands coming up or questions being
posed, I would like the committee to start taking a vote on this
specific issue. So let\'s just break this up into two bits again just so
that we are clear.

The first question is, has the aprepitant regimen been demonstrated to
be effective in the prevention of nausea and vomiting in the acute
phase? I am going to start asking Dr. Proschan. Would you give us your
vote?

DR. PROSCHAN: I would vote yes.

CHAIRPERSON CAMILLERI: Dr. Desta?

DR. DESTA: I will vote yes.

DR. McLEOD: Howard McLeod. Yes.

DR. BRAWLEY: Otis Brawley. Yes.

DR. KELSEN: Yes.

CHAIRPERSON CAMILLERI: That was Dr. David Kelsen, yes.

DR. LaMONT: LaMont. Yes.

DR. LEVINE: Levine. Yes.

DR. METZ: Metz. Yes.

CHAIRPERSON CAMILLERI: Camilleri. Yes.

DR. CRYER: Cryer. Yes.

DR. FOGEL: Fogel. Yes.

MS. COHEN: Cohen. Yes.

MS. HOFFMAN: Hoffman. Yes.

CHAIRPERSON CAMILLERI: Okay. We can address the second question now or
part 2 of question number 1, has the aprepitant regimen been
demonstrated to be effective in the prevention of nausea and vomiting in
the delayed phase?

DR. PROSCHAN: We have to vote or is there a discussion of that? Are we
at the voting stage on that?

CHAIRPERSON CAMILLERI: I am happy to entertain further discussion. This
is a very important point. Thank you, Dr. Proschan.

DR. PROSCHAN: Okay. Yes. I think it is difficult to tell because of the
fact that the rescue medication could have saved them or they may have
not thought about the fact that the rescue medication meant that they
did have nausea. And once they took the medication, they didn\'t feel
that they had it anymore. So I think it is difficult.

The other issue is much cleaner to answer.

CHAIRPERSON CAMILLERI: Can I ask for a clarification perhaps from the
agency side? It is my impression that one of the presentations said that
rescue medication was used in 28 percent in the control group and 18
percent in the aprepitant group. Is my recollection correct?

DR. DELLA\'ZANNA: That\'s correct. I am not sure if you are
understanding what I was also trying to emphasize. Their complete
response in the overall phase as well as acute and delayed phases
excluded the use of rescue therapy.

So if you just focus on the primary endpoint as well as the secondary
endpoints of complete response, we\*\* are ignoring the use of rescue
therapy because they didn\'t have any.

So I don\'t have as much of a concern regarding that for the delayed
phase because it was statistically significant without the use of rescue
therapy and then in support of their findings that the use of rescue
therapy now was no longer considered a responder and the patients had
failed the primary endpoint, the use of rescue therapy was used more
frequently in the standard therapy group.

I don\'t know if that better answers what you were saying.

DR. PROSCHAN: When you look at whether they had nausea or not, their
scores if they had the rescue therapy are likely to be different than
their scores if they didn\'t have the rescue therapy.

So I still think there is a problem. It is certainly much less clean to
try and answer that question tan the first question.

CHAIRPERSON CAMILLERI: Other clarifications needed on this point? Yes.
Go ahead, Dr. Desta.

DR. DESTA: Yes. I\'m not sure whether a single dose or a multiple dose
is recommended. I mean, if we see the figure 7‑3, it seems that the
single dose does it. I don\'t know whether there is a difference between
the 52 and the 43 percent difference in the delayed effect.

So I am not sure about the dosing interval. Is a single dose enough?
According to this figure, it seems that a single dose is also doing
that.

CHAIRPERSON CAMILLERI: Dr. Cryer is indicating to me that the five‑day
results are indicated here. And presumably that is what the sponsor is
recommending, that this would not just be a one‑day treatment, but it
would go on for three days.

DR. HORGAN: The Phase III regimen.

CHAIRPERSON CAMILLERI: According to the Phase III regimen.

Maybe I could have a clarification from the agency. Is it possible to
answer yes to this question but then to make recommendations on the
indication? I think there is some discomfort with regard to the
over‑encompassing conclusion that there is about nausea here. I think
there is a practical discomfort around the committee members.

So is it, in turn, inconsistent or is it still possible to work with a
general statement in response to question number 1 but to clarify the
implications perhaps clearly in the indication?

DR. JUSTICE: Certainly if you can clarify it, we would appreciate it
greatly.

CHAIRPERSON CAMILLERI: Dr. Fogel and then Dr. Levine.

DR. FOGEL: As we are going on, I am getting more and more confused. So I
guess my question is for the agency. In this study when the data was
presented and then in the initial presentation by the agency, there was
agreement that the delayed phase was effective.

If I understood correctly, there is a significant reduction in the use
of rescue therapy in the delayed phase. And, as I have been listening to
the discussion, it seems to be revolving around the VAS scores, where
there does not seem to be a significant difference. Is that correct?

DR. DELLA\'ZANNA: Well, it is a little more than just the VAS scores.
Historically we have used and we are concerned about applying an
indication that this could be used for nausea. Okay? Independently if
you look at that endpoint, it doesn\'t become significant.

I agree with Dr. Brawley that it is difficult or impossible to separate
nausea and vomiting from one another. And I agree in practice that
vomiting is the progression of severe nausea. Historically we have to
also be concerned with the potential that this could be used as an
indication for nausea. And because of that, that is the only reason we
separated these out as a question for the committee.

We have similar concerns as far as yes, we agree it was significant in
the overall, complete response overall, phase, acute phase, and delayed
phase. But if you looked at it independently for nausea, it wasn\'t as
convincing.

The \*\*firm has done a very good job and a good argument stating that
the use of rescue therapy is a surrogate for the degree of nausea. We
have not used that in the past. And so we are setting a precedent.

DR. FOGEL: The question I have about the nausea scores, it was my
understanding from the previous discussion that when people marked their
score, it was if they took rescue therapy, they still got to mark a
score. Is that correct?

DR. HORGAN: Yes.

DR. FOGEL: And when you calculated the number of people who were less
than 5 and less than 25, you did not exclude those who had not already
taken rescue therapy.

DR. HORGAN: Absolutely. Every patient in the study was making daily
nausea recordings, irrespective. And that is one of the key issues, that
despite the fact that patients in an active control group were taking
more rescue therapy, we consistently found an advantage with the
aprepitant treatment in our nausea VAS scores.

DR. FOGEL: Did you do a subset analysis? Since you have been slicing the
data a number of different ways, did you do a subset analysis where you
excluded those who took rescue therapy and just looked at the nausea
scores?

DR. HORGAN: We didn\'t think that was a valid way to look at it from the
perspective of the syndrome of chemotherapy‑induced nausea and vomiting
because there are complex relationships between emesis and nausea or
rescue and nausea. So we focused on looking at the total patient
population in our assessments of nausea and also rescue therapy, though
we did note that rescue therapy was associated with higher nausea scores
in general.

CHAIRPERSON CAMILLERI: Dr. Levine?

DR. LEVINE: My question is really for the agency. I think it is
marginal, the effects on nausea, but I think what I am concerned about
is in the labeling. I don\'t have a problem with labeling that might
even say \"highly emetogenic,\" but I think if we put the word
\"nausea\" in the label at all eventually, that this drug is for nausea,
it may be another subject. But forgetting the off‑label possible use,
forgetting that it is limited to chemotherapy, I am concerned in that
delayed period, that doctors will be looking at what they think is a
good drug for nausea. It is that simple.

And I just wondered, are we mandated in any reason? I think it is a
sticky wicket to try to get into the word \"nausea.\" I agree with Dr.
LaMont. They are linked together in patients. I don\'t have a problem
with that. But I think if it is going to come to putting a label on this
with nausea, I would be hesitant about it.

CHAIRPERSON CAMILLERI: Dr. Brawley?

DR. LEVINE: Can they clarify that? Can the company clarify whether this
is going to be in the label or not?

DR. HOUN: Well, this is what they are proposing for labeling. I imagine
this is what they desired, nausea and vomiting. They are saying yes. I
think we are looking for your recommendations. You know, I think there
are safety concerns, as you know, as we will discuss more this
afternoon.

I think, actually, if you can help us understand. Our standard is safe
and effective as labeled, but that is for approval. But to stay on the
market, it is safe and effective as used because drugs run into trouble
if they are used inappropriately.

So I am interested in GIs\' as well as other docs\', cancer docs\'
opinion on what are the problems we might run into in real use.

CHAIRPERSON CAMILLERI: Dr. Metz?

DR. METZ: Can I just clarify something? My understanding is what the
company is asking for is a regimen that is going to be given to people
up front who are going to be getting chemotherapy to prevent them from
getting chemotherapy‑induced nausea and vomiting, which is bad. This
affects a lot of people and can be reduced by 20‑plus percent with this
particular regimen.

Giving PRN drug for nausea in patients who happen to have received
chemotherapy beforehand to me is going to ultimately be a big off‑label
use unrelated to what we are talking about here today. If we talk about
chemotherapy‑induced nausea and vomiting that you are going to prevent
with this regimen, you can\'t separate the nausea and vomiting. That is
the syndrome.

But if you want to ask us as a separate use, are we worried about
off‑label use for another indication, whether it is in patients who
receive chemotherapy or patients with totally unrelated disease states,
that is a different question entirely.

This question, as I read it, is the CINV syndrome. And you have got to
have the two together. And personally I think it affects the acute
phase, and I think it affects the delayed phase.

CHAIRPERSON CAMILLERI: Dr. Brawley?

