1 March 2003 ODAC: DOXIL ®, AIDS-KS ODAC Discussion on Accelerated Approval March 12-13, 2003 DOXIL...

11March 2003 ODAC: DOXILMarch 2003 ODAC: DOXIL®®, AIDS-KS, AIDS-KS

ODAC Discussion on ODAC Discussion on Accelerated ApprovalAccelerated Approval

March 12-13, 2003March 12-13, 2003

DOXILDOXIL®®

(doxorubicin HCl liposome injection)(doxorubicin HCl liposome injection)

Treatment of Treatment of AIDS-Related Kaposi’s Sarcoma AIDS-Related Kaposi’s Sarcoma


Individuals Available for QuestionsIndividuals Available for Questions

Sponsor RepresentativesSponsor Representatives Martine George, MD Martine George, MD Steven Hamburger, PhDSteven Hamburger, PhD Surya Mohanty, PhD Surya Mohanty, PhD April Teitelbaum, MD April Teitelbaum, MD Margaret Tonda, PharmD Margaret Tonda, PharmD Alex Zukiwski, MDAlex Zukiwski, MD

ConsultantConsultant Susan Krown, MDSusan Krown, MD

Member and Attending PhysicianMember and Attending PhysicianDepartment of MedicineDepartment of MedicineMemorial Sloan-Kettering Cancer CenterMemorial Sloan-Kettering Cancer Center


DOXILDOXIL®® (doxorubicin HCl liposomal injection) (doxorubicin HCl liposomal injection) is indicated for:is indicated for:

““The treatment of AIDS-related Kaposi’s sarcoma The treatment of AIDS-related Kaposi’s sarcoma (AIDS-KS) in patients with disease that has progressed on (AIDS-KS) in patients with disease that has progressed on prior combination chemotherapy or in patients who are prior combination chemotherapy or in patients who are intolerant to such therapy.”intolerant to such therapy.”

AIDS-KS IndicationAIDS-KS Indication


Status UpdateStatus Update

Original Phase IV commitment trial Original Phase IV commitment trial

New Phase IV commitment trialNew Phase IV commitment trial

– Discussions ongoingDiscussions ongoing

– CompletedCompleted

– Non-approvable letter received from FDANon-approvable letter received from FDA


Ongoing Challenges for Ongoing Challenges for AIDS-KS Studies AIDS-KS Studies

Incidence of AIDS-KS in the USIncidence of AIDS-KS in the US



SEER Incidence Age-Adjusted Rates 9 Registries, 1973-1999

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

1973

1974

1975

1976

1977

1978

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

Year of diagnosis

Ra

te p

er

10

0,0

00

SEER Incidence Age-Adjusted Rates 9 Registries, 1973-1999

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

1973

1974

1975

1976

1977

1978

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

Year of diagnosis

Ra

te p

er

10

0,0

00



Incidence of AIDS-KS in the US Incidence of AIDS-KS in the US

Introduction of highly active anti-retroviral therapy (HAART) Introduction of highly active anti-retroviral therapy (HAART)

DOXILDOXIL®® is regarded as standard of care when systemic is regarded as standard of care when systemic chemotherapy is appropriatechemotherapy is appropriate

NDA studies

Sequus submits DOXILSequus submits DOXIL®® NDA based on 4 clinical studies NDA based on 4 clinical studies

Efficacy data on 383 patients Efficacy data on 383 patients

– FDA medical review focused on 77 patients retrospectively identified as FDA medical review focused on 77 patients retrospectively identified as having disease progression on prior systemic combination having disease progression on prior systemic combination chemotherapy or as being intolerant to such therapychemotherapy or as being intolerant to such therapy

Safety data on 753 patientsSafety data on 753 patients

SepSep

AIDS-KS TimelineAIDS-KS Timeline

NDA NDA submittedsubmitted

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

88

Discussions at ODAC (Feb 14, 1995)Discussions at ODAC (Feb 14, 1995)

March 2003 ODAC: DOXILMarch 2003 ODAC: DOXIL®®, AIDS-KS, AIDS-KS

NDA studies

FDA agrees to Phase IV commitment Study 30-38FDA agrees to Phase IV commitment Study 30-38

Double-Blind, Randomized Evaluation of the Clinical Benefits Double-Blind, Randomized Evaluation of the Clinical Benefits of DOXILof DOXIL®® in Patients with AIDS-Related Kaposi’s Sarcoma in Patients with AIDS-Related Kaposi’s Sarcoma Treated with DOXIL or DaunoXomeTreated with DOXIL or DaunoXome®®

Study start dependent upon commercial availability of Study start dependent upon commercial availability of DaunoXome (approved for AIDS-KS: Apr 1996) DaunoXome (approved for AIDS-KS: Apr 1996)

