# Presentation: 437926

## 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**
**Division of Metabolic and Endocrine Drug Products**

**Center for Drug Evaluation and Research**** **

## 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**

## 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**

## 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**

## 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****®****?**

## Efficacy

## Type 1 Diabetes Efficacy, Adults

## 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**

## 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)**

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

|  | Inh Ins
(n = 103) | SQ
(n = 103) |
| --- | --- | --- |
| Baseline HbA1c (%) | 7.8 (0.9) | 7.8 (1.0) |
| Change from BL to Wk 24 | -0.3 (0.8) | -0.2 (0.8) |
| LSM Diff
(95% CI) | -0.1
(-0.3, +0.1) |  |

## Study 107 Secondary Efficacy Endpoints:  Treatment to Goal

**28% of inhaled insulin**** ****adult 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%**

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

|  | Inh Ins
N = 101 | SQ
N = 97 |
| --- | --- | --- |
| Mean BL FPG (SD) | 178 (69) | 191 (68) |
| Mean Δ BL to Wk 24, LOCF (SD) | -21 (98) | +5 (89) |
| LSM Diff
(95% CI) | -35
(-59, -12) |  |

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

|  | Inh Ins
N = 81 | SQ
N = 80 |
| --- | --- | --- |
| Mean BL 2-hr PPG Incr (SD) | 101.6 (93.4) | 99.9 (93.3) |
| Mean Δ from BL to 24 Wks (SE) | +24.4 (9.8) | -9.1 (9.9) |
| LSM Diff
(95% CI) | +33.5
(+5.9, +61.0) |  |

## 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**

## DCCT HbA1c Control

## 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%**

## 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) **

## 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?**

## Pediatric Efficacy

## 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)**

## Pediatric Efficacy Results

**In all three studies, pediatric patients began with ****mean HbA1cs**** ****>8%,**** with ****little**** ****change**** 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**

## Safety EvaluationDiabetes Types 1 and 2

## 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**

## Hypoglycemia:  Adverse Event or Outcome Variable

## 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**

## 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**

## Prospective Protocol-defined Severe Hypoglycemic Events

**Must meet ALL 3 of the following criteria:**
**Subject ****unable to self-treat;**
**Subject exhibited at least one ****neurologic**** ****symptom**** (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 manifestations**** ****reversed by oral carbohydrates, SQ glucagon, or IV glucose**

## Retrospective Hypoglycemic Event Definition

**Hypoglycemic event requiring assistance of another person, or**
**Measured blood glucose **_**<**_** 36 mg/dL**

## 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**

## 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**

## 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**

## 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) more**** ****frequent with inhaled insulin**

## Insulin Antibodies

## 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**

## 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?**

## 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?**

## 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**

## Insulin Binding ActivityMean Change from Baseline 

## 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**

## 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   **

## 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)**

## 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**

## 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**

## 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**

## 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**

## 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 **

## 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**

## 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**

## 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 **

## 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**

## Acknowledgments (cont)

**Laura A. Governale, PharmD, MBA, Drug Utilization Specialist Team Leader, RMP Team; Division of Surveillance, Research and Communication Support**
**Lahn Green, PharmD, MPH, Team Leader Safety Evaluator, DDRE, RMP Team**
**Cathy Groupe, RN, BSN, Executive Secretary for the Endocrine and Metabolic Drugs Advisory Committee, Office of Executive Programs, Advisors and Consultants Staff (ACS)**
**Charles Hoppes, RPH, MPH, Safety Evaluator, Division of Medication Errors and Technical Support (DMETS)**
**David Hussong, PhD, Associate Director for New Drug Microbiology, Office of Pharmaceutical Science (OPS)**
**Edwin Jao, PhD, Review Chemist, DNDC2**

## Acknowledgments (cont)

**Kati Johnson, RPh, Chief, Project Management Staff, DMEDP**
**Claudia Karwoski, PharmD, Scientific Coordinator, ODS-IO, RMP Team**
**Lois La Grenade, MD, MPH, Epidemiologist, ODS, RMP Team**
**Richard Lostritto, PhD, Chemist, DNDC1**
**Alina R. Mahmud, RPh, Team Leader, DMETS, RMP Team**
**James L. McVey, Team Leader, Product Quality Microbiology Team, OPS **

## Acknowledgments (cont)

**Joy Mele, MS, Statistical Reviewer, Division of Biometrics II**
**Robert Meyer, MD, Director, Office of Drug Evaluation II**
**Stephen Moore, PhD, Chemistry Team Leader, DMEDP**
**David Orloff, MD, CPT, USPHS, Director, DMEDP**
**Prasad Peri, PhD; Chemistry, Manufacturing and Controls Reviewer, ONDC, Division of Pulmonary and Allergy Drug Products (DPADP)**
**Brian Rogers, PhD, Chemistry Reviewer, DNDC2, DPADP**

## Acknowledgments (cont)

**Todd Sahlroot, PhD, Team Leader, Biometrics, DMEDP**
**Alan Schroeder, PhD, CPT, USPHS, Review Chemist, Director Regulatory Scientist Officer, DPADP**
**Sally Seymour, MD, Pulmonary Clinical Reviewer, DPADP**
**Arthur Shaw, PhD, Chemistry Reviewer, DNDC2**
**Andrea Slavin, RN, Clinical Inspector, Division of Scientific Investigations**
**Dornette Spell-Lesane, MHA, NP-C, Supervisory Health Science Administrator, ACS**

## Acknowledgments (cont)

**Eugene J. Sullivan, MD, FCCP, Deputy Director, DPADP**
**Joslyn R. Swann, PharmD, MGA, Safety Evaluator, DDRE**