DR. BRAWLEY: Yes. I have a couple of questions for the company. They are
very brief. As I look at the data, ‑‑ tell me if I am wrong ‑‑ when you
look at the randomized trials of people taking aprepitant, there is less
use of breakthrough medications or salvaged anti‑vomiting and
anti‑nausea medication in people who are on aprepitant versus not on
aprepitant. Is that correct?

DR. HORGAN: That is correct.

DR. BRAWLEY: Okay. Now, of people who end up taking breakthrough
medications, even though they are on aprepitant, is there evidence here
that their quality of life is better, even though they are taking
aprepitant and the breakthrough medications, when compared to
individuals who are not taking the aprepitant?

CHAIRPERSON CAMILLERI: I guess I am going to allow you to show that
quality of life slide after all.

(Laughter.)

DR. HORGAN: We didn\'t break it out. We looked at the global patient
population. My colleague will show you that data assessing the impact of
nausea and vomiting on patients\' daily lives.

DR. BRAWLEY: Sorry.

CHAIRPERSON CAMILLERI: That\'s okay. Thank you.

DR. MARTIN: Good afternoon. My name is Allison Martin. I am from the
Epidemiology Department at Merck Research Laboratories.

Prior to showing the results of the quality of life data, I would like
to give a little bit of background about the questionnaire so that you
are fully informed about how we collected this data.

Slide 1602, please. So, as you know, the treatment goal for the
aprepitant program was to prevent nausea and vomiting following
chemotherapy. As a corollary goal, we wanted to assess the impact of
nausea and vomiting on patients\' daily lives and ideally eliminate any
impact on their lives. And so we use the functional living index emesis
questionnaire, which is a validated nausea and vomiting‑specific measure
to assess the impact of these symptoms on patients\' daily lives.

The questionnaire contains 18 items, 9 of which refer to nausea, 9 of
which refer to vomiting, which are 2 separate domains. The questionnaire
was given to patients where they were asked to complete the
questionnaire on day six, and it had in cycle 1 with a five‑day recall.

So basically it was asking the patients to rate the extent of the impact
on the items shown on the bottom over the past five days. As you can
see, it contains functioning items, such as enjoying meals daily,
functioning household tasks, spending time with family and friends, et
cetera.

The pre‑specified endpoint, though, that was used for this questionnaire
was a dichotomous endpoint. It was similar to the nausea visual analog
scale. This is also the patients were making their ratings on a visual
analog scale, which ranged from one, which is a great deal of impact, to
seven, not at all or no impact.

The score, an average item score, greater than six was predefined as no
impact on daily life because this is the uppermost bucket where patients
were placing their marks anchored by not at all.

The next slide, please. This slide presents the results from the two
Phase III protocols on the total score of proportion of patients in
protocols 052 and 054 reporting no impact on daily life. So, as you can
see in both protocols 052 and 054, a significantly greater proportion of
patients in the aprepitant‑treated group reported no impact on daily
life.

Can I have 1605? This is the same data, but, then, also included is a
combined analysis of the two protocols, which was with nominal *p*
values here, which, again, it shows the consistency of those data.

To head off Dr. Proschan\'s next question, can I please have slide 1606?
This shows the cumulative distribution of these average slide scores
based on the total score.

The way this works is the vertical axis is the percent of patients. The
horizonal again is the scale that the patients were using to mark their
responses. We have drawn in here the six cutoff that we used.

As you can see, over the full distribution, almost over the entire
distribution, the aprepitant‑treated patients had significantly greater
scores. If you look at here, this is the 64 percent on the total score
in the control group who had a score of 6 or greater versus the
aprepitant group, which had a score of 74 percent who had a score of 6
or greater. Again, on slide 1607 is protocol 054, which shows that these
data are consistent.

The last thing that I will show is slide 1614, which, as Dr. Kevin
alluded to in his presentation and what I had mentioned earlier that
this questionnaire does contain two domains, a nausea domain and a
vomiting domains, the analyses here show ‑‑ this is the results from
protocol 052; 054; and, again, combined, and this was a post hoc
analysis. These are nominal *p* values. But, as you can see, the data
are consistent that we were superior to the control group in both the
nausea domain and the vomiting domain across the two studies and in a
combined analysis.

So overall I think these data are highly consistent with our clinical
efficacy endpoints. And it shows that the aprepitant‑treated patients
had a benefit in terms of their ability to maintain their functioning in
that five days following chemotherapy, during a period when they would
expect to have debilitating symptoms.

CHAIRPERSON CAMILLERI: Dr. Brawley, any supplementary question?

DR. BRAWLEY: No, sir. Thank you very much.

CHAIRPERSON CAMILLERI: Okay. Dr. Della\'Zanna?

DR. DELLA\'ZANNA: Okay. I don\'t want to complicate this whole
discussion any more than we already have, but I do want to point out a
couple of things in response to the firm\'s presentation.

As far as the impact on daily life in the overall phase, which was a
predefined analysis, when the agency performed what they considered the
appropriate multiplicity adjustment, including all predefined secondary
and exploratory analysis, these *p* values were not significant. For
study 054, it was 0.06. And for study 052, it was 0.25.

I don\'t want to distract from the focus of this question. I think we
kind of are going in a little more detail than necessary to make our
decision. But I don\'t want necessarily to put all of our support on the
data that was just presented.

CHAIRPERSON CAMILLERI: Dr. Michael Proschan?

DR. PROSCHAN: Yes. You know, one thing that one could do is say, \"Okay.
Everyone who took rescue medication would have had nausea if they
hadn\'t taken it.\" That\'s one way of looking at it. And if you make
that assumption, then effectively your endpoint is either nausea or
rescue medication.

Now, that wasn\'t quite one of their secondary endpoints. I see
everything except that on here. And I am wondering if that analysis was
done and what the results of that were.

I mean, you could make various assumptions. You could assume everyone
who goes on rescue medication would have had nausea or 80 percent of
those would have had nausea. And if it\'s the case when you look at
nausea or rescue medication, that is still significant, then that would
be more evidence. I don\'t know if they have that.

CHAIRPERSON CAMILLERI: Have we got a quick answer to that question?

DR. DELLA\'ZANNA: I can interject on that a little bit and probably
answer your response in a way you will like.

(Laughter.)

DR. DELLA\'ZANNA: They did. With blinding, they analyzed and removed the
\"rescue therapy\" that was inappropriately given as prophylaxis. So
they pretty much did what you were just recommending. And the people who
received or were counted as rescue therapy received it because they had
established nausea.

So I know what you were saying as far as people who receive rescue
medication, 20 percent were nauseous. Now, we can almost assume that the
people who received rescue mediation, 100 percent were complaining of
either nausea or vomiting.

DR. PROSCHAN: Right. What I am getting at is what percentage of those
would have had a VAS score bigger than five because that is the real
question. If 100 percent of them would have had a VAS score bigger than
five, then essentially what it comes down to is looking at the endpoint
of either rescue medication or nausea.

And if that is highly significant or even lowly significant, that is
some evidence.

DR. HORGAN: I think the best that we can do to address your concern is
just show what the relationship was in the patients who did take rescue
and what their visual analog scale scores were. We weren\'t able to
because of the daily nausea ratings define the precise relationship, but
we can show, slide 303 ‑‑

DR. PROSCHAN: I\'m sorry, but you have all of these secondary endpoints.
I was just wondering whether as a secondary endpoint, you looked at the
endpoint of either bigger than five on the VAS score or rescue
medication.

I mean, I see things that are very close to that under these secondary
endpoints, but I don\'t quite see that one. There is a no emesis, no
rescue, and maximum nausea less than five. But there isn\'t just no
rescue and nausea less than five. So I was wondering if that were done.

CHAIRPERSON CAMILLERI: Would it be fair to assume that if people got
rescue medication, their nausea score should have been greater than
five?

DR. PROSCHAN: Well, my point is that if you make that assumption, then
the relevant question is for the endpoint of greater than five or rescue
medication, what are the results for that endpoint?

DR. HORGAN: One of our composite endpoints was total control. A patient
in order to have total control was no emesis, no rescue, and maximum VAS
score of less than five.

DR. PROSCHAN: Right.

DR. HORGAN: Would that address your ‑‑

DR. PROSCHAN: No. I mean, I see things that are tantalizingly close to
what I want but not quite exactly.

DR. HORGAN: Right. The other thing that I think is probably the best
thing that we can do to approximate your question is to look at the
relationship between the nausea ratings and the patients who took
rescue. To illustrate ‑‑

CHAIRPERSON CAMILLERI: Twenty seconds. Okay. Then let\'s move on. I
think we have discussed this point. When I heard the term \"total
control,\" I thought they were referring to Dr. Metz.

(Laughter.)

CHAIRPERSON CAMILLERI: Okay. I think we have discussed this
sufficiently. We have clarified it. Let\'s get back to answer or at
least respond to the question. We are kind of doing question 1B, has the
aprepitant regimen been demonstrated to be effective in the prevention
of nausea and vomiting in the delayed phase? Dr. Proschan?

DR. PROSCHAN: Yes.

DR. DESTA: Desta. Yes.

DR. McLEOD: McLeod. Yes.

DR. BRAWLEY: Brawley. Yes.

DR. KELSEN: Kelsen. Yes.

DR. LaMONT: LaMont. Yes.

DR. LEVINE: Levine. Yes.

DR. METZ: Metz. Yes.

CHAIRPERSON CAMILLERI: Camilleri. Yes.

DR. CRYER: Cryer. Yes.

DR. FOGEL: Fogel. Yes.

MS. COHEN: Cohen. Yes.

