1. 1 Progress Towards an Artificial Pancreas for T1D WILLIAM TAMBORLANE, MD Chief of Pediatric Endocrinology, Yale University, Deputy Director, Yale Center for Clinical Investigation

2. Progress Towards Development of an Artificial Pancreas for Type 1 Diabetes William V. Tamborlane, MD Professor of Pediatrics Yale University School of Medicine

3. Georgetown University Class of ’68 

4. “There are Careers Other Than Medicine”

5. Objectives Review how far we have come in treating T1D How far we still need to go in treating T1D how much progress has been made in a mechanical solution to more effective treatment of T1D

6. “Bad Old Days” of Diabetes (Before 1980) Aggressive therapy unsafe and of unknown benefits HbA1c 11-12% Eye & kidney complications

7. Era of Intensive Treatment (1980’s)

8. First Successful Study of Pumps in T1DM Reduction to normal of plasma glucose in juvenile diabetes by subcutaneous administration of insulin with a portable infusion pump WV Tamborlane, RS Sherwin, M Genel, and P Felig NEJM 1979; 300:573-8

9. Diabetes Control and Complications Trial Lowering HbA1c levels to 7.0% with intensive vs 9.0% with conventional treatment decreased the risk of development and progression of early: Retinopathy by 50-75% Nephropathy by 35-55% Neuropathy by 60%

10. DCCT Recommendation Most children and adults with T1D should be treated with intensive therapy to prevent or markedly delay the development of diabetic complications

11. Treatment Advances Past 20 years Insulin Analogs Smart Insulin Pumps Improved Blood Glucose Meters Continuous Glucose Monitoring Systems New T2D Drugs for T1D

12. Why do we need an artificial pancreas? Too many T1D patients fail to achieve target A1c goals Rates of severe hypoglycemia and DKA remain too high Too few pediatric patients take full advantage of advances in diabetes technologies

13. T1D Exchange Clinic Network & Clinic Registry >70 Adult and Pediatric Clinics – >150,000 patients with T1D > 26,000 T1D Patients (age 2-95 yrs) Enrolled

14. Most Recent HbA1c Levels by Age in T1DX Registry

15. Percent of Patients Meeting HbA1c Targets A1c Goal = <7.0% A1c Goal = <7.5%

16. Frequency of Severe Hypoglycemia by Age * Seizure or LOC: 1 or more events in 12m

17. Frequency of Diabetic Ketoacidosis byAge 1 or more events in 12 months

18. Insulin Delivery Method

19. Continuous Glucose Monitoring Use

20. Why not pancreas transplants? Limited to small segments of population due to limitations in supply Problems with rejection have not been overcome They are not well suited for children with T1DM due to excessive morbidities related to immuno-suppression.

21. Essential elements of CL Systems Already Available Continuous glucose sensor Control Algorithm Insulin pump

22. Proof of Concept: 2006 UCLA Medtronic Study Steil GM, et al. Diabetes. 2006;55:3344-3350.

23. Lessons Learned Exaggerated post-meal excursions and a tendency to late post-prandial hypoglycemia due to lags in: Carbohydrate absorption Increases in interstitial glucose concentrations Insulin absorption from subcutaneous site Excellent overnight control but lingering concerns re sensor accuracy

24. Possible Solutions Exaggerated post-meal excursions: Hybrid, semi-automatic control with “priming” conventional pre-meal bolus to cover some of carbohydrate in meal Sensor error: Set slightly higher than normal target glucose value (e.g. 120 rather than 90 mg/dL) to avoid nocturnal hypoglycemia

25. First Pediatric Study: 2008 Yale Hybrid vs Full CL Study 6ANoon6PMidN6ANoon6P 0 100 200 300 Closed Loop (N=8) meals setpoint Hybrid CL (N=9) Glucose (mg/dl) MeanDaytimePeak PP Full CL 147  58154  60219  54 Hybrid 138  49143  50196  52 Weinzimer SA. Diabetes Care 2008; 31:934-939.

26. Conclusions Short-term closed-loop control is feasible in children with T1D Night-time control is outstanding Meal-related excursions are as good or better than traditional open-loop therapy and improved with manual priming bolus

27. Learnings from Inpatient CRC Studies Last 6 Years Testing of improved controller algorithms Testing under simulated outpatient conditions –Exercise –Varied meal plans Testing of dual hormone systems –Insulin + Glucagon to prevent hypoglycemia –Insulin + Pramlintide or GLP1 Agonists to reduce post-meal hyperglycemia

28. Learnings from Inpatient CRC Studies Last 6 Years Testing of improved controller algorithms Testing under simulated outpatient conditions –Exercise Testing of dual hormone systems –Insulin + Glucagon to prevent hypoglycemia –Insulin + Pramlintide to reduce post-meal hyperglycemia Testing ways to accelerate insulin absorption and action –Ultra-fast acting insulin preparations –Infusion site warming –Hyaluronidase

29. Hardware and Software Improvements: Still A Work in Progress More reliable and accurate sensors Dual sensors Integrity of RF transmissions Preventing computer malfunctions Limiting maximal delivery rates Minimizing the risk of user error Better and easier systems for patients to operate

30. Major Obstacle to Outpatient Use: Patient Safety Outpatient systems must have as many safety features as possible in place to ensure that excessive insulin administration due to a system malfunction is extremely unlikely.

31. Essential CL Functions Turn off insulin if glucose  Safe Turn on insulin if glucose  Dangerous

32. First Step to Outpatient CL Control: Veo (AKA 530G) Threshold Suspend System System automatically suspends basal insulin for 2 hrs if: the hypoglycemia alarm level has been reached the patient has not responded to the alarm

33. Perth Low Glucose Suspend Study (2012) 126 episodes of LGS before 3am with no patient response insulin suspended insulin resumed No adverse outcomes after suspension

34. Rationale: Prolonged Nocturnal Hypoglycemia Prior to Seizures Buckingham B, et al., Diabetes Care, 2008, 31:2110

35. Next Step: Automatic Shut Off for Projected Hypoglycemia Shuts off the pump for a predicted low based on the rate of fall of glucose System alarms only for actual low glucose event Hypoglycemia averted in 13 of 16 cases

36. Outpatient Full CL Studies Overnight only Diabetes Summer Camp Studies “Bionic Pancreas” (Insulin + Glucagon) Studies Hybrid CL Studies with Hourly Limits on Rate of Insulin Delivery

37. Overnight CL – Camp Phillip, N Engl J Med 2013

38. Dual Hormone Delivery in 20 Adults and 32 Adolescents Russell SJ et al. N Engl J Med 2014;371:313-325

39. Medtronic Hybrid CL with Restricted Insulin Infusion Rates

40. Hotel Android CL Study: Getting Yale Subject 201 Started

41. Hotel Android CL Study: Yale Subject #201 (Day – 02)

42. Hotel Android CL Study: Yale Subject #203 (Day 04)