# Presentation: 505960

## Endocrine and Metabolic Drugs Advisory Committee Meeting - Human Recombinant Inhaled Insulin (Exubera)

- Pulmonary Safety Review
- Sally Seymour, M.D.
- Medical Officer
- Division of Pulmonary and Allergy Drug Products
- September 8, 2005

## Why is pulmonary safety a concern?

- Administered via inhalation
- Novel drug substance and excipients for inhalation
- Chronic administration
- Insulin is a polypeptide associated with immune response
- Insulin has growth promoting properties

- EMDAC Meeting

- September 8, 2005

## Agenda

- Pulmonary Safety Database
- Respiratory Adverse Events
- Pulmonary Function Tests
- FEV1 and DLCO
- Imaging
- CXR
- High resolution computed tomography (HRCT)
- Underlying Lung Diseases
- Asthma and COPD
- Conclusions

- EMDAC Meeting

- September 8, 2005

## Agenda

- Pulmonary Safety Database
- Respiratory Adverse Events
- Pulmonary Function Tests
- FEV1 and DLCO
- Imaging
- CXR and HRCT
- Underlying Lung Diseases
- Asthma and COPD
- Conclusions

- EMDAC Meeting

- September 8, 2005

## Pulmonary Safety Database - Controlled Studies in Type 1 DM

- INH – Inhaled insulin; COMP – Comparator; AE - Adverse Event; PFT – Pulmonary Function Test; HRCT – High Resolution Computed Tomography; CXR – Chest X-ray

- EMDAC Meeting

- September 8, 2005

## Pulmonary Safety Database - Controlled Studies in Type 2 DM

- INH – Inhaled insulin; COMP – Comparator; AE - Adverse Event; PFT – Pulmonary Function Test; HRCT – High Resolution Computed Tomography; CXR – Chest X-ray

- EMDAC Meeting

- September 8, 2005

## Agenda

- Pulmonary Safety Database
- Respiratory Adverse Events
- Pulmonary Function Tests
- FEV1 and DLCO
- Imaging
- CXR and HRCT
- Underlying Lung Diseases
- Asthma and COPD
- Conclusions

- EMDAC Meeting

- September 8, 2005

## Respiratory Serious Adverse Events (SAEs)

- EMDAC Meeting

- September 8, 2005

## Respiratory Adverse Events in Type 1 DM

- EMDAC Meeting

- September 8, 2005

## Respiratory Adverse Events - Discontinuation

- EMDAC Meeting

- September 8, 2005

## Cough

- Majority mild in severity
- Duration longer in inhaled insulin group
- Cough questionnaire
- Mild in severity, non-productive
- Frequently noted within seconds to minutes of inhaled insulin administration

- EMDAC Meeting

- September 8, 2005

## Respiratory Adverse Events

- Lung neoplasm – 5 cases
- 4 malignant
- 3 in controlled studies
- 2 inhaled insulin, 1 comparator
- 1 in extension study in inhaled insulin group
- Pulmonary fibrosis
- Pleural Effusion
- Sarcoidosis

- EMDAC Meeting

- September 8, 2005

## Agenda

- Pulmonary Safety Database
- Respiratory Adverse Events
- Pulmonary Function Tests
- FEV1 and DLCO
- Imaging
- CXR and HRCT
- Underlying Lung Diseases
- Asthma and COPD
- Conclusions

- EMDAC Meeting

- September 8, 2005

## Approach to Pulmonary Function Test (PFT) Analyses

- Individual studies
- Pooled controlled phase 2 and 3 studies by diabetes type
- Reversal of effect
- Long term exposure
- Uncontrolled extension Studies 111 and 1036

- EMDAC Meeting

- September 8, 2005

## Change from Baseline FEV1 in Type 1 Pooled Phase 2 and 3 Studies (Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Reversal of Effect on FEV1 in Type 1 

- Study 1027
- 12 wks on treatment then 12 wks off inhaled insulin
- Limitations
- Only 12 weeks exposure to inhaled insulin
- No treatment group difference at 12 weeks
- Study 111
- Uncontrolled extension study amended to include randomized withdrawal of inhaled insulin
- Limitations
- Self-selected population
- Varying lengths of exposure to inhaled insulin
- Available data not conclusive

- EMDAC Meeting

- September 8, 2005

## Change from Baseline FEV1 in Type 1in Study 1027  (Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Reversal of Effect of FEV1 in Type 2

- Study 1001-1002
- 24 wk treatment extended to 104 wks
- 104 wks on treatment, 12 wks off inhaled insulin
- Provides data following long term (2 yrs) exposure
- Data suggests some reversal of effect of inhaled insulin on FEV1

- EMDAC Meeting

- September 8, 2005

## Change from Baseline FEV1 in Type 2in Study 1001-1002  (Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Summary – Inhaled Insulin and FEV1

- Inhaled insulin associated with greater decline in FEV1 than comparator
- Effect noted within first few wks
- Treatment group difference  of ~40mL does not appear to progress out to 2 yrs
- Results comparable in type 1 and type 2
- Reversal of effect
- Data not conclusive in type 1
- Data from Study 1001-1002 suggest some reversal of effect after 2 years exposure in type 2

- EMDAC Meeting

- September 8, 2005

## Change from Baseline DLCO in Type 1 Pooled Phase 2 and 3 Studies (Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Change from Baseline DLCO in Type 2 Pooled Phase 2 and 3 Studies (Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Change from Baseline DLCO in Type 1in Study 1027 (Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Change from Baseline DLCO in Type 2in Study 1001-1002 (Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Summary – Inhaled Insulin and DLCO Type 1