MS. HOFFMAN: Hoffman. Yes.

CHAIRPERSON CAMILLERI: Okay. Thank you very much. I think we can move on
to the second question, is the designation of \"highly emetogenic
chemotherapy\" appropriate given the regimens used in the clinical
studies? I think what I would like to do here is ask our clinical
oncologists to give us their opinion.

DR. KELSEN: I think it is. Cisplatin is a very difficult drug to take.
Most of the patients, 80 percent, have 70 milligrams per meter^2^ or
higher. It is not fun to take 58 to 60 milligrams per meter^2^. I think
it is an emetogenic regimen.

DR. BRAWLEY: I would totally agree.

CHAIRPERSON CAMILLERI: Does the committee require any further discussion
after the expert opinion? Dr. Fogel?

DR. FOGEL: I have a question. The wording here is \"highly emetogenic.\"
Can you explain clinically is there any difference between highly and
moderate emetogenic? I mean, is this an issue that we need to address in
great detail?

DR. KELSEN: I don\'t think we need to address in great detail. This is a
highly emetogenic regimen. I mean, in the days before antiemetics
existed for platinum, it was very difficult.

I think by moderately emetogenic, they mean patients don\'t feel great,
but they\'re not crippled as they would be when you take platinum
without any coverage at all.

DR. BRAWLEY: In the doses that we frequently give, platinum before
Reglan, very frequently people would become totally dysfunctional.
Nowadays most people are able to function. Perhaps they can do even
better with drugs like this.

So highly emetogenic in my mind means the person would be unable to
function without drugs to treat the condition.

CHAIRPERSON CAMILLERI: Thanks, Dr. Brawley.

Dr. Cryer?

DR. CRYER: As I understand it, I think the reason that we are being
asked this question is that the previous standard to determine or define
highly emetogenic was a previous cisplatin dose of greater than 100
milligrams per meter^2^ based upon ondansetron approval.

So while I would like to get some clarification from Dr. Della\'Zanna,
when you removed the people who were on the lower doses of cisplatin, I
guess that was less than 70. Did you say that it was maintained?

DR. DELLA\'ZANNA: It maintained efficacy.

DR. CRYER: Efficacy?

DR. DELLA\'ZANNA: Yes. And I should point out in the firm\'s behalf,
which I\'m sure they will state if I don\'t now, that the dose itself
has varied in literature. If you look at the ondansetron oral
formulation, greater than 50 was utilized and described as a highly
emetogenic dose.

The one reason I brought this up is for two points, that this dose has
evolved and that I just wanted to have clarification for future
applications that this is now an acceptable dose that we can use as a
label. And that\'s it.

CHAIRPERSON CAMILLERI: Thank you.

I believe that we are ready to take a vote on this. This time I am going
to start with Ms. Hoffman.

MS. HOFFMAN: Hoffman. Yes.

MS. COHEN: Cohen. Yes.

DR. FOGEL: Fogel. Yes.

DR. CRYER: Cryer. Yes.

CHAIRPERSON CAMILLERI: Camilleri. Yes.

DR. METZ: Metz. Yes.

DR. LEVINE: Levine. Yes.

DR. LaMONT: LaMont. Yes.

DR. KELSEN: Kelsen. Yes.

DR. BRAWLEY: Brawley. Yes.

DR. McLEOD: McLeod. Yes.

DR. DESTA: Desta. Yes.

DR. PROSCHAN: Proschan. I have no idea. So I am going to abstain.

CHAIRPERSON CAMILLERI: Thank you. I think we can move on to the third
question, can the recommended regimen be expanded beyond that used in
the clinical studies to include the use of any 5‑HT~3~ antagonist as
part of the aprepitant regimen?

We have to remind you that there were no studies with dolasetron. The
studies that were presented in the documents pertain to granisetron and
ondansetron.

The second part of the question, if not, what additional studies would
you recommend?

Now, what I am going to ask, just to refresh our memories, Dr.
Della\'Zanna, can you remind us what other studies you had suggested
might be appropriate, additional studies might be appropriate, as part
of your presentation?

DR. DELLA\'ZANNA: Presently we have intravenous studies on ondansetron
and oral studies on granisetron. We do not have any oral information on
ondansetron. Now, agreeing with our PK information, it is metabolized
for multiple pathways.

So the likelihood of a PK interaction is not that high. But the other
interactions we can\'t predict. As far as dolasetron, we have no safety
data whatsoever.

CHAIRPERSON CAMILLERI: Okay. This is where we need our clinical
pharmacology colleagues also to help us out. Would you like to make any
statements or clarifications?

DR. McLEOD: I believe Dr. Desta pointed out that the way that dolasetron
is activated and then metabolized does mean that a fairly large fraction
of the population is going to be relying on CYP3A4 for the inactivation
of the drug.

So that while carbonyl reductase is involved, it\'s reactivating it.
There are two enzymes, the CYP2D6 and 3A4, that are then inactivating
that metabolite, that active moiety.

As Dr. Desta mentioned, ten percent or so of the general population are
defective in that pathway. And so they basically are 3A4‑dependent. So
it does raise the question of whether there is a viable interaction at
that point.

Without any data, it is hard to decide whether it is relevant or not. It
could have zero relevance or it could be dramatically important.

I also would like some clarification from probably Dr. Della\'Zanna on
the robustness or whatever you can call it of the QT prolongation
concerned with dolasetron to see whether this is a true problem or one
that is just a concern. If in practice this 5‑HT~3~ antagonist behaves
as the other two, then I think we are just talking about theory and not
reality.

CHAIRPERSON CAMILLERI: Dr. Della\'Zanna, have you got a response on QTc
prolongation with dolasetron?

DR. DELLA\'ZANNA: I do not have access to that information now to
present.

CHAIRPERSON CAMILLERI: Dr. Desta?

DR. DESTA: I think with ondansetron, oral drug interaction, I don\'t
think there will be a big difference ‑‑ that is my opinion ‑‑ with
ondansetron oral because we didn\'t see it or they didn\'t see it with
the other drug, which is exclusively a substrate drug. So I don\'t think
that will really matter unless otherwise this drug inhibits 2B6 in a
significant way because 2B6 is involved with also ondansetron.

The other one I agree with Howard is how concerned are you or is there
any dose‑response relationship of dolasetron and QT interval
prolongation? For example, in poor metabolizers, are there any
documented things or is there any drug interaction that really concerns
you?

Otherwise if you take that drug, the metabolic pathway, which is shared
by 3A, is small. So if you block that, could we get higher plasma
concentration whereby we can have some QT interval concerns?

CHAIRPERSON CAMILLERI: So if I am understanding you correctly, Dr. Desta
‑‑ and excuse me. I am not a pharmacologist. Your first statement was
that, even though there haven\'t been studies with oral ondansetron, you
as a pharmacologist, you are quite reassured by the data that you see
pertaining to the pharmacokinetics of granisetron, another 5‑HT~3~
antagonist that shares the same metabolic pathway as ondansetron. That
was the first point. Is that correct?

DR. DESTA: Yes, correct.

CHAIRPERSON CAMILLERI: Okay. Second point pertained to the question as
to, again reflecting Dr. McLeod\'s question, how much of a risk is there
with the dolasetron relative to QTc prolongation? I am assuming that
somebody from the company has something they really want to say.

DR. GRUNDBERG: I am Steve Grundberg. I am a medical oncologist from the
University of Vermont here as a consultant to the company. We have done
a lot of the developmental work on these various antiemetics.

The QTc question has been around for a long time. I would have to say we
are partly responsible for it because when we did the Phase I\'s on
dolasetron, it went to extraordinarily high doses and we were able to
see a QT change.

It is not just the effect of dolasetron. That is a common misconception.
It has also been described for ondansetron by both Gralla in New York
and by Benedict in Texas. There has really not been any clinical
significance to it. I don\'t know any oncologist who would not use any
one of these three drugs for that reason.

CHAIRPERSON CAMILLERI: Dr. Kelsen, is that in agreement?

DR. KELSEN: I can\'t comment on the QTc interval. That is not my area of
expertise. But the drugs are widely used interchangeably.

I guess the question here is if you\'re precedent‑setting and you are
looking a little bit down the line, if you didn\'t actually study the
drug with the other drug, what do you do?

CHAIRPERSON CAMILLERI: I think that really encapsulates our dilemma.

DR. BRAWLEY: Pardon me. I never knew dolasetron existed until I started
reading this stuff. Granisetron and ondansetron are very commonly used
in my experience, but dolasetron I don\'t think is a wide market share.

CHAIRPERSON CAMILLERI: Go ahead, Dr. Metz.

DR. METZ: It seems to me that from the agency\'s point of view, people
are concerned that unless you actually have tested a specific agent, it
is going to be a problem to make a statement going forward.

But, on the other hand, I think from the company\'s point of view, you
have to sort of say that we are going to look at representative examples
of each class because you cannot expect that you are going to do a study
on every single member of every single class.

I was just very reassured by the most recent comment that these drugs
are really used interchangeably and that the QTc issue doesn\'t really
pertain only to this one particular agent.

CHAIRPERSON CAMILLERI: In addition to that, I am assuming that you are
quite reassured that dolasetron is not primarily metabolized by the 3A4
pathway.

DR. McLEOD: Well, in 90 percent of the people out there, there are two
enzymes degrading the drug. So you knock out 3A4 and you\'ve got 2D6 to
pick up the slack. In ten percent of the population, at least in theory,
you would predict they would be very reliant on 3A4.

