Benefit and Managing the Risk

1. Benefit and Managing the Risk Dr. Neville Jackson

2. Benefit • As efficacious as short-acting SC regular insulin in patients with type 1 diabetes or insulin requiring type 2 diabetes • Effective in type 2 DM used alone, in combination with basal insulin, and in combination with oral agent • Provides long-term glycemic control in both type 1 and type 2 diabetes • Most patients preferred INH over previous SC insulin and OA treatments

3. Risks • Hypoglycemia event rates as for other insulins • Increased insulin antibodies compared to injected insulins • No association with clinical outcomes • Pulmonary effects • Cough – mostly post-inhalational • PFT declines – small, early, non-progressive, reversible • Risk management plan to explore mechanism and follow the longer-term effect

4. Risk Minimization and Proposed Studies

5. Education and Customer Care • Labeling • Call center • Healthcare professional training • Patient training support • Instruction video • Instruction manual • Quick reference guide • Device replacement • Enhanced pharmacovigilance to increase the follow up on the reporting of rare respiratory adverse events

6. Use of 1 mg and 3 mg Blisters in the Clinical Program • 1 mg and 3 mg blisters were used safely and effectively in the clinical program • All patients were dispensed 1 mg and 3 mg blisters at treatment initiation • Patients were instructed to self-titrate by 1 mg increments, dependent upon home glucose monitoring • Instructions were given to use as few blisters as possible at each dosing session

7. Pre-Breakfast Pre-Lunch Pre-Supper Use of Doses in Phase 3 Efficacy Studies Percent of Patients Dose (mg insulin, nominal)

8. Proposed Dosing Information for the Label

9. Assuring Safe Use of 1 & 3 mg Blisters • Education of patients to self-titrate by 1 mg increments • Clear tactile and visual differentiation of the blisters • Education of physicians to closely monitor patients on initiation of INH therapy • Manage the risk of substitution of 1 x 3 mg with 3 x 1 mg blisters by clear labeling, including secondary packaging, and education • Where unavoidable substitution is necessary, specific instructions to use 2 x 1 mg in place of 1 x 3 mg

10. Risk Management - Protocols

11. Multinational, Long-term Large Simple Trial to Evaluate Pulmonary Safety • Objectives • Persistent decline in FEV1 of 20% or more • Serious respiratory adverse events • Enroll 5,000 patients - North America, Europe, LA • Broad entry criteria as per approved label • Recruitment from primary care practices with diverse patient population • Targeted recruitment of 5-10% very elderly (75 years) • Randomization to Exubera or usual care for 5 years • Spirometry measurements (FEV1) at baseline and then prospectively, consistent with approved label • Follow up per usual medical care with concomitant medications permitted • All randomized patients followed for collection of SAEs even if they discontinue treatment