JunJun



19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

FDA agrees FDA agrees to 30-38 to 30-38 study study designdesign


Nov 1995Nov 1995

Accelerated approval for AIDS-KSAccelerated approval for AIDS-KS

– Based on objective response rateBased on objective response rate

NovNov


NDA studies

Accelerated Accelerated approval approval receivedreceivedNDA NDA

submittedsubmitted

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

FDA agrees FDA agrees to 30-38 to 30-38 study study

designdesign


NDA studies


Double-blind, randomized study Double-blind, randomized study

– 50 US sites contacted, 7 sites participated50 US sites contacted, 7 sites participated

– 60 patients – DOXIL60 patients – DOXIL®® 20 mg/m 20 mg/m22 q 2 wk x 6 q 2 wk x 6

– 19 patients – DaunoXome19 patients – DaunoXome®® 40 mg/m 40 mg/m22 q 2 wk x 6 q 2 wk x 6

Patients with AIDS-KS, either previously-treated Patients with AIDS-KS, either previously-treated or chemo-naïve or chemo-naïve

Primary endpoint – clinical benefitPrimary endpoint – clinical benefit

– Not designed to test for differences between Not designed to test for differences between DOXIL and DaunoXomeDOXIL and DaunoXome

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

NovNov



designdesign

Phase IV Commitment Study 30-38

Accelerated Accelerated approval approval receivedreceived



Patient PopulationPatient Population

Key Eligibility Criteria:Key Eligibility Criteria:

AIDS-KS of a severity requiring systemic chemotherapy AIDS-KS of a severity requiring systemic chemotherapy with one or more of the following:with one or more of the following:

– Edema impairing functional activity Edema impairing functional activity (extremities, groin or face)(extremities, groin or face)

– Symptomatic evaluable pulmonary KSSymptomatic evaluable pulmonary KS

– Symptomatic evaluable gastrointestinal KSSymptomatic evaluable gastrointestinal KS

– Associated painAssociated pain

– Disfiguring lesionsDisfiguring lesions

Five or more measurable mucocutaneous lesionsFive or more measurable mucocutaneous lesions

Study 30-38 Study 30-38


Efficacy ParametersEfficacy Parameters

Clinical benefit (primary endpoint)Clinical benefit (primary endpoint)

Tumor response (ACTG criteria)Tumor response (ACTG criteria)

Photographs of patients also evaluated by Photographs of patients also evaluated by an independent reviewer blinded to patient an independent reviewer blinded to patient treatment treatment

Relationship between clinical benefit and tumor Relationship between clinical benefit and tumor responseresponse



Primary Endpoint: Clinical BenefitPrimary Endpoint: Clinical Benefit

Improvement in 1 of the 5 symptom categories lasting Improvement in 1 of the 5 symptom categories lasting for at least 4 wks in the absence of tumor progression for at least 4 wks in the absence of tumor progression or severe drug-induced toxicityor severe drug-induced toxicity

Patients assessed the 5 symptom categories using a Patients assessed the 5 symptom categories using a questionnaire questionnaire

Patients rated degree of symptom interference with Patients rated degree of symptom interference with daily activities daily activities



Assessment of Clinical BenefitAssessment of Clinical Benefit

Symptom CategorySymptom Category SymptomsSymptoms

LymphedemaLymphedema Difficulty wearing shoes or clothingDifficulty wearing shoes or clothingDifficulty moving due to swellingDifficulty moving due to swelling

Pulmonary KSPulmonary KS Shortness of breathShortness of breathCoughCough

Gastrointestinal KSGastrointestinal KS Difficulty swallowing or eatingDifficulty swallowing or eatingAble to eat only small amounts of foodAble to eat only small amounts of foodBloatingBloatingDiarrheaDiarrheaNausea and / or vomitingNausea and / or vomiting

Disfiguring KS lesionsDisfiguring KS lesions Unsightly skin lesionsUnsightly skin lesions

KS-associated painKS-associated pain PainPain



Efficacy ResultsEfficacy Results

DOXILDOXIL®®

(n = 60)(n = 60)DaunoXomeDaunoXome®®

(n = 19)(n = 19)

Clinical Benefit Clinical Benefit (Primary Endpoint)(Primary Endpoint) 48 (80%)48 (80%) 12 (63%)12 (63%)

Objective Tumor Objective Tumor ResponseResponse 33 (55%)33 (55%) 6 (32%)6 (32%)


Median time to objective tumor response ~ 30 days Median time to objective tumor response ~ 30 days