It\'s the consequence of that that is unclear to me. If you alter the
3A4 metabolism of the active metabolite of dolasetron, is that a big
issue? I don\'t know the answer to that.

CHAIRPERSON CAMILLERI: Very brief comment.

DR. PETTY: A very brief comment regarding dolasetron. Dolasetron\*\* is
cleared primarily by CYP2D6. Although it is not in the label, there is
reference in documents available by Freedom of Information to indicate
that poor metabolizers of CYP2D6 had a roughly two‑fold increase in
their AUC of hydrodolasetron and in patients who received verapamil and
diltiazem, which would have comparable 3A4 inhibition to aprepitant.
There was no effect on hydrodolasetron clearance.

CHAIRPERSON CAMILLERI: So do you want to interpret that for clinical
gastroenterologists?

(Laughter.)

DR. McLEOD: Since we\'re on record, I will give a formal interpretation.
It looks like if you take patients who are deficient in 2D6 based on
what was just stated, if you have the two enzymes that degrade the drug,
the active metabolite, if you take patients who have one of them knocked
out because of genetic abnormalities and you then inhibit or alter in
any way, inhibit or induce on the examples he gave, the 3A4 component,
the remaining component, there were not dramatic changes in either the
pharmacokinetics or the toxicity profile. So the statement that was made
suggests that in those people that we were worrying about, it is not
going to be an issue.

CHAIRPERSON CAMILLERI: Thanks for that clarification. Dr. Fogel?

DR. FOGEL: I just want to make a comment about QTc intervals in studies
since we are going to be precedent‑setting. One of the things we learned
from cisapride is that if you have electrolyte abnormalities or
concurrent illnesses or comorbid conditions, your risk of having fatal
arrhythmias tends to be increased.

Since we are going to be dealing with patients who are off studies, not
protocols, who are going to be very sick, who get these regimens, I
think we need to be databased in any decisions that we make.

CHAIRPERSON CAMILLERI: Thanks for the comment. Other discussion on this
point or clarifications requested?

(No response.)

CHAIRPERSON CAMILLERI: If not, I think we should move ahead to try to
answer the first part of this question, can the recommended regimen be
expanded beyond that used in the clinical studies to include the use of
any 5‑HT~3~ antagonist as part of the aprepitant regimen? Dr. Proschan?

DR. PROSCHAN: This is another ‑‑

DR. McLEOD: Let\'s start on that side.

DR. PROSCHAN: This is another one where I think I have to abstain
because I think it takes clinical judgment. And I have at most
statistical judgment.

CHAIRPERSON CAMILLERI: Dr. Desta?

DR. DESTA: Desta. Yes.

DR. McLEOD: McLeod. Yes.

DR. BRAWLEY: Yes with a request for post‑marketing studies.

CHAIRPERSON CAMILLERI: That was Dr. Brawley.

DR. KELSEN: Kelsen. Yes.

DR. LaMONT: LaMont. Yes.

DR. LEVINE: Levine. Yes.

DR. METZ: Metz. Yes.

CHAIRPERSON CAMILLERI: Camilleri. Yes with a request for further
studies.

DR. CRYER: Cryer. Yes.

DR. FOGEL: Fogel. No. You have at least one 5‑HT~3~ receptor that has
been approved that has been shown to be safe and effective. I think
unless you have additional data, you should not generalize. Even though
other combinations may very well be safe, you just don\'t have the data
at this time.

MS. COHEN: Cohen. No. I think this is precedent‑setting. If there is
another study, we shouldn\'t be making these decisions. And there are
consequences, and there is not any data. This rush to publish is very
frightening to me.

MS. HOFFMAN: I\'m tossing back and forth here. I am going to go with no
with further dolasetron studies recommended.

CHAIRPERSON CAMILLERI: Thank you.

Have we recorded that for the record? Thank you.

The second part of that question was, what additional studies would you
recommend? Was it, Dr. Brawley, you recommended some additional studies?

DR. BRAWLEY: Yes. I would like to see some pharmacologic studies with
dolasetron and EMEND. very much as we saw with ondansetron and
granisetron.

CHAIRPERSON CAMILLERI: I am assuming that you are happy with the oral
ondansetron story.

DR. BRAWLEY: Yes, I am happy with the oral ondansetron study. Actually,
Dr. McLeod\'s conversation a little earlier made me much more
comfortable with approval of a dolasetron and EMEND combination.

CHAIRPERSON CAMILLERI: Yes. I was also requesting further studies with
dolasetron. My overall reason to say yes was that I was quite
\*\*persuaded by the information that the metabolism of dolasetron was
unlikely to be very dramatically altered in this context. But I think
further studies would be very useful.

Other comments?

(No response.)

CHAIRPERSON CAMILLERI: Okay. Can we move on to question number 4? This
is a long one. Aprepitant is an inhibitor of the CYP3A4 metabolic
pathway. For chemotherapeutic drugs that are metabolized by this
pathway, moderate inhibition of their metabolism could result in serious
or life‑threatening toxicity.

So the first thing we are going to do is we are going to address the
issue pertaining to 4A. The applicant has analyzed the safety data by
chemotherapy regimen. And a significant number of patients received
etoposide, vinorelbine, or paclitaxel, all of which are substrates for
CYP3A4, in combination with cisplatin and the aprepitant regimen.

Here are the questions. Is this data sufficient to support the safety of
aprepitant in combination with these specific drugs; that is, etoposide,
vinorelbine, and paclitaxel?

Would anybody like any questions answered or can we go ahead and address
and answer the question?

(No response.)

CHAIRPERSON CAMILLERI: I see no lights coming on. So I think this will
probably be the easier part of the question. So we want to know is there
sufficient data to support the safety of aprepitant in combination with
the drugs etoposide, vinorelbine, and paclitaxel? This time we will
start with Ms. Hoffman.

MS. HOFFMAN: There was a comment about sepsis being three times as high
with the vinorelbine. Can you just discuss that briefly again?

CHAIRPERSON CAMILLERI: Dr. Proschan, I believe you sort of addressed
that question slightly by saying there are multiple comparisons being
done here and you felt that the signal here was relatively small
considering the very small number of instances.

DR. PROSCHAN: Right. And that\'s why I think it is impossible from this
data to say, \"Okay. It is harmful.\" Likewise, I think it is impossible
to rule out harm.

So to me, there hasn\'t been sufficient data to establish safety, but it
might be very hard to have sufficient data to establish to a high degree
of certainty that it is safe.

CHAIRPERSON CAMILLERI: Dr. Della\'Zanna, do you have any other comments?

DR. DELLA\'ZANNA: That was exactly what I was trying to get across. I
wasn\'t trying to say that this should not be used in conjunction with
vinorelbine. I was trying to suggest that this might represent a small
signal that we could not define. One of my concerns was some of these
respiratory serious adverse events as well as the incidence of
infections.

Like I said, ‑‑ and I will emphasize it again ‑‑ the numbers are very
small. However, the numbers that were serious infection‑related adverse
events were only seen in the aprepitant group. So that was what I was
trying to focus on.

And from that, I wasn\'t necessarily looking for condemning the use with
vinorelbine, just the committee\'s opinion on whether additional
information is necessary.

DR. PROSCHAN: Wasn\'t it also the case that several of those events were
at the same site, same ‑‑

DR. DELLA\'ZANNA: The significance of that is uncertain for me only
because this one site focused predominantly on lung cancers. So the fact
that these all occurred in one site does not surprise me that this site
focused and is concentrated in lung cancer.

The firm stated that it was balanced between the two treatment groups at
the number of patients with these primary lung cancers. It wasn\'t
biased.

CHAIRPERSON CAMILLERI: Dr. Kelsen?

DR. KELSEN: I think we have all indicated that it works to decrease
nausea and vomiting. So it is effective in that setting. I have a
question for the agency because I think this is where ‑‑ you know, I am
just a visitor to this. But as an oncologist, is there a precedent for
using an agent like this in which one feels pressed into indicating
exactly which drugs it can be given with, as opposed to it\'s
recommended for highly emetogenic chemotherapy, as represented by
cisplatin, because we are now facing a situation where you are going to
try to tailor the specific combination regimens, not only class by class
but almost drug by drug, on the basis of not much data?

Has this ever come up to you all before? Is there anything to guide us?

DR. HOUN: Well, it frequently comes up because when drugs are tested and
to be used with other drugs, what are these other drugs? How do you
label? And so the reason why we are airing this is because we want the
public to know that we have discussed this.

So when the agency gets criticized that you didn\'t look carefully that
they only had enough patients in these three drugs, why are you giving
it broad labeling for everything, we want to say, \"Well, you know, we
are aware of those issues. And we brought it to the public\'s attention.
We have had a discussion about it.\"

So that is why it is here. It is not our desire necessarily to state
specifically which of these drugs, but those were the ones that had a
lot of patients. And there will be other drugs that didn\'t. How do you
guys help us with advice on handling that?

DR. KELSEN: I would like to make just one other point, that these are
all intravenous drugs. I was struck by the comment that it may be oral
agents that become an issue. We are working very, very hard to switch to
oral chemotherapy. There are a number of models of that. I don\'t think
this is a trivial issue at all.

DR. DELLA\'ZANNA: The other think I would like to bring up ‑‑ and I
realize that the inhibitory effect is greatest on the oral. We seem to
play down the fact that the IV methylprednisolone had a 35 percent
increase.

The tables that were demonstrated on the slides were somewhat
misleading, as far as I\'m concerned, when you considered the
dexamethasone dose and the divergence of the two lines were generous.
Then when they showed the methylprednisolone IV, you can almost
superimpose them, even though there was a 35 percent difference.