- Inhaled insulin associated with greater decline in DLCO than comparator
- Effect noted within first few wks
- Treatment group difference  of ~0.5 to 0.6 mL/min/mmHg did not progress out to 2 yrs
- Reversal
- Data from Study 1027 suggest reversal of effect of inhaled insulin on DLCO after short term    (12 wk) exposure

- EMDAC Meeting

- September 8, 2005

## Summary – Inhaled Insulin and DLCOType 2

- Both treatment groups demonstrated similar decline in DLCO at 2 yrs
- Maximum treatment group difference was ~0.5mL/min/mmHg during treatment

- EMDAC Meeting

- September 8, 2005

## Agenda

- Pulmonary Safety Database
- Respiratory Adverse Events
- Pulmonary Function Tests
- FEV1 and DLCO
- Imaging
- CXR and HRCT
- Underlying Lung Diseases
- Asthma and COPD
- Conclusions

- EMDAC Meeting

- September 8, 2005

## Imaging

- Chest X-ray
- More significant CXR changes noted in the inhaled insulin group
- Notable changes included nodular density, opacity, nodule, atelectasis, and cardiomegaly
- High Resolution Computed Tomography (HRCT)
- Two year HRCT data does not suggest an increase in abnormal findings associated with inhaled insulin use

- EMDAC Meeting

- September 8, 2005

## Agenda

- Pulmonary Safety Database
- Respiratory Adverse Events
- Pulmonary Function Tests
- FEV1 and DLCO
- Imaging
- CXR and HRCT
- Underlying Lung Diseases
- Asthma and COPD
- Conclusions

- EMDAC Meeting

- September 8, 2005

## Pulmonary Safety Database – Controlled Studies in Asthma & COPD

- INH – Inhaled insulin; COMP – Comparator; AE - Adverse Event; PFT – Pulmonary Function Test; HRCT – High Resolution Computed Tomography; CXR – Chest X-ray

- EMDAC Meeting

- September 8, 2005

## Study 1028 - Asthma

- 139 subjects treated (goal 250)
- Respiratory AEs
- Cough -14% INH, 3% comp
- Respiratory tract infection - 43% INH, 33% comp
- 3 discontinuations due to respiratory AEs
- All in inhaled insulin group
- Asthma AEs more common in comp group
- Non-severe asthma exacerbation and severe asthma exacerbation more common in inhaled insulin group
- Asthma Control Questionnaire

- EMDAC Meeting

- September 8, 2005

## Change from Baseline FEV1 in Study 1028 – Asthma(Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Change from Baseline DLCO in Study 1028 – Asthma(Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Study 1030 - COPD

- Respiratory AEs
- Cough – 8.6% INH, 3.1% comp
- Dyspnea – 11.4% INH, 6.3% comp
- One discontinuation due to respiratory AE
- COPD exacerbation in inhaled insulin group
- Non-severe COPD exacerbation (protocol defined)
- 10 subjects with 14 events (INH)
- 4 subjects with 9 events (comp)
- Severe COPD exacerbation (protocol defined)
- One event in INH, none in comparator

- EMDAC Meeting

- September 8, 2005

## Change from Baseline FEV1 in Study 1030 - COPD(Mean +/- SD)

- Change from Baseline FEV1 in Study 1030 - COPD(Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Change from Baseline DLCO in Study 1030- COPD (Mean +/- SD)

- Change from Baseline DLCO in Study 1030- COPD (Mean +/- SD)

- EMDAC Meeting

- September 8, 2005

## Summary - Underlying Lung Disease

- Limited data at 52 weeks
- Asthma (Study 1028)
- Separation of treatment groups for FEV1 and DLCO after week 39, favoring comparator
- COPD (Study 1030)
- FEV1 – 30mL greater decline in FEV1 in inhaled insulin group at 52 weeks
- DLCO – inhaled insulin with increase in DLCO at 52 weeks

- EMDAC Meeting

- September 8, 2005

## Agenda

- Pulmonary Safety Database
- Respiratory Adverse Events
- Pulmonary Function Tests
- FEV1 and DLCO
- Imaging
- CXR and HRCT
- Underlying Lung Diseases
- Asthma and COPD
- Conclusions

- EMDAC Meeting

- September 8, 2005

## Conclusions – Inhaled Insulin

- Increase in respiratory adverse events
- Cough
- Decline in pulmonary function
- Effect occurs within first few weeks
- Not progressive out to 2 years
- Some evidence for reversal of effect after discontinuation of inhaled insulin, but not conclusive in type 1 DM
- No increase HRCT findings at 2 years
- Limited controlled data in asthma & COPD

- EMDAC Meeting

- September 8, 2005

## Questions to the Committee

- 5.  Are there sufficient data to assess the pulmonary safety profile of Exubera ® in patients without underlying lung disease?
- A.  If yes, do the data suggest an acceptable pulmonary safety profile in patients without underlying lung disease?
- B.  If no, what additional information is needed?

- EMDAC Meeting

- September 8, 2005

## Questions to the Committee

- 6.  Are there sufficient data to assess the pulmonary safety of Exubera®  in patients with underlying lung disease?
- A.  If yes, do the data suggest an acceptable pulmonary safety profile in patients with underlying lung disease?
- B.  If no, what additional information is needed?

- EMDAC Meeting

- September 8, 2005

## Division of Pulmonary and Allergy Drug Products

- Parklawn Building, Room 10B-45
- 5600 Fishers Lane,   HFD-570
- Rockville, MD   20857

- Phone:  301-827-1050
- Fax:      301-827-1271

- EMDAC Meeting

- September 8, 2005