PulminiqTM (cyclosporine) Inhalational Solution - CyIS Pulmonary Drug Advisory Committee June 6, 2005

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PulminiqTM (cyclosporine) Inhalational Solution -
CyISPulmonary Drug Advisory Committee June 6,
2005

• Renata Albrecht, M.D.
• Director, Division of Special Pathogen and
  Immunologic Drug Products, Office of Drug
  Evaluation IV, CDER/FDA

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Introduction

• There are no FDA-approved drugs for prevention of
  chronic rejection and increased survival in lung
  transplantation
• 1100 transplants annually in US
• Survival at 5 years
• Prevention of rejection and mortality is critical
• Clear need for safe and effective therapy

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Chiron NDA 50-799

• Cyclosporine inhalational solution (CyIS) for
  increase in survival and prevention of chronic
  rejection in lung transplant patients
• Drug development program and NDA not conventional
  - One Phase II study, single center enrolled 10
  56 patients total
• Reported survival advantage 23/26 (88) on
  tacrolimus-based systemic immunosuppression plus
  CyIS vs 16/30 (53) on the tacrolimus regimen
  plus aerosolized propylene glycol vehicle

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NDA review

• Agency agreed to file and review this NDA
  application
• Based on the NDA review,
• unable to conclude that observed differences in
  mortality and chronic rejection are due to study
  drug

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Why AC meeting for cyclosporine inhalational
solution (CyIS)?

• First product for immunosuppresion in patients
  with lung transplant
• New Drug Application
• New formulation, new indication, new route, new
  dosage regimen
• Unable to conclude that observed differences
  (mortality, chronic rejection) are due to study
  drug

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Why AC meeting for cyclosporine inhalational
solution (CyIS)?

• Pulmonary product advisory committee
• Standing AC with expertise in pulmonary disease
• Invited experts in statistics and transplantation
• Interested in AC input regarding adequacy of the
  clinical and statistical evidence whether CyIS is
  safe and effective for the proposed indication

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Chiron presentations

• Provide most of the background
• History of development program
• Preclinical results
• Clinical outcome
• Safety information

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FDA presentations

• Focus on areas that raised review challenges
• Clinical issues including
• Demographic characteristics
• Dosing
• Safety Considerations
• Statistical Issues

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Charge to the Committee

• QUESTION 1
• Is there sufficient information to make the
  determination whether the observed survival
  difference in study ASC001 is due to study
  treatment or some other factor(s)?
• In your deliberations, please consider the
  statistical issues raised by this application, as
  well as the differences in baseline
  donor/recipient characteristics, and whether the
  product has demonstrated an effect on another
  endpoint that is related to the mortality
  endpoint, including acute rejection,
  bronchiolitis obliterans syndrome (BOS), and
  histological bronchiolitis obliterans (OB). Also
  consider whether the product has demonstrated a
  benefit on some other clinical endpoint?

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Charge to Committee

• QUESTION 1 (continued)
• If YES
• (a) Please discuss the generalizability of these
  results obtained from a single study at one
  institution to the treatment of lung
  transplantation recipients in the US?
• If NO
• (b) What additional information would be needed
  to make this determination?
• In your discussion please consider what
  additional clinical studies you would recommend
  be conducted. Do you have any specific
  recommendations regarding patient population,
  drug dosing regimen and administration, efficacy
  endpoint(s)?

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Charge to the Committee

• QUESTION 2
• Has the safety of the product been adequately
  characterized for its intended use?
• In your deliberations, please consider the
  amount of pre-clinical and clinical information
  available on the administration of cyclosporine
  and the vehicle through this route, as well as
  the number of human subjects in this application
  exposed to the proposed recommended dosage.

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Charge to the Committee

• QUESTION 2
• If YES
• (a) For what population should the product be
  labeled?
• (b) What information should be included on
  dosing regimen, dose preparation/administration,
  dosing intervals and duration?
• (c) What information should be included in the
  labeling regarding expected benefit on acute
  rejection, BOS or OB?
• If NO
• (d) What additional preclinical or clinical
  information would be needed?