Pulmonary-Allergy Drugs Advisory Committee July 13, 2005

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Pulmonary-Allergy Drugs Advisory CommitteeJuly
13, 2005

• Safety of Long-acting Beta-agonist
  Bronchodilators
• Formoterol
• J.H. Gunkel, M.D.
• Medical Officer
• Division of Pulmonary and Allergy Drug Products

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Order of Presentation

• Product Information
• Product Regulatory History
• Overview of NDA with Relevant Phase 3 Study
  Results
• Phase 4 Post-marketing Study
• Post-marketing Spontaneous Reports
• Summary and Conclusions

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Product Information

• Foradil Aerolizer (formoterol fumarate
  inhalation powder) Novartis Pharmaceuticals
  Corporation
• Foradil is a capsule dosage form containing a dry
  powder for oral inhalation using the
  breath-actuated Aerolizer inhaler
• Formoterol fumarate is a racemate of (R,R)- and
  (S,S)- enantiomers

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Order of Presentation

• Product Information
• Product Regulatory History
• Overview of NDA with Relevant Phase 3 Study
  Results
• Phase 4 Post-marketing Study
• Post-marketing Spontaneous Reports
• Summary and Conclusions

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Foradil Regulatory History

• NDA for asthma submitted June, 1997
• Foradil clinical program evaluated two doses
• 12 mcg twice daily
• 24 mcg twice daily
• Results with 24 mcg BID dose indicated
• Higher rate of serious asthma exacerbations than
  with 12 mcg BID
• No evidence of efficacy advantage over 12 mcg BID

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Foradil Regulatory History

• Therefore, only Foradil 12 mcg BID dose approved
  for maintenance treatment of asthma in adults and
  children 5 years of age and older (February 2001)
• Finding of ? asthma exacerbations with 24 mcg BID
  dose warranted additional investigation, but
  routine post-marketing surveillance might not be
  helpful when event of concern was also underlying
  disease

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Foradil Regulatory History

• Approval included Phase 4 commitment to conduct
  a large, simple, placebo-controlled postmarketing
  study to further evaluate the safety and efficacy
  of one or more dose levels of Foradil Aerolizer
  above that of the approved dosein comparison to
  the safety and efficacy of the approved dose.
• Results of SMART not known when Foradil Phase 4
  study was designed

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Order of Presentation

• Product Information
• Product Regulatory History
• Overview of NDA with Relevant Phase 3 Study
  Results
• Phase 4 Post-marketing Study
• Post-marketing Spontaneous Reports
• Summary and Conclusions

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Foradil NDA

• 3 asthma studies in the NDA were considered
  pivotal
• Studies 040, 041 in adults, adolescents
• Pediatric study (5-12 years) 049

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Foradil NDA

• Studies 040, 041 Adults and adolescents
• Randomized, double-blind, placebo- and
  active-controlled
• 12-week treatment
• Asthmatics ? 12 yrs, FEV1 ? 40 predicted, 15
  reversibility
• Treatments
• Foradil 12 mcg BID
• Foradil 24 mcg BID
• Albuterol 180 mcg QID
• Placebo

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Foradil NDA

• Study 049 Children
• 1-year study
• Asthmatics 5-12 yrs, FEV1 50-85 predicted, 15
  reversibility
• Treatments
• Foradil 12 mcg BID
• Foradil 24 mcg BID
• Placebo

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Foradil NDA Efficacy
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Foradil NDA Serious Asthma Exacerbations
Study Foradil 12 mcg BID Foradil 24 mcg BID Albuterol Placebo
040a 0/136 (0) 4/135 (3.0)c 2/134 (1.5) 0/136 (0)
041a 1/139 (0.7) 5/136 (3.7)d 0/138 (0) 2/141 (1.4)
049b 8/171 (4.7) 11/171 (6.4) N.A. 0/176 (0)
aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died
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Foradil NDA Summary

• Foradil 24 mcg BID not approved because serious
  asthma exacerbations were more common than with
  12 mcg BID in all 3 pivotal studies
• There was no efficacy advantage of Foradil 24 mcg
  BID
• Serious asthma exacerbations were more common in
  children than adults at both doses
• Phase 4 study commitment

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Order of Presentation

• Product Information
• Product Regulatory History
• Overview of NDA with Relevant Phase 3 Study
  Results
• Phase 4 Post-marketing Study
• Post-marketing Spontaneous Reports
• Summary and Conclusions

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Foradil Phase 4 Study

• Randomized, parallel group, placebo-controlled.
  Run-in period followed by 16-week treatment
  period with 5 study visits
• Patient population intended to be similar to
  Phase 3 studies to allow comparison of outcomes

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Foradil Phase 4 Study Design

• Patient Inclusion
• Asthmatics ? 12 yrs
• Using inhaled beta-agonist
• FEV1 ? 40 predicted, 12 reversibility
• Patient Exclusion
• Hospitalization or ER visit within 1 month
• Parenteral, oral steroids within 1 month
• Combination LABA and steroid must be replaced by
  monotherapies
• Changing medications or dosages within 3-4 weeks