Clinical Benefit by Symptom CategoryClinical Benefit by Symptom Category

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t w

ith

Cli

nic

al B

enef

it

Lymphedema Pulmonary KS Gastrointestinal KS Disfiguring Lesions KS-associated pain

DOXIL® DaunoXome®

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t w

ith

Cli

nic

al B

enef

it

Lymphedema Pulmonary KS Gastrointestinal KS Disfiguring Lesions KS-associated pain

DOXIL® DaunoXome®


NDA studies

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

sNDA sNDA submittedsubmitted

Oct 2001Oct 2001

ALZA submits sNDA containing AIDS-KS Phase IV ALZA submits sNDA containing AIDS-KS Phase IV commitment datacommitment data

OctOct





designdesign



Jul 2002Jul 2002

Regulatory conclusionRegulatory conclusion

– Changes in anti-retroviral therapy confounded efficacy Changes in anti-retroviral therapy confounded efficacy assessment assessment

JulJul


NDA studies

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

Action Action letterletter

receivedreceivedsNDA sNDA

submittedsubmitted




designdesign



Regulatory conclusionRegulatory conclusion

– Changes in anti-retroviral therapy confounded efficacy Changes in anti-retroviral therapy confounded efficacy assessment assessment


NDA studies

Highly active anti-retroviral therapy (Highly active anti-retroviral therapy (HAART) HAART)

Anti-retroviral therapyAnti-retroviral therapy

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

JulJul



receivedreceived





designdesign


Sep – Nov 2002Sep – Nov 2002 Convened an advisory board of US AIDS-KS experts Convened an advisory board of US AIDS-KS experts Submitted a new Phase IV commitment trial protocol outlineSubmitted a new Phase IV commitment trial protocol outline


NDA studies



19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

New Phase IVNew Phase IVStudy DesignStudy Design


Action letterAction letterreceivedreceived





designdesign


Nov 2002 – PresentNov 2002 – Present Ongoing communication with FDA regarding a new protocol Ongoing communication with FDA regarding a new protocol

and development plan to confirm the clinical benefit of DOXILand development plan to confirm the clinical benefit of DOXIL®® in AIDS-KSin AIDS-KS

Feb 3, 2003 Feb 3, 2003 FDA meeting to discuss our proposed study design and alternativesFDA meeting to discuss our proposed study design and alternatives


NDA studies



19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

FebFeb

FDA meeting



receivedreceived





designdesign

New Phase IVNew Phase IVStudy DesignStudy Design



AIDS-KS Protocol Design and AIDS-KS Protocol Design and Implementation IssuesImplementation Issues

Declining incidence of AIDS-KS in the USDeclining incidence of AIDS-KS in the US

In practice, DOXILIn practice, DOXIL®® is regarded as the first-line systemic is regarded as the first-line systemic chemotherapy of choice chemotherapy of choice

Patients who present with AIDS and KS who require Patients who present with AIDS and KS who require aggressive intervention are treated concomitantly with aggressive intervention are treated concomitantly with HAART and chemotherapyHAART and chemotherapy

– The effect of HAART alone on AIDS-KS regression is The effect of HAART alone on AIDS-KS regression is not well documented not well documented

– The contribution of each treatment component is The contribution of each treatment component is difficult to assess difficult to assess

The introduction of new anti-retroviral agents will further The introduction of new anti-retroviral agents will further confound interpretation of future study resultsconfound interpretation of future study results


AIDS-KS Protocol Design and AIDS-KS Protocol Design and Implementation IssuesImplementation Issues

Not all patients with AIDS-KS require systemic Not all patients with AIDS-KS require systemic chemotherapychemotherapy

It is not acceptable to delay cytotoxic chemotherapy It is not acceptable to delay cytotoxic chemotherapy when medically indicated and such a trial design may when medically indicated and such a trial design may not be executablenot be executable

It will be difficult to conduct a placebo-controlled or It will be difficult to conduct a placebo-controlled or active comparator-controlled trial in this patient active comparator-controlled trial in this patient populationpopulation

– Insufficient accrual in recently terminated ECOG, Insufficient accrual in recently terminated ECOG, SWOG, and AMC Study: TaxolSWOG, and AMC Study: Taxol®® vs. DOXIL vs. DOXIL®® in in AIDS-KS AIDS-KS


ConclusionConclusion

We are committed to design and implement, with FDA We are committed to design and implement, with FDA

agreement, a new Phase IV trial as quickly as possible to agreement, a new Phase IV trial as quickly as possible to

convert this accelerated approval to full approvalconvert this accelerated approval to full approval

1 March 2003 ODAC: DOXIL ®, AIDS-KS ODAC Discussion on Accelerated Approval March 12-13, 2003 DOXIL...

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