1 november 2005 odac: doxil ®, aids-related ks odac discussion on accelerated approval 8 november...

1November 2005 ODAC: DOXIL®, AIDS-related KS

ODAC Discussion on Accelerated Approval

8 November 2005

DOXIL®

(doxorubicin HCl liposome injection)

Treatment of AIDS-related Kaposi’s Sarcoma

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.


Individuals Available for Questions

Johnson & Johnson Pharmaceutical Research & Development Wayne Rackoff, MD Alex Zukiwski, MD Paul Manley

Consultant Susan Krown, MD, Memorial Sloan-Kettering Cancer Center


DOXIL (doxorubicin HCl liposomal injection) is indicated for:

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

AIDS-related KS Indication

Ovarian cancer indication converted to regular approval in January 2005


DOXIL AIDS-related KS

NDA submitted

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

FDA agrees to 30-38 study

design

Accelerated approval for

AIDS-related KS

Study 30-38

Highly active anti-retroviral therapy (HAART)

DaunoXome® approved


Study 30-38 Design

Objective

– Evaluate clinical benefit based on patients’ self assessment• Response: improvement in 1 of 5 symptom

categories• Lymphedema• Pulmonary KS• Gastrointestinal KS• Disfiguring KS lesions• KS-associated pain

Not designed to test for differences between groups


Study 30-38 Design

Key eligibility criteria

– AIDS-related KS of a severity requiring systemic chemotherapy

– Five or more measurable mucocutaneous lesions

Secondary end point

– Tumor response (ACTG criteria)

Treatment: blinded, randomized 3:1

– DOXIL 20 mg/m2 Q 2 weeks x 6 (n = 60)

– DaunoXome 40 mg/m2 Q 2 weeks x 6 (n = 19)


Study 30-38 Efficacy Results

DOXIL(n = 60)

DaunoXome (n = 19)

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

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

Median Time to Response 30 days 27 days

35 of 39 patients with tumor response also had clinical benefit



NDA submitted

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006


design


AIDS-related KS

sNDA submitted

Study 30-38


DaunoXome approved



NDA submitted

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006


design


AIDS-related KS

Action letter

received

sNDA submitted

Study 30-38


DaunoXome approved



NDA submitted

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006


design


AIDS-related KS

Action letter

received

sNDA submitted

Study 30-38


DaunoXome approved

FDA meetings Request to

waive commitment


Study 30-38Reanalysis Tumor Response Rate

DOXIL DaunoXome

Not confounded patients *

50%

(11/22)

50%

(5/10)

All patients55%

(33/60)

32%

(6/19)

* No change in anti-retroviral therapy within 60 days before study treatment start and no change on study, unless that change occurred after the start of response



NDA submitted

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006


design


AIDS-related KS

Action letter

received

sNDA submitted

Study 30-38


sNDA resubmitted with new analysis

of Study 30-38

DaunoXome approved

FDA meetings Request to

waive commitment



NDA submitted

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006


design


AIDS-related KS

Action letter

received

sNDA submitted

Study 30-38



of Study 30-38

DaunoXome approved

FDA meetings

Randomized Spanish study

published

Request to waive

commitment



NDA submitted

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006


design


AIDS-related KS

Action letter

received

sNDA submitted

Study 30-38



of Study 30-38

DaunoXome approved

FDA meetings


published

Meeting with

Spanish study group

Request to waive

commitment



NDA submitted

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006


design


AIDS-related KS

Action letter

received

sNDA submitted

Study 30-38



of Study 30-38

Withdrawal of sNDA

DaunoXome approved

FDA meetings


published

Meetings with

Spanish study group

Request to waive

commitment


Highly Active Antiretroviral Therapy (HAART)

(N = 15)Moderate-severe AIDS-related KS

HAART naïve or failing HAART

DOXIL + HAART (N = 13)

DOXIL 20 mg/m2 every 3-weeks

Recently Published Data:DOXIL + HAART in AIDS-related

Kaposi’s Sarcoma

Martín-Carbonero et al., AIDS 12: 1737, 2004


HAART

N = 15

DOXIL + HAART

N = 13

Response Rate (48 wks)

(95% CI)

20%

(4.3, 48.1)

76%*

(46.2, 95)


Kaposi’s Sarcoma

*P = 0.003

Martín-Carbonero et al., AIDS 12: 1737, 2004



Kaposi’s Sarcoma

10 of 15 patients required rescue treatment with DOXIL

Reasons for cross-over

– 9 of 10 had progression

– 1 had no response to HAART alone after 9 months

8 of 10 had CR after cross-over treatment with DOXIL


Recently Published Data:Tumor Remission and CD4 Recovery with

DOXIL + HAART for AIDS-related KS

Cases HIV-1-infected with advanced KS (n = 54)

– Treatment with DOXIL + HAART Matched controls (n = 54) without KS Recovery of CD4 counts not impaired by combination therapy Response rate (complete + partial) = 81.5%, all within 8 weeks

– Maintained at 1 year

Lichterfeld et al., Infection 33: 140-7, 2005


AIDS-related KS

Tumor confined to skin, lymph nodes, oral cavity, and non-symptomatic visceral disease

Symptomatic visceral disease, rapidly progressive cutaneous lesions with extensive ulcerations,

oedema and pain

Treat with HAART*

Complete remission

Partial remission or stable disease

Progressive disease

Liposomal anthracycline + HAART

Complete remission

Partial remission or stable disease

Progressive disease

Continue HAART

Continue HAART; consider local

therapy

Continue HAART

Continue HAART; consider second-

line chemotherapy

Paclitaxel+ HAART

Progressive disease

____________________________________________________________________________________

* Monthly evaluation of KS clinical response, CD4+ cell count and HIV-RNA levels are obtained.

° HAART regimen should be changed in the case of immuno-virological failure.

Treatment of AIDS-related KS

Aversa et al., Critical Rev in Oncology/Hematology 53:253-65, 2005


New Anti-retrovirals in Development

Nucleoside and Nucleotide Reverse

Transcriptase Inhibitors

Non-nucleoside Reverse Transcriptase

Inhibitors

Protease Inhibitors Entry inhibitors

–SPD 754 (DOTC)

–Amdoxovir

–D-d4FC

–Racivir (± FTC)

–SN1212

– TMC125

– GW678248 (prodrug=GW695634)

– TMC278

– BILR 355 BS

– CSIC

– DAPY/DATA

– UC781

– GW0385

– TMC114

–Aplaviroc

–Maraviroc

–BMS-488043

–TNX-355

–NB-2, NB-64


Issues with an AdditionalRegistration Study for AIDS-related KS

Delay of systemic chemotherapy for patients who require it is not acceptable

New anti-retrovirals: confounding issue remains


Conclusion

Due diligence by conducting and reporting Study 30-38

– Agreed upon with the FDA

AIDS-related KS patients still progress on HAART or present with aggressive, advanced disease

– Benefit of the availability of the current indication

Body of evidence supports clinical benefit

1 november 2005 odac: doxil ®, aids-related ks odac discussion on accelerated approval 8 november...

Documents

aidsrelated ks study

aidsrelated ks snda

aidsrelated ks action

study design

efficacy results doxil

accelerated approval

clinical benefit slide

daunoxome n