1. Pramlintide Acetate Safety Review Dragos Roman MD Center for Drug Evaluation and Research

2. Pramlintide Acetate Safety Review Outline Phase 3 Trials –Motor vehicle accident (MVA)-related events Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes) –Other accident/injury-related events Assisted hypoglycemia

3. Pramlintide Acetate Safety Review Outline Phase 3 Trials –Motor vehicle accident (MVA)-related events Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes) –Other accident/injury-related events Assisted hypoglycemia

4. Phase 3 Clinical Trials Long-term controlled studies in patients with type 1 diabetes: –137-121 1 year –137-112 1 year –137-117 6 months Long-term controlled studies in patients with type 2 diabetes: –137-122 1 year –137-123 6 months –137-111 1 year

5. Phase 3 Clinical Trials (Type 1 Diabetes)

6. First Month Nausea-Related Withdrawals -Type 1 Diabetes % withdrawals

7. Phase 3 Clinical Trials (Type 2 Diabetes)

8. First Month Nausea-Related Withdrawals -Type 2 Diabetes % withdrawals

9. Pramlintide Acetate-Safety Review Outline Phase 3 Trials –Motor vehicle accident (MVA)-related events Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes) –Other accident/injury-related events Assisted hypoglycemia

10. Assisted Hypoglycemia: Definition Hypoglycemic event that requires: –oral carbohydrates –glucagon –IV glucose

11. Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: First Month Incidence % patients

12. Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: End of the First Month to The End of the Trial Incidence % patients

13. Change in HbA1c: Study 137-121 Type 1 Diabetes

14. Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: Summary Pramlintide therapy is associated with a two fold increase in incidence of assisted hypoglycemia when compared to placebo, during the first month of treatment.

15. Assisted Hypoglycemia-Type 1 Diabetes Phase 3 Trials: Summary The difference in incidence of assisted hypoglycemia between pramlintide and placebo groups persists following the first month of treatment albeit to a lower extent. This decrease in hypoglycemic events associated with pramlintide takes place in the context of prior nausea-related patient withdrawals and waning drug efficacy.

16. Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: First Month Incidence % patients

17. Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: End of the First Month to The End of the Trial Incidence % patients

18. Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: Summary Pramlintide therapy is associated with a three fold increase in incidence of assisted hypoglycemia when compared to placebo, during the first month of treatment.

19. Assisted Hypoglycemia-Type 2 Diabetes Phase 3 Trials: Summary The difference in incidence of assisted hypoglycemia between pramlintide and placebo groups wanes following the first month of treatment. This decrease takes place in the context of prior nausea-related patient withdrawals although to a lower extent than in type 1 diabetes.

20. Assisted Hypoglycemia : Summary The incidence of assisted hypoglycemia was higher during the type 1 and type 2 diabetes trials when compared to controls during both time intervals analyzed. Hypoglycemia associated with pramlintide was, however, more common in type 1 diabetes patients.

21. Pramlintide Acetate Safety Review Outline Phase 3 Trials –Motor vehicle accident (MVA)-related events Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes) –Other accident/injury-related events Assisted hypoglycemia

22. Serious Adverse Events-Definition Death Life-threatening Hospitalization Disability

23. Deaths Possibly Related to Hypoglycemia A 48-year-old male with a 12-year history of type 1 diabetes mellitus with a prior history of “diabetes- related seizures“ died during a nocturnal hypoglycemic seizure (pramlintide 30µg QID). 35-year-old male with a 6-year history of type 1 diabetes mellitus died in a motor vehicle accident within 24 hours from the beginning of the trial. “Food was present in the stomach at the post-mortem examination, indicating that the subject had eaten lunch prior to the event.” (pramlintide 90 µg TID).

24. Pramlintide Acetate Safety Review Outline Phase 3 Trials –Motor vehicle accident (MVA)-related events Serious adverse events (SAEs) associated with hypoglycemia (type 1 diabetes) –Other accident/injury-related events Assisted hypoglycemia

25. Hypoglycemia and Accidents-Type 1 Diabetes Motor vehicle accident (MVA)-related events. Automobile-related adverse events with no motor vehicle accident reported. Other accident/injury-related events (e.g. falls, fractures, lacerations).

26. MVAs and Automobile-Related Adverse Events-Type 1 Diabetes (All Clinical Development Program)

27. Driving-Related Events Associated With Hypoglycemia -Phase 3 Trials (Type 1 Diabetes)

28. Driving-Related Events Associated With Hypoglycemia - Type 1 Diabetes: Conclusion Pramlintide use in addition to insulin is associated with a four fold increase in driving-related events in type 1 diabetes patients.

29. Other Accidents and Injuries-Type 1 Diabetes (All Clinical Development Program)

30. Other Accidents and Injuries-Phase 3 Trials (Type 1 Diabetes)

31. Other Accidents and Injuries- Type 1 Diabetes: Conclusion Pramlintide use in addition to insulin is associated with a four fold increase in non- MVA injuries in type 1 diabetes patients.

32. Severe Hypoglycemia: Labeling Question Do we know how to initiate safely pramlintide treatment and avoid the risk of first month hypoglycemia in both patients with type 1 and type 2 diabetes ?

33. Severe Hypoglycemia: Labeling Question Sponsor’s suggestions: “Initiate treatment with 30 µg or 60 µg of pramlintide per dose in type 1 diabetics and 120 µg per dose in type 2 diabetics”. FDA comments: All above doses have been shown to be associated with a two fold increased risk of assisted hypoglycemia during the phase 3 trials.

34. Severe Hypoglycemia: Labeling Question Sponsor’s suggestions: “In clinical practice it would be prudent to reduce the patient’s insulin dose, particularly the short-acting insulin administered preprandially by 10-20% at the time of initiation of pramlintide therapy.” FDA comments: While such an approach seems prudent it has not been tested in a clinical trial and its potential usefulness remains unknown.

35. Accidents Associated With Hypoglycemia-Labeling Question How can one prevent the four fold risk of driving-related events and the four fold risk of non-MVA injuries associated with hypoglycemia observed in the type 1 diabetes trials?

36. = pramlintide = placebo

37. Summary Pramlintide therapy results in a small but statistically significant reduction in HbA1c. This reduction is associated with a two fold increase of severe hypoglycemia during the first month of treatment. In addition, a four fold increase in hypoglycemia- associated MVAs and non-MVA trauma, was observed in patients with type 1 diabetes.