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Exubera ® (insulin powder, rDNA origin, for oral-pulmonary inhalation) Pfizer Pharmaceuticals New Drug Application 21-8

Exubera ® (insulin powder, rDNA origin, for oral-pulmonary inhalation) Pfizer Pharmaceuticals New Drug Application 21-868 . Endocrine and Metabolic Drugs Advisory Committee Meeting Silver Spring, Maryland September 8, 2005 Karen Murry Mahoney, MD, FACE

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Exubera ® (insulin powder, rDNA origin, for oral-pulmonary inhalation) Pfizer Pharmaceuticals New Drug Application 21-8

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  1. Exubera® (insulin powder, rDNA origin, for oral-pulmonary inhalation)Pfizer PharmaceuticalsNew Drug Application 21-868 Endocrine and Metabolic Drugs Advisory Committee Meeting Silver Spring, Maryland September 8, 2005 Karen Murry Mahoney, MD, FACE Division of Metabolic and Endocrine Drug Products Center for Drug Evaluation and Research

  2. Topics for Presentation • Scope of development program • Brief overview of efficacy evaluation in Type 1 diabetes • Focus on use in “intensive” management of Type 1 diabetes • Brief overview of nonpulmonary safety evaluation in Types 1 and 2 diabetes • Focus on hypoglycemia and insulin antibody evaluations

  3. Scope of Development Program • Over 50 Phase 2 and Phase 3 clinical trials • 4,959 patients reported in NDA • 3,603 exposed to inhaled insulin • 16,571 patient-months exposure for Type 1 diabetes; 30,688 patient-months for Type 2 diabetes • 1,581 patients had >1 year of exposure • Exposure as long as 7 years for some patients

  4. Key Findings Before Phase 3 • After inhalation of Exubera®, insulin was absorbed from the lung into the blood • The insulin absorbed via the lung lowered blood glucose

  5. Key Questions for Phase 3 • Can Exubera® be used to effectively manage Types 1 and 2 diabetes? • Will the risk of hypoglycemia or other adverse events with inhaled insulin be different than the risk with comparators (given comparable HbA1c)? • What is the pulmonary risk associated with Exubera®?

  6. Efficacy

  7. Type 1 Diabetes Efficacy, Adults

  8. Efficacy in Type 1 Diabetes Two major completed studies: • Study 106 (“conventional” control) • Study 107 (“intensive” control) Emphasis on Study 107; intensive glycemic control is the standard for optimal management

  9. Study 107 Design • 6-month, open-label, parallel group, noninferiority • Premeal inhaled or subcutaneous regular insulin • All received NPH insulin pre-breakfast and pre-bed • Males and females, ages 12-65 years, HbA1c 6-11% at entry • 162 pts inhaled insulin, 165 “SQ only” (103 adults each group)

  10. Mean (SD) Percent Change in HbA1c from Baseline, Study 107 Adults

  11. Study 107 Secondary Efficacy Endpoints: Treatment to Goal • 28% of inhaled insulinadult patients and 30% of SQ adult patients had HbA1c <7% at 24 weeks • In both groups, those who had baseline HbA1c <7% were more likely to have 24-week HbA1c <7%

  12. Study 107 Secondary Efficacy Endpoints: Fasting Plasma Glucose (mg/dL)

  13. Study 107 Secondary Efficacy Endpoints: 2-hr Postprandial Glucose Excursion (mg/dL)

  14. Will Type 1 Diabetics Achieve “Tight” Control with Exubera®? Inhaled insulin was noninferior to SQ for change from baseline in HbA1c, but: • Neither treatment group achieved “DCCT-level” mean HbA1c • Only 28% of adults in the inhaled insulin group achieved HbA1c <7% • Postprandial glucose excursion increased from baseline to 24 weeks with inhaled insulin

  15. DCCT HbA1c Control

  16. Current Recommendations for HbA1c in Type 1 Diabetes • American Diabetes Association: <7% • American Association of Clinical Endocrinologists: 6.5% • Mean HbA1c achieved in Study 107 inhaled insulin group adults: 7.5%

  17. Current Recommendations for Postprandial Glucose • American Diabetes Association: maximum PPG <180 mg/dL • American Association of Clinical Endocrinologists: 2 hr PPG <140 mg/dL • Study 107 inhaled insulin mean 2-hr PPGs: 287 mg/dL at 24 weeks (standard meal) 182 mg/dL at 24 weeks (home monitoring)

  18. Questions About Study 107 and its Implications • Does Study 107 show that patients are likely to be able to achieve “DCCT-level” tight control with inhaled insulin? • Is it even reasonable to expect “DCCT-level” control from Study 107? • If we can’t expect “DCCT-level” control for the average Type 1 diabetic, is it acceptable that at least some patients may achieve tight control?

