1. Sweet or Sour? The Future of Diabetes Treatment
Dana Staat, PharmD
Clinical Pharmacy Lead-Internal Medicine
Spectrum Health, Grand Rapids, Michigan
May 2015

2. Conflict of Interest
This speaker has no actual or potential conflicts of interest to disclose in relation to this presentation

3. Objectives
Discuss the mechanism of distribution