ODAC Discussion on Accelerated Approval 8 November 2005

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ODAC Discussion on Accelerated Approval 8
November 2005

• DOXIL(doxorubicin HCl liposome injection)
• Treatment of AIDS-related Kaposis Sarcoma
• Johnson Johnson Pharmaceutical Research
  Development, L.L.C.

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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

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AIDS-related KS Indication

• DOXIL (doxorubicin HCl liposomal injection) is
  indicated for
• The treatment of AIDS-related Kaposis sarcoma
  (AIDS-KS) in patients with disease that has
  progressed on prior combination chemotherapy or
  in patients who are intolerant to such therapy.

• Ovarian cancer indication converted to regular
  approval in January 2005

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DOXIL AIDS-related KS
Accelerated approval for AIDS-related KS
FDA agrees to 30-38 study design
DaunoXome approved
NDA submitted
Study 30-38
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
2004 2005 2006
Highly active anti-retroviral therapy (HAART)
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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

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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 31
• DOXIL 20 mg/m2 Q 2 weeks x 6 (n 60)
• DaunoXome 40 mg/m2 Q 2 weeks x 6 (n 19)

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Study 30-38 Efficacy Results
35 of 39 patients with tumor response also had
clinical benefit
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DOXIL AIDS-related KS
Accelerated approval for AIDS-related KS
FDA agrees to 30-38 study design
DaunoXome approved
sNDA submitted
NDA submitted
Study 30-38
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
2004 2005 2006
Highly active anti-retroviral therapy (HAART)
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DOXIL AIDS-related KS
Accelerated approval for AIDS-related KS
Action letterreceived
FDA agrees to 30-38 study design
DaunoXome approved
sNDA submitted
NDA submitted
Study 30-38
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
2004 2005 2006
Highly active anti-retroviral therapy (HAART)
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DOXIL AIDS-related KS
Accelerated approval for AIDS-related KS
FDA meetings
Request to waive commitment
Action letterreceived
FDA agrees to 30-38 study design
DaunoXome approved
sNDA submitted
NDA submitted
Study 30-38
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
2004 2005 2006
Highly active anti-retroviral therapy (HAART)
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Study 30-38Reanalysis Tumor Response Rate
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
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DOXIL AIDS-related KS
sNDA resubmitted with new analysis of Study 30-38
Accelerated approval for AIDS-related KS
FDA meetings
Request to waive commitment
Action letterreceived
FDA agrees to 30-38 study design
DaunoXome approved
sNDA submitted
NDA submitted
Study 30-38
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
2004 2005 2006
Highly active anti-retroviral therapy (HAART)
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DOXIL AIDS-related KS
Randomized Spanish study published
sNDA resubmitted with new analysis of Study 30-38
Accelerated approval for AIDS-related KS
FDA meetings
Request to waive commitment
Action letterreceived
FDA agrees to 30-38 study design
DaunoXome approved
sNDA submitted
NDA submitted
Study 30-38
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
2004 2005 2006
Highly active anti-retroviral therapy (HAART)
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DOXIL AIDS-related KS
Randomized Spanish study published
sNDA resubmitted with new analysis of Study 30-38
Accelerated approval for AIDS-related KS
FDA meetings
Request to waive commitment
Action letterreceived
FDA agrees to 30-38 study design
DaunoXome approved
Meeting with Spanish study group
sNDA submitted
NDA submitted
Study 30-38
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
2004 2005 2006
Highly active anti-retroviral therapy (HAART)
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DOXIL AIDS-related KS
Randomized Spanish study published
sNDA resubmitted with new analysis of Study 30-38
Accelerated approval for AIDS-related KS
FDA meetings
Withdrawal of sNDA
Request to waive commitment
Action letterreceived
FDA agrees to 30-38 study design
DaunoXome approved
Meetings with Spanish study group
sNDA submitted
NDA submitted
Study 30-38
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
2004 2005 2006
Highly active anti-retroviral therapy (HAART)
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Recently Published DataDOXIL HAART in
AIDS-related Kaposis Sarcoma
Martín-Carbonero et al., AIDS 12 1737, 2004
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Recently Published DataDOXIL HAART in
AIDS-related Kaposis Sarcoma
P 0.003
Martín-Carbonero et al., AIDS 12 1737, 2004
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Recently Published DataDOXIL HAART in
AIDS-related Kaposis 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

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Recently Published DataTumor 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
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Treatment of AIDS-related KS
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
Liposomal anthracycline HAART
Complete remission
Partial remission or stable disease
Progressive disease
Complete remission
Partial remission or stable disease
Progressive disease
Paclitaxel HAART
Continue HAART
Continue HAART consider second-line chemotherapy
Continue HAART
Continue HAART consider local therapy
__________________________________________________
__________________________________ 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.
Progressive disease
Aversa et al., Critical Rev in Oncology/Hematology
53253-65, 2005
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New Anti-retrovirals in Development
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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

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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