  19. Pediatric Efficacy

  20. Pediatric Efficacy • Applicant not seeking pediatric indication at this time • FDA anticipates significant interest in information regarding potential use in pediatric patients • Studies 106 and 107 included total of 180 adolescents ages 12-17 years (92 inhaled insulin group) • Study 1009 included 119 children ages 6-11 years (60 inhaled insulin group)

  21. Pediatric Efficacy Results • In all three studies, pediatric patients began with mean HbA1cs>8%, with littlechange in either group over study • In Study 1009, slightly more children achieved HbA1cs <8% and <7% with inhaled insulin than with SQ • 18% of Study 1009 children in inhaled insulin group achieved HbA1c <7% • Little difference between groups in FPG and PPG in Study 1009

  22. Safety EvaluationDiabetes Types 1 and 2

  23. Nonpulmonary Safety: Deaths • Little difference in incidence between inhaled insulin and comparator groups • Incidence of death similar to that seen in large diabetes trials • Most deaths from cardiovascular causes • No difference in causes of death between inhaled insulin and comparator groups • No pediatric trial participants died

  24. Hypoglycemia: Adverse Event or Outcome Variable

  25. Hypoglycemia Analyses: Definitions of Hypoglycemic Events Four ways to compare rates of hypoglycemic events: • Prospective protocol-defined total hypoglycemic episodes • Prospective protocol-defined severe hypoglycemia • Retrospective definition after FDA request • Investigators could report episodes as adverse events

  26. Prospective Protocol-defined Hypoglycemic Events: Total Events Any ONE of the following: • “Characteristic symptoms of hypoglycemia” with blood glucose < 59 mg/dL, OR • “Characteristic symptoms of hypoglycemia” with no blood glucose check (clinical picture must have included prompt resolution with food intake, SQ glucagon, or IV glucose), OR • Any glucose measurement < 49 mg/dL, with or without symptoms

  27. Prospective Protocol-defined Severe Hypoglycemic Events Must meet ALL 3 of the following criteria: • Subject unable to self-treat; • Subject exhibited at least one neurologicsymptom (memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, seizure, suspected seizure, loss of consciousness) • Measured blood glucose < 49 mg/dL, or if BG not measured, clinical manifestationsreversed by oral carbohydrates, SQ glucagon, or IV glucose

  28. Retrospective Hypoglycemic Event Definition • Hypoglycemic event requiring assistance of another person, or • Measured blood glucose < 36 mg/dL

  29. Hypoglycemia as an Adverse Event Serious adverse events of hypoglycemia included any event that: • resulted in death; or • was life-threatening; or • required inpatient hospitalization or prolongation of existing hospitalization; or • resulted in persistent or significant disability/incapacity; or • resulted in congenital anomaly or birth defect

  30. Nonpulmonary Safety: Serious Adverse Events, Adults • Comparable frequency of total SAEs between inhaled insulin and comparator patients • Serious hypoglycemia most common SAE • Inhaled insulin patients not more likely to have accident or injury with hypoglycemia • Little difference between treatment groups for incidence of other SAEs

  31. Nonpulmonary Pediatric Serious Adverse Events • Serious hypoglycemic adverse events slightly more frequent for inhaled insulin patients than for SQ patients • More frequent serious hypoglycemic adverse events for pediatric patients than for adult Type 1 patients • Rates of DKA and other SAEs did not differ between treatment groups

  32. Nonpulmonary Safety: Common Adverse Events • Hypoglycemia most common adverse event: inhaled insulin rate = SQ rate > OA rate • Nasopharyngeal AEs (rhinitis, sinusitis, pharyngitis) more frequent with inhaled insulin for Type 1 diabetics • Slightly higher frequency of “allergic reaction” in inhaled insulin group for Type 1 diabetics (4.4% vs 3.3%) • Little difference between groups for accidents or malignancies • For pediatric patients, ear AEs (otitis media, ear pain, ear disorder) morefrequent with inhaled insulin

  33. Insulin Antibodies

  34. Insulin Antibodies • Greater increases in serum insulin binding activity for patients taking inhaled insulin than for patients taking comparators • Led to concerns regarding possible clinical consequences of insulin antibody formation with inhaled insulin

  35. Questions Regarding Insulin Antibodies • What were the rates of seroconversion (undetectable to detectable)? • How did change from baseline compare between treatment groups? • What types of patients were more likely to have increases in insulin antibodies with inhaled insulin? • What was the qualitative nature of the antibodies?