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Foradil Phase 4 Study Design

• Study Treatments
• Foradil 24 mcg BID
• Foradil 12 mcg BID
• Placebo BID
• Foradil 12 mcg BID 2 on-demand doses/day
  (open-label)
• Albuterol rescue 90 mcg up to 8 doses/day (4
  doses/day for open-label)

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Foradil Phase 4 Study Results Patient Disposition

• Study conducted February, 2002 - March, 2004, in
  194 U.S. centers
• 3820 patients screened
• 2085 patients treated
• 1791 patients completed
• 294 patients discontinued (adverse event gt
  withdrawn consent gt lost to follow-up gt protocol
  violation gt unsatisfactory therapeutic effect)

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Foradil Phase 4 Study Amendments

• Study protocol amended 3 times after enrollment
  began (February 2002)
• April 2002 and March 2003 amendments modified
  the use of concomitant medications to be
  consistent with GINA guidelines more use of
  corticosteroids
• April 2003 to accelerate enrollment (age, FEV1
  criteria, medication washouts)

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Foradil Phase 4 Study Results Baseline
Foradil 12 mcg BID N527 Foradil 24 mcg BID N527 Placebo N514 Foradil Open-label N517 Phase 3 Studies N1095
Mean age (yr) 39.2 38.5 37.8 36.9 34.3
Male () Female 47.6 52.4 44.4 55.6 41.1 58.9 46.4 53.6 45.4 54.6
Caucasian African American Asian Other 81.6 11.2 1.9 5.3 78.0 14.2 2.1 7.2 78.2 11.9 2.7 7.2 77.6 14.1 2.1 6.2 86.5 6.7 0 6.8
Baseline FEV1 ( predicted) 68.2 68.5 69.0 69.5 64.3
FEV1 reversibility () 24.2 24.1 23.3 22.4 18.3
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Foradil Phase 4 Study Results Baseline
Foradil 12 mcg BID N527 Foradil 24 mcg BID N527 Placebo N514 Foradil Open-label N517
Oral steroid courses N () None 1-2 gt2 438 (83.1) 79 (15.0) 10 (1.9) 432 (82.0) 76 (14.4) 17 (3.2) 432 (84.0) 77 (15.0) 5 (1.0) 430 (83.2) 77 (14.9) 8 (1.5)
ER Visits - N () None 1-2 gt2 493 (93.5) 29 (5.5) 5 (0.9) 487 (92.4) 31 (5.0) 7 (1.3) 480 (93.4) 33 (6.4) 1 (0.2) 481 (93.0) 28 (5.4) 6 (1.2)
Hospitalizations N () None 1-2 gt2 517 (98.1) 10 (1.9) 0 518 (98.3) 6 (1.2) 0 508 (98.8) 6 (1.2) 0 506 (97.9) 7 (1.4) 2 (0.4)
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Foradil Phase 4 Study ResultsAdverse Events
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Foradil Phase 4 Study Results Serious Adverse
Events
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Summary Serious Asthma Exacerbations in Foradil
Studies
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Order of Presentation

• Product Information
• Product Regulatory History
• Overview of NDA with Relevant Phase 3 Study
  Results
• Phase 4 Post-marketing Study
• Post-marketing Spontaneous Reports
• Summary and Conclusions

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Post-marketing Spontaneous Reports

• AERS contains 180 domestic reports for
  formoterol, as of June 14, 2005
• 11 reports of bronchospasm and obstruction
• Since June, 2001, 4 domestic deaths were reported
• Of 4 domestic deaths, 2 were from myocardial
  infarction, 2 other causes not reported

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Order of Presentation

• Product Information
• Product Regulatory History
• Overview of NDA with Relevant Phase 3 Study
  Results
• Phase 4 Post-marketing Study
• Post-marketing Spontaneous Reports
• Summary and Conclusions

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Summary and Conclusions

• In Phase 3 studies, serious asthma exacerbations
  occurred more frequently with Foradil 24 mcg BID
  than Foradil 12 mcg BID
• Foradil 24 mcg BID not approved
• Serious asthma exacerbations more frequent in
  children
• Phase 4 study results inconclusive
• Small N and no children

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Questions To Committee

• The label of the formoterol containing product
  does not include warnings comparable to the
  warnings that are present in the salmeterol
  containing products.
• Based on the currently available information,
  should the label of formoterol containing
  products include warnings similar to those in the
  salmeterol label?
• Based on the currently available information, do
  you agree that formoterol should continue to be
  marketed in the United States?

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Questions To Committee

• What further investigation, if any, do you
  recommend to be performed by Novartis that can
  improve the understanding of the nature and
  magnitude of the risk of formoterol?

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Division of Pulmonary and Allergy Drug Products
Parklawn Building, Room 10B-45 5600 Fishers Lane,
HFD-570 Rockville, MD 20857
Phone [phone] Fax [phone]