And if you want to pull up your slide that I am talking about, I have it
here. Where is it? We can just keep going forward, though.

CHAIRPERSON CAMILLERI: Ms. Hoffman, do you have another question? Yes,
Dr. Levine?

DR. LEVINE: Just we shouldn\'t jump ahead to the next sentence, but I
would like to know whether pre‑approval or post‑approval, what kind of
time frame would it be to get satisfactory numbers and data for either
pre or post‑approval regarding the issue we are talking about from the
agency?

DR. JUSTICE: I think we discussed the wording of this question to some
extent. I think in terms of pre‑approval, we are talking we could deal
with that in labeling if we thought there was a potential drug‑drug
interaction that was significant enough that the drug should not be used
in combination with another drug. We could address that in labeling and
until a study was done to document that there is or is not a drug
interaction.

So I don\'t think we are asking whether an actual study would have to be
done pre‑approval. So our question is a little bit misleading.

DR. LEVINE: Thank you,

CHAIRPERSON CAMILLERI: Maybe I could ask Dr. Della\'Zanna whether there
would be any advantage in splitting up this trial of drugs. It seems to
me that you had very little concern about the combination with etoposide
and paclitaxel. And, yet, from the response to Ms. Hoffman\'s question,
there still are some reservations with regard to vinorelbine in
combination.

DR. DELLA\'ZANNA: The most significant thing that I noticed on the
vinorelbine was the pulmonary insufficiency that was ultimately fatal
and then that you included an additional two fatalities that were
serious infection‑related. And then in the corresponding standard
therapy group, there were only two fatalities, neither of which were
related to truly a pulmonary problem other than a pulmonary emboli and a
death that was reported as unknown.

CHAIRPERSON CAMILLERI: But I remember that we got some information that
the vinorelbine toxicity appeared not to be related to the usual
bronchospasm and acute syndrome but appeared more related to the
underlying lung disease.

Thirty seconds.

DR. REINES: Okay. If I could have slide 755, please? I really want to
echo the comment that when we pull things apart in different ways, the
results aren\'t always balanced. We pre‑specified the AEs, as I told you
in my main talk, that were indicative of chemotherapy‑induced toxicity.

These are the data for vinorelbine. The pre‑specified AE incidences were
the same for both groups. The infections were higher, as we have been
discussing, in this group.

If you look at hematological AEs, it goes in the other direction, which
you haven\'t been shown yet. But that is how the numbers come out
overall the same.

So we have looked very carefully at this. We did think that the
respiratory issue was not a vinorelbine type of toxicity. And we looked
very carefully at the hematological toxicity with this drug. There is no
evidence that aprepitant is enhancing that toxicity.

CHAIRPERSON CAMILLERI: Thank you.

Dr. Levine?

DR. LEVINE: Just in reference to another large study that is just
developing post‑marking on an approved drug, was there any evidence on
pulmonary function tests that were done in these patients, either before
or after death? And was there a diffusion defect or pulmonary
hypertension that developed in these patients due to drug?

DR. REINES: No.

DR. LEVINE: It was done or not done, pulmonary function tests?

DR. REINES: We don\'t have that information. It was not done as far as I
know.

DR. BRAWLEY: Quick question for a statistician. Are we technically doing
the subset analysis here? And substantive analysis is inherently flawed
and likely to give you the wrong answer.

DR. PROSCHAN: Right. I mean, that\'s why I said earlier if you try and
attach a statistical significance to this, it is going to be very
difficult because you are looking at so many different drugs, so many
different outcomes.

We have been focusing on the ones in which you see some trend. But even
in the ones in which there is no trend, where it looks dead even, there
still could be harm that you just can\'t see with this number of
patients.

So if you really want to prove that there is no interaction with any of
these drugs, it is going to take thousands of patients to do that.

DR. BRAWLEY: That brings us back to Dr. Della\'Zanna\'s original
comment, which is that we should be cautious because these are all small
numbers and small trends that may mean nothing, may mean something.

CHAIRPERSON CAMILLERI: Okay. I believe we have had sufficient
discussion. Any other clarifications needed on this specific point?

(No response.)

CHAIRPERSON CAMILLERI: Dr. Proschan, I am going to start asking you to
vote this time again. The question, therefore, is, are the data
sufficient to support the safety of aprepitant in combination with the
drugs etoposide, vinorelbine, and paclitaxel?

DR. PROSCHAN: I don\'t think they are, but I think it would take
thousands to make it so.

CHAIRPERSON CAMILLERI: I am assuming that Dr. Proschan\'s answer is no.

DR. PROSCHAN: As stated, to this question as stated, I would have to say
no.

CHAIRPERSON CAMILLERI: Dr. Desta?

DR. DESTA: I\'m not sure.

CHAIRPERSON CAMILLERI: This is the time to come off the fence, Dr.
Desta.

(Laughter.)

CHAIRPERSON CAMILLERI: You could abstain. Sorry. I thank you.

DR. DESTA: Because the question is \"Is this data sufficient to
support?\" it is \"Yes\" or \"No.\" And we don\'t know. I don\'t know.

CHAIRPERSON CAMILLERI: I am assuming that is an abstention, then. Dr.
McLeod?

DR. McLEOD: McLeod. Taking all three drugs together, which is the way
the question is posed, I would say yes.

DR. BRAWLEY: Brawley. I\'m very much on that fence, but I\'m leaning
over into the yes. So I\'ll go yes.

DR. KELSEN: I\'ll say yes. And they will need those additional studies.

CHAIRPERSON CAMILLERI: That was Dr. Kelsen.

DR. LaMONT: No. The data is insufficient. LaMont.

DR. LEVINE: I\'m uncomfortable with it, but I will say yes. From these
other experiences with post‑marketing, as all of you are saying, these
are very serious consequences. Therefore, I am looking forward to the
next sentence, but I would say yes.

CHAIRPERSON CAMILLERI: That was Dr. Levine. Now Dr. Metz.

DR. METZ: I\'m going to say yes within the limitations that this is
designed in such a way that you actually cannot answer the question
because there are not enough patients. But what I would like to see is
post‑marketing data. I think that is very important. I don\'t want the
fact that this may ultimately be an issue to limit the availability of
this agent. So that is why I am voting yes.

CHAIRPERSON CAMILLERI: Camilleri. Yes with additional studies
post‑marketing.

DR. CRYER: Cryer. Yes with additional studies as well.

DR. FOGEL: Fogel. Yes with additional post‑marketing studies.

MS. COHEN: Cohen. No because can you tailor a regimen? What kind of
advertising is there going to be? Was this oral versus the IV? There is
just not enough data.

Post‑marketing, what happens to us who get caught before the
post‑marketing if it\'s used? I think it is too chancy.

MS. HOFFMAN: Hoffman. Yes with post‑marketing studies.

CHAIRPERSON CAMILLERI: Thank you.

So I think we have kind of answered what additional studies are going to
be needed. Do we need to address it any further? Does the agency want us
to specify what sort of post‑marketing or other studies?

DR. HOUN: I think if people do want to give suggestions on endpoints,
that would be helpful.

CHAIRPERSON CAMILLERI: Thank you.

Dr. Metz?

DR. METZ: If I may comment, it is not so much what the endpoint is and
it is not so much on what the design of the study is going to be. What I
think is important is you have to realize that any drug that is ever
going to be marketed for a specific indication ultimately is only going
to be studied in so many patients. We will have to learn as time goes
on.

They will certainly be patients who get this drug or any other drug at
any time with a life‑threatening cancer illness who may get sick. And
the signals are hard to find. You people are the experts on
post‑marketing surveillance problems and also on the fact that there\'s
no really good way to fix it, which brings us back to all the other
previous discussions we have had in this committee.

I think it is important to just realize that this is a possibility and
that patients will get as good care as they can from the individual
doctors and that as data accumulates, information will be acquired.

CHAIRPERSON CAMILLERI: Yes. Dr. Kelsen?

DR. KELSEN: I am going to make a suggestion sort of to us at ODAC. One
way to address the survival issue, which we were not able to address, is
to recommend that when future studies are done in lung cancer, that they
specific the antiemetic regimen very rigidly so that all patients not
only get the same chemotherapeutic regime, they get the same EMEND or
whatever this is regimen. And then you will have an answer as to whether
there is an effect on survival.

We will not be able to address safety because I think both arms will get
the same thing. But you will know what the survival outcome is.

CHAIRPERSON CAMILLERI: Dr. LaMont?

DR. LaMONT: Yes. I wonder if we could learn anything from the times of
exclusions that were used in the clinical studies because, as someone
has already mentioned, this is going to be opened up to all kinds of
cancer patients with all kinds of backgrounds.

So I assume that the patients who had had previous infection or recent
infection or fever, et cetera, et cetera, leukopenia, neutropenia were
excluded. Perhaps we can build some of those safeguards into the
indications and post‑marketing surveillance.

CHAIRPERSON CAMILLERI: Thank you.

Dr. Horgan?

DR. HORGAN: The enrollment criteria were quite broad. And we obviously
wanted to exclude anybody with an active serious infection. We had
exclusions for low neutrophil counts and abnormal white cell counts and
renal function and liver function that would be consistent with what the
normal criteria for the administration of chemotherapy were.

In general, we excluded patients who are receiving potent inhibitors of
CYP3A4 and inducers of CYP3A4, but apart from that, the exclusion
criteria were very similar to what have been used in previous antiemetic
trials to allow a population that was as representative as possible to
clinical practice to be studied.

CHAIRPERSON CAMILLERI: Dr. McLeod?

DR. McLEOD: I think as we get into Part B of this question, it will come
out even further. But as far as suggested studies, most of the concerns
that have been raised so far have been of a pharmacokinetic nature.

Now, whether it starts with pharmacodynamic variability is to be seen,
but certainly there could be some very defined minimum studies where the
presence of a pharmacokinetic interaction is evaluated.

These studies do not have to be done fairly quickly, but if there is no
pharmacokinetic interaction clear from even single‑dose combination
studies with this agent and the chemotherapy drug, that will give us
some further confidence on its use.

It would not be enough to declare that it is safe for all mankind, but
in the context of Dr. Metz\'s comments, we are not robots. This is not
computer circuitry and engineering. There are some studies that have to
be done and learning that has to go on that is beyond the scope of the
FDA.

CHAIRPERSON CAMILLERI: Dr. Kelsen?

DR. KELSEN: Just one last comment to follow that up. You could imagine a
study where women with breast cancer commonly receive single‑agent
vinorelbine. It\'s not very emetogenic, but you could easily do a small
trial with this agent. And with single‑agent vinorelbine, you would get
your answer in 15‑20 women.

CHAIRPERSON CAMILLERI: I\'m assuming somebody would want to know about
pulmonary function, transfer factors, and all the other things related
to vinorelbine, peak flow rates, capacity, et cetera, to at least start
to address that question in the context of the pharmacokinetic study as
well.

I believe we can move on to question 4B, few or no patients received
docetaxel, vinblastine, vincristine, ifosfamide, irinotecan, or
imatinib, which are all substrates for CYP3A4, in combination with the
cisplatin and the aprepitant regimen. The docetaxel drug‑drug
interaction study has accrued only five patients. We have seen the data.

So the question is, is there sufficient data to support the safety of
aprepitant in combination with these drugs? Does anybody want further
discussion before we take a vote on this? Dr. Metz?

DR. METZ: Yes. I\'m sorry to harp on the same point today. I don\'t know
actually if there is any real difference if you say five people have had
docetaxel, nobody has had vinblastine, and a whole number but not enough
have had vinorelbine.

So I think it is the same question. I think you are really asking us the
same question. In the subgroup that wasn\'t big enough, well, here is a
subgroup that is even smaller. It is going to be the same kind of
response that I would have to make.

So no. But the only way we are going to find out is by testing enough
patients.

CHAIRPERSON CAMILLERI: We have a quick, enlightening question. Dr.
Levine can tell us in the meantime this question.

DR. LEVINE: It would just seem to me from the former answer that we had
on pharmacokinetics I would feel reassured with a pharmacokinetic study
for all of these pre‑approval.

CHAIRPERSON CAMILLERI: Let\'s have some further insights. Good.

DR. ROWLAND: Yes. I was reflecting on the question that I was asked this
morning.

CHAIRPERSON CAMILLERI: Can you introduce yourself, sir?

DR. ROWLAND: I was reflecting on the answer that ‑‑

CHAIRPERSON CAMILLERI: Who are you?

DR. ROWLAND: Sorry. My name is Malcolm Rowland.

I was asked the question before about the docetaxel study. And I was
reflecting on it over lunch and asked the company if they would have
data available to bring up a number of points. If I could have slide
1113? Can I have that? Because I think there are several things that are
going around. And I think we may not have as clear a picture.

The point I was making before was that, in fact, in answer to the
docetaxel issue is that this is an intravenously administered drug. The
interaction we are looking at is whether intravenously drugs are
affected.

There are three or four substrates that are affected. This is the group
of drugs over here that we are talking about that was actually done. So
we have already talked about methylprednisolone, ondansetron,
erythromycin, and docetaxel. Docetaxel, it is inferred that that may not
be representative.

I am a little worried about that because the FDA has and many people
have advocated the use of enzymology and an understanding of that
enzymology in order to make some statements about how we think some
things are happening so that we don\'t have to study every drug X that
comes along but we use sound scientific principles.

Docetaxel, to my knowledge, has been one which has been correlated with
what is known as ear, throat, mouth and breath test, which is used as a
test for the systemic activity of 3A4 and has been correlated with
midazolam. So to say that this is not representative of 3A4 doesn\'t
make sense to me. You may want to think about that.

I think the other thing is, as I said, there is very little effect on
intravenously administered 3A4 substrates. Where we see the effect more
‑‑ and I think it was pointed out that they are moderate ‑‑ is to drugs
where the drugs are given orally. And that is because it occurs in the
\*response of the drug at the interstinal level. And so we see it there.
These were the magnitudes that were discussed this morning. So I want to
indicate to you that the route of administration is very important.

Another thing that was suggested was this issue of polymorphism. To my
knowledge, there is no polymorphism in CYP3A4. It is a unimodal
dispersion in the population. We know very little about what correlates
with that variability. I know of no diagnostic that would predict the
CYP3A4 activity other than giving the drug and looking at what is going
to happen. So we don\'t have polymorphism, but we do have variability.

So if I can relate this back to a slide which was done, 36, if I can
have that, which was the thing that was striking me, ‑‑ this is 36 ‑‑
and we are talking about this drug being in this thing, which is
moderate, the same or very similar to grapefruit juice, verapamil, and
diltiazem, then it seems to me that if there is a question of concern
about this drug, then presumably there is a question of concern about
these other drugs, too, because, as far as I can see, I can\'t tell the
difference. If you just gave me the data and didn\'t tell me the drug, I
wouldn\'t know the difference. So those are my comments.

CHAIRPERSON CAMILLERI: Thank you. I guess the other drugs and grapefruit
juice are not up for discussion today.

DR. ROWLAND: All right. I appreciate that.

CHAIRPERSON CAMILLERI: Dr. Della\'Zanna?

DR. DELLA\'ZANNA: I have two points I want to bring up. Okay? First of
all, the other drugs that you were talking about do not have the same
narrow therapeutic index. The effect that we saw with IV
methylprednisolone was a 35 percent increase in area under the curve.
Okay?

Now, that still might be labeled for you as a small increase, but if you
increase the plasma levels of some of these cytotoxic agents by 35
percent, you might be breaching into a toxic level.

DR. ROWLAND: Can I just respond? I mean, I think there are two aspects.
One is the magnitude of change that occurs when you bring drugs
together. And the other one is the therapeutic implication of a degree
of change.

I think one thing that is very clear about 3A4, it\'s highly variable.
If I give a drug, a standard dose, to anyone, I have no knowledge of
what that variability is going to be. So people who are getting standard
doses are getting a four to five‑fold variability and exposure full
stop, before we even start.

And we live somehow. Somebody lives with that. I mean, presumably it\'s
clinical management. Maybe one day we will have diagnostics associated
with that.

DR. HOUN: You expressed our responsibility in terms of FDA\'s public
health responsibility and the difficulty of it very well.

DR. ROWLAND: I appreciate that. We are all looking for the diagnostic,
the prognostic that would predict the handling in individuals.

CHAIRPERSON CAMILLERI: Thank you for your intervention.

Yes, Dr. Cryer?

DR. CRYER: I just wanted to follow up on a comment that you were making,
Dr. Della\'Zanna, with respect to the corticosteroid‑related increases
in serum concentration. So in the clinical studies that were done, as I
understand it, the dexamethasone dose on subsequent days was reduced to
provide plasma concentrations that were similar to control.

So the question, the specific question, I have in that regard is, is it
proposed for the label that the dexamethasone dose would similarly be
reduced in subsequent days\' doses with the aprepitant‑antiemetic
combination?

DR. DELLA\'ZANNA: Yes. The dexamethasone dose was decreased not only for
subsequent days but also on day one. My concern is we saw that
interaction, resulted in decreasing the regimen by 50 percent, but we
haven\'t applied or even really analyzed whether that same interaction
is going to occur with cytotoxic agents.

There are no recommendations mentioned in the label saying that if
you\'re on vinorelbine, decrease your dose by 50 percent. It\'s not
there because we don\'t know. It hasn\'t been evaluated. That is my
concern for this.

If we saw these kind of effects in dexamethasone and the effect was
enough to decrease and change the regimen but we haven\'t looked in the
cytotoxic agents, realizing that yes, the inhibitory effect is much more
on oral drugs, we can\'t ignore the fact that the IV methylprednisolone
resulted in a 35 percent increase.

DR. CRYER: You raised an important point that I actually had forgotten.
That was a point that struck me earlier, which was that the effect of
aprepitant on the potential to raise plasma levels of chemotherapeutic
agents was, as you rightly pointed out, has only been done with
aprepitant alone, rather than the combined antiemetic combination, which
will actually be suggested for use in clinical practice.

And so that would definitely be an area for studies that would need to
be looked at. And that would be the effect, I think, with the combined
antiemetic therapy, for which we have no data on at all, as I understand
it.

DR. ERB: But we have clinical data on it.

DR. REINES: Yes. The point that we wanted to make was that that is what
our clinical safety data reflect. That is what we are asking you to
consider. All of those clinical data, of course, in Phase III were with
the regimen, not with aprepitant alone. And so our safety argument is
the argument for the regimen.

CHAIRPERSON CAMILLERI: Dr. Fogel?

DR. FOGEL: I have a question for the agency. Given the dynamic nature of
chemotherapy and given, as has already been alluded to, we are going to
be moving from intravenous to oral medications, hopefully there will be
lots of new and more effective medications coming to market in the
course of the next few years, what is the agency\'s thoughts about sort
of how drugs are approved?

Is the agency believing that to avoid criticism, these approvals should
be very narrow so that you can only use certain combinations or does the
agency believe that there should be a certain amount of openness in the
approvals with extensive post‑marketing data collection?

DR. HOUN: I think that\'s a difficult question. I think it will depend
on the specific drug alternatives, the indication. And if you have a new
drug for a life‑threatening indication, no alternatives, what amount of
safety data you have may be less than if you had a me, too,
fifth‑of‑a‑kind that you are trying to bring to the market as a new
molecular entity.

I am thinking that because these are difficult questions and because the
public should not, as our consumer representative, patient
representative said, be blind‑sided, that this is a public discussion,
it\'s for the record, it\'s on the internet, that issues be publicly
vetted so that we can hear what the experts are saying, there is a
chance for the company to respond as well as public input because these
are difficult questions. These are policy questions. There is not a
right or wrong. It\'s judgment.

DR. FOGEL: The reality is that you are probably going to be
second‑guessed, no matter what happens. If this is a safe drug, you are
going to be criticized for not having a broad use. And if it turns out
that, unfortunately, somebody has a serious adverse side effect that
kills them, you are going to be criticized for being too liberal. You
can\'t make a decision based on the data that we have.

We are all stuck by this. And I think that by having these discussions
and sort of having the label written with this ambivalence put in where
it\'s clear that the data is not available for a broader use would be
very helpful. And I think it would help direct physicians.

CHAIRPERSON CAMILLERI: Thank you, Dr. Fogel.

Other questions or clarifications required on this point?

(No response.)

CHAIRPERSON CAMILLERI: If not, I want to remind you of the question that
we are asked to try to answer. The question is very specific, is there
sufficient data to support the safety of aprepitant in combination with
the drugs docetaxel, vinblastine, vincristine, ifosfamide, irinotecan,
imatinib? Dr. Proschan?

DR. PROSCHAN: I think the answer is no as written here.

DR. DESTA: No as written here.

CHAIRPERSON CAMILLERI: That was Dr. Desta.

DR. McLEOD: McLeod. No with specific post‑approval or pre‑approval if
deemed necessary studies.

DR. BRAWLEY: Brawley. No.

DR. KELSEN: Kelsen. No.

DR. LaMONT: LaMont. No.

DR. LEVINE: Levine. No.

DR. METZ: Metz. No with a request for post‑marketing studies and
specific concerns relating to future oral chemotherapeutics.

CHAIRPERSON CAMILLERI: Camilleri. No.

DR. CRYER: Cryer. No.

DR. FOGEL: Fogel. No. And I think that small studies actually aren\'t
going to help you very much. It is only when there is widespread use of
a drug that you are actually going to get the answers that you need.

MS. COHEN: No. And I hope I don\'t have to give an answer to it.

MS. HOFFMAN: Hoffman. No.

CHAIRPERSON CAMILLERI: Thank you.

Do you require any further clarification on the types that would be
useful to address 4B?

DR. HOUN: Yes. I think we should have some discussion. Everybody voted
no. There has been a proposal that this be handled strongly in labeling
so that this ambivalence on we don\'t have information be placed in the
label.

My interpretation means that you are interested in studies
post‑marketing. I just want to confirm that. Are there people who are
saying some of these studies should hold up the approval for the drug?

CHAIRPERSON CAMILLERI: Ms. Cohen seems to have an answer.

MS. COHEN: Well, as you can gather by now, I spent part of my life in
consumer protection. And part of my expertise is in advertising. I see
advertising for pharmaceuticals that FDC and FDA is finally recognizing
is deceptive. I am looking at one of the proposals for a package insert.
If that is plain language, then it is certainly not English that I
understand.

I am concerned that you don\'t have enough studies. People are not
getting the care that they need nowadays. Doctors don\'t have time to
speak to them. They become a little cavalier.

And I don\'t think people should have to say post‑marketing, \"If
someone dies, then we have learned something.\" Why can\'t we learn
something before they die? I think it is very cavalier.

The practice of medicine today has changed dramatically. I am boring
some of you. I am looking at your faces. But when it hits a member of
your family, then you care. And I am here to see that consumers get the
attention they need and they are not getting anymore.

There is just not enough evidence. When I hear about sepsis and
toxicity, oral versus IV, there are so many adverse events. Just making
notes, drug‑drug reaction, drug reaction to the drug, I am sitting here.
Is this safe and effective? What are we here for? It is not the bottom
line.

I own Merck stock. But, believe me, I would rather take less money for
it and know that my consumers are going to be protected. This is a tough
world, and we have to help people.

I am sorry if I am giving you this speech, but you can see I am upset. I
am worried. What is the next generation going to do?

CHAIRPERSON CAMILLERI: Thank you.

Can I ask Dr. McLeod to specify what pre‑approval studies he would
recommend? Did I understand you correctly?

DR. McLEOD: Well, I didn\'t know whether to define whether it needs to
be pre‑approval or not because I haven\'t had time to think through the
implications of that.

One thing I was just doing right now because of Ms. Cohen\'s comments
was looking through the drugs that were commonly co‑administered with
this agent as a place to start because, I mean, all anti‑cancer drugs
are possibilities to be combined with cisplatin and this antiemetic
regimen, but there are certain players that are going to be very common,
such as the ones there.

So, for example, the docetaxel study that is ongoing now is recognized
by everyone, including the applicant, that that is an issue, that
cisplatin, docetaxel is going to be a common combination in which this
drug will be added. So they are already on their way with that study.
And that needs to be expedited. I think that needs to be done
pre‑approval because of its importance in establishing one way or the
other what it is going to mean.

DR. HOUN: Could the company please just give us the time line on the
completion of that study?

DR. GOTTESNER: We have been working on that study for over two years. We
are accumulating patients on the average of about one every two to three
months. That is despite the fact that we have looked at sites throughout
the whole world in order to find such patients.

It is not easy to do these studies. I just want to make it very clear.

CHAIRPERSON CAMILLERI: I saw Dr. Kelsen\'s eyebrows move.

DR. KELSEN: What\'s the design of the trial? I got the PK part of it.

DR. EGORIN: My name\'s Merrill Egorin. I am serving as a consultant to
Merck. University of Pittsburgh was one of the sites chosen to try and
get this study done.

It was a very simple drug‑drug interaction study, patients getting
single‑agent docetaxel with aprepitant as the antiemetic. There was
really no incentive for patients to be hospitalized overnight in the
GCRC unit.

We tried to get informed consent. We got no patients to sign up for two
years. And that was despite taking a fair amount of time sitting and
talking with patients.

I also, as long as I am up here, think it is fair to say that just
because we went to medical school doesn\'t mean that people in our
family haven\'t had a malignancy. So I think that is an important thing
for consumers to understand.

The other thins is it is sort of an oxymoron. If you have a drug that
orally makes you throw up a lot, you are not going to give it to
patients. So the orally administered drugs that are coming forward are
not highly emetogenic because if they were, you would never be able to
give them to anybody.

DR. KELSEN: I was referring to the ones that are going to be given with
cisplatin. Those studies are with platinum. They are all being written,
and they are all underway.

DR. EGORIN: The reality is if you are looking at approved drugs, we
could not get patients with no real benefit to agree to spend two nights
in a GCRC away from their families. It is a very, very hard sell.

DR. HOUN: So, Dr. McLeod, I just wanted you to see when you say
\"pre‑approval,\" there are some difficulties.

DR. McLEOD: Well, I think this speaks to the need for a change in stage
design, rather than a lack of need for the data. Within the cooperative
groups, we do studies where we do limited sampling. And it is very slow.
We all complain about how slow it is going, but it is not that slow.

I think the study design is probably fantastic and so thorough that we
can\'t get people in. I mean, for this sort of study, when we do an
institutional study of this sort, we would not be putting patients
inpatient. We would be sampling, doing the sampling, in the outpatient
facility.

Maybe it is not rigorous enough for what you require. I don\'t know the
answer to that because certainly we are not submitting our data as part
of an FDA application. And so it may be that the rigor is just
obstructive to be able to do the study.

I think the issue is still there. I can\'t remember the wording Ms.
Cohen used, but we either have to just throw it out there and see what
happens, which is paraphrasing a bit, or try to do these studies.

If it is impossible to do these studies, this drug in my view ‑‑ I guess
I will be on the record saying this ‑‑ looks to be an important advance.
I would not want this drug held up for this issue, but Ms. Cohen\'s
point as well as Dr. Egorin\'s, patients out there, if they are harmed,
one will be too many.

CHAIRPERSON CAMILLERI: Dr. Cryer?

DR. CRYER: Right. So, as I remember, I think Ms. Cohen\'s terminology
was \"cavalier.\" Actually, listening to the sponsor, I think that there
has been an earnest effort to acquire these patients with these specific
combinations.

Your question, Dr. Houn, was, is it our opinion that the approval should
be held up for these additional studies which we are recommending? From
my personal perspective, having heard the arguments, I would say the
answer would be no primarily because of the advancement that this drug
represents compared to the difficulty of acquiring patients in the
clinical trial experience.

However, I would like to make what I consider to be an important comment
with respect to the post‑marketing acquisition of data. And that is that
we just don\'t know what the adverse event profile is going to be with
these drugs in combinations with specific chemotherapeutic agents. And
in the Phase IV experience, we are going to be dependent upon
spontaneous reporting of physicians.

Education, physician education, I think is going to be integral, going
to be key to that mechanism. The label is really going to be the only
tool or one of the best tools that you have for educating physicians to
appropriately alert us as to these potential interactions.