  36. Questions Regarding Insulin Antibodies (cont) • Did patients who increased their insulin antibodies have more adverse events of any kind? • Was there evidence that these antibodies could neutralize the action of insulin? • What happened with regard to insulin antibodies after discontinuation of inhaled insulin?

  37. Insulin Antibody Seroconversion Type 1 Diabetics: • 88% of inhaled insulin patients • 23% of SQ patients Type 2 Diabetics: • 71% of inhaled insulin patients • 6% of comparator patients

  38. Insulin Binding ActivityMeanChange from Baseline

  39. Demography of Insulin Antibody Changes: Age Pediatric Type 1 Patients (compared to Type 1 Adults): • seroconverted more frequently • had higher mean end-of-study insulin binding activity • had greater changes from baseline in mean insulin binding activity Type 2 Patients: No clear age differences

  40. Demography of Insulin Antibody Changes: Gender • Type 1 diabetics: female patients had greater change from baseline in antibodies than did males • Type 2 diabetics: no clear gender difference

  41. Qualitative Nature of Insulin Antibodies • Predominantly IgG (same as seen with SQ) • Binding capacity profile = mostly low affinity, high binding capacity (same as usually seen with SQ)

  42. Adverse Events Associated with Insulin Antibodies? • In Ph 2/3 controlled studies, slightly higher incidence of “allergic reaction” among Type 1 inhaled insulin patients (4.4% vs 3.3%). Did not correlate with degree of insulin binding activity or occur more frequently among patients with very high binding activity • No correlation between degree of insulin binding activity and frequency or severity of hypoglycemic events

  43. Evidence of Neutralization of Insulin Action? • Applicant made extensive attempts to develop neutralizing antibody assay • No association between degree of insulin binding activity and HbA1c, PPG, FPG, overall insulin requirement, or change in insulin requirement

  44. Insulin Antibodies after Discontinuation of Inhaled Insulin • Began to decline within 2 weeks • Declined by about 70% by 12 weeks (end of follow-up phase) • Return to baseline not documented

  45. Summary of Insulin Antibody Observations • Inhaled insulin group patients more likely to seroconvert • Inhaled insulin patients had greater degree of insulin binding activity • For Type 1 inhaled insulin group patients, females and children had greater binding • No apparent clinical correlate over the period of observation

  46. Summary- Efficacy • Questions remain about whether Type 1 diabetics can expect to achieve “tight” control with Exubera® • Pediatric efficacy not clear and may warrant further study; pediatric indication not sought

  47. Summary- Nonpulmonary Safety • No clear differences between treatment groups for deaths and serious adverse events • Hypoglycemia most common adverse event; in general, did not appear to occur more frequently with inhaled insulin than with subcutaneous insulin

  48. Summary- Nonpulmonary Safety (cont) • Nonserious nasopharyngeal adverse events in Type 1 patients: inhaled insulin > SQ • Nonserious adverse events related to the ear in pediatric patients: inhaled insulin > SQ • Inhaled insulin associated with greater insulin antibody response than comparators, but no apparent clinical correlate over the period of observation

  49. Acknowledgments • Hae Young Ahn, PhD, Team Leader, Office of Clinical Pharmacology and Biopharmaceutics (OCPB), Division of Metabolic and Endocrine Drug Products (DMEDP) • Sayed Al Habet, RPh, PhD, Senior Clinical Pharmacologist/Reviewer, OCPB • Fred Alavi, PhD, Toxicology Reviewer, DMEDP • Sandra Birdsong, RN, BSN, Chief, Project Management Staff, Division of Drug Risk Evaluation (DDRE), Risk Management Plan (RMP) Team • Allen Brinker, MD, Epidemiologist Team Leader, DDRE, RMP Team • Janice Brown, PhD, Chemistry Reviewer, Office of New Drug Chemistry (ONDC), DMEDP

  50. Acknowledgments (cont) • Joan Buenconsejo, PhD, Mathematical Statistician, Division of Biometrics II • Mary Dempsey, Project Management Officer, RMP Team, Office of Drug Safety Immediate Office (ODS-IO) • Eric Duffy, PhD, Supervisory Chemist, Division of New Drug Chemistry II (DNDC2) • Jeri El Hage, PhD, Toxicology Team Leader, DMEDP • Oluchi Elekwachi, PharmD, MPH, LCDR, USPHS, Project Manager, DMEDP • Blair Fraser, PhD, Deputy Director, DNDC2

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