And so with respect to the specific wording in the label, I did want to
bring the discussion to a precautionary section that was in Dr.
Della\'Zanna\'s slides, in which it says, \"EMEND should be used with
caution in patients receiving concomitant medicinal products that are
metabolized through CYP3A4. Some chemotherapy agents are metabolized by
CYP3A4.\"

I am not so certain that physicians will know in the walking inventory
what those chemotherapeutic agents are that are metabolized via that
pathway. And if reporting in the post‑marketing experience is going to
be important and improve the analysis of this product, I also then would
think it would be important to specifically state in the label in that
precautionary statement what those chemotherapeutic agents metabolized
through that pathway might be.

CHAIRPERSON CAMILLERI: Thank you, Dr. Cryer.

Dr. Metz?

DR. METZ: Yes. I think we are all grappling with the same problem and
taking it around and round in circles. To put it into perspective, I
think there is a certain defined 20 percent benefit that we are all
very, very comfortable with here and was not an issue for any of us.

We now are getting concerned about a theoretical concern that actually
cannot be asked before release. And I think the point is you need to see
lots of patients with lots of experience.

Therefore, I would second what has just been said by Dr. Cryer. The
label has to say that the testing was done with this particular agent
and have had so many patients in and wasn\'t done with this particular
agent and it was done with this particular agent, but it was so few
patients. That is the database, which is growing as time goes on.

So you are absolutely correct to raise the concern. I would hate to see
the patients who are clearly going to benefit from an important advance
limited because of theoretic worries we have about where we want to come
down on our votes.

CHAIRPERSON CAMILLERI: And I think, Dr. McLeod, you actually specified
at the very end the same philosophy ‑‑

DR. McLEOD: That is correct.

CHAIRPERSON CAMILLERI: ‑‑ that this medication should move ahead.

DR. McLEOD: I totally agree. That is not the point I wanted to make with
this, but I will reiterate that. I mean, I would love to see those PK
studies but not at the expense of slowing down this drug out there.

There may be some patients that end up having some adverse events that
weren\'t predicted. We know that there are going to be patients, a lot
of patients, benefitting from this.

The point I wanted to make was if you look at this list of drugs that we
were just voting on, only one of them is an oral agent. And that oral
agent is not highly emetogenic and also has quite a lot of variability
already in its blood levels. That\'s the imatinib.

So of those agents we are voting on, it is not a big issue. Now,
worrying about the future, certainly that is something that has been
raised. But I just wanted to point out for those of you who are not
familiar with these agents that only one of them is currently oral. And
it is not likely to be a big issue in terms of interaction here.

CHAIRPERSON CAMILLERI: Thank you.

Dr. Brawley?

DR. BRAWLEY: First, I agree with what Dr. Cryer and Dr. Metz said
wholeheartedly. And that was part of my comment. I want to speak
partially to the consumer community. I see a lot of patients who vomit
an awful lot. Even with the drugs that we currently have, they vomit an
awful lot. And they need something better. I see here something that
sounds like it\'s better.

Now, we may not have 100 percent assurance that it is absolutely safe at
this point, but scientifically to find out that it is 100 percent safe
with all of these drug combinations is actually probably impossible.

If you went to the old Soviet Union and dictated that everybody go onto
a clinical trial and run a clinical trial of 100,000 cancer patients for
5 years, you are not going to find all the ins and outs, all of the
nuances of this drug in combination with other drugs.

I think we have to realize that every drug that is approved has some
risk associated with it. I think all of us have seen people die from
aspirin.

Thank you.

CHAIRPERSON CAMILLERI: Thank you.

Ms. Hoffman?

MS. HOFFMAN: Yes. As a parent whose child went through BMT pre‑5‑HT~3~
therapy, *et al*., in 1987, it was hell. I do want to say, too, that I
don\'t want to see this drug stopped. I think there is great value to
it. It was horrendous. We are talking vomiting every five minutes day
in, day out 24 hours a day.

That said, I do want to see some post‑marketing studies done. And I
would like to know what steps are being taken? Now that you have done a
Phase III trial in adults, what is happening in terms of pediatrics? Are
there tests and studies planned? Where are you in that process?

You talked about patient population. We have got COG. And kids are
pretty much in‑hospital and a cooperative group. So there is a patient
population there.

CHAIRPERSON CAMILLERI: Thanks.

Can we have a very brief comment on what other studies are being done in
particularly children with cancer?

DR. HORGAN: As we mentioned, this is something that has been actively
concerning us. That is why we enrolled a few patients at a specific site
in our Phase III program where they had access to a pediatric
population. They were very eager to see how the drug would benefit their
patients.

We are actively considering pediatric studies with a view to doing a
study in adolescent patients initially to assess the efficacy in an
adolescent \*\*population getting highly emetogenic chemotherapy.

CHAIRPERSON CAMILLERI: Thank you.

Dr. Fogel?

DR. FOGEL: I agree with Dr. Brawley\'s comments regarding the importance
of this new drug and the fact that we cannot know with absolute
certainly about its safety. I also agree with what he said, that the
drug should be released in these post‑marketing studies, can be obtained
obviously after the drug has been released.

There is just one concern I have. When a new drub comes to market,
particularly one that has been shown to be effective, doctors will tend
to generalize and expand the indications. You may find that there are
doctors who will use this for nausea and vomiting that is not
chemotherapy‑related.

I make a strong urge to the agency to make sure that this possibility is
excluded by specific wording that this drug is only approved for
chemotherapy‑induced nausea and vomiting.

DR. HOUN: What is the GI experts\' view on the potential for off‑label
use for nausea and vomiting for a variety of GI conditions? Is there
anticipation?

DR. LEVINE: Yes. Levine.

I would say definitely yes. And I would say this is the time on the
labeling to put it in bold. The only thing a general practitioner looks
at is the bold print usually. And if he is lucky enough to look at that,
it must be a small percentage.

I would put something like this in bold print, exactly what we have
discussed. I would agree with the post‑approval with kinetic studies,
pharmacokinetic studies, also.

CHAIRPERSON CAMILLERI: Dr. Metz?

DR. METZ: Yes. I would like to actually support that. And I would agree
entirely with Dr. Fogel. Off‑label use might be the dangerous situation
here. Treating for more than five days might be an issue because of this
auto‑metabolism and a few other things that were mentioned earlier.

Also, I think we jumped to assume that rescue therapy is ‑‑ this drug
cannot be used for rescue therapy. That\'s treating somebody for nausea.
I would make sure the label has that this is a prophylactic regimen that
is going to be used. It works, and it\'s safe. There are a lot of
problems in terms of patients who are vomiting. It should be restricted.

Now, do I think that it is going to really be overused? You know, I
don\'t know. I think that clearly if I do an endoscopy on somebody and
blow in too much air and they are in the recovery room vomiting, my
nurses will come to me and say, \"You know, Zofran is good for this.\"
Are they then going to come to me and say, \"Hell, EMEND is potentially
good for this\"? They may.

But I also think that what is out there and what is used for off‑label
acute, once, uses is probably good enough most of the time. It would be
the chronic administration that I think you are really worried about.
And I think you must put that in the label.

CHAIRPERSON CAMILLERI: I think I have heard the same message a few
times. Any other comments or questions pertaining to the additional
information that we\'re providing to the agency pertinent to question
4B? Do you have any questions from the agency side? Have we addressed
this?

DR. JUSTICE: No. I think you have been very helpful.

CHAIRPERSON CAMILLERI: Okay. Question number 5, does the committee have
specific concerns regarding potential drug‑drug interactions with other
chemotherapeutic agents or other drug classes? Do we think that we have
already addressed this during the course of our discussion? Yes, Dr.
McLeod, please?

DR. McLEOD: One thing that has been brought up but hasn\'t been
discussed ‑‑ and I don\'t think it needs to be discussed, but it needs
to be brought up again ‑‑ is the warfarin interaction.

It wasn\'t clear to me that the INR change that was seen was ‑‑ it
wasn\'t clear whether it was clinically relevant or not. And also
because it was done in normal volunteers, the dynamics of changes in
warfarin metabolism are not always the same as they are in patients,
especially elderly patients, with a lot of co‑morbidity and
co‑medication.

So I don\'t know what is required in that context, but certainly the
applicant has done a very nice job in showing that there is an issue
there. It will always be flagged in the label, but I think there may be
some post‑marketing issues in the context of the age groups in which
cancer patients are seen.

So there isn\'t a lot of warfarin use in childhood malignancy patients,
at least from my time at St. Jude, but in the adult side, where the
average cancer patient age is 65 to 70, in a general setting like that,
there are a lot of people on warfarin and not just for their afib and
for their hip replacement, not just for their cancer‑induced
coagulopathy. And so it will be an issue that needs to be better defined
so that someone doesn\'t get in trouble, as Ms. Cohen mentioned.

CHAIRPERSON CAMILLERI: Other recommendations or comments?

(No response.)

CHAIRPERSON CAMILLERI: Okay. The final part of that question was, if
yes, please discuss them. I think we have done that. Are there any other
questions or comments that need to be addressed? Any questions, any
final questions, from the agency side?

DR. JUSTICE: No. Thanks. We appreciate your work here.

CHAIRPERSON CAMILLERI: On behalf of the agency side, then I would like
to thank all of the members, members of the public. I would like to
thank the company for the very thorough and clear presentations and our
colleagues at the agency, who provided a very good summary and important
questions to make sure that if this drug comes on the market and when it
does, it is done in as safe a manner as possible. Thank you very much.

We are going to have a 15‑minute break. And then we are going to come
back for the closed session. Everybody else is excused.

(Whereupon, at 3:03 p.m., the foregoing matter was adjourned and the
meeting reconvened in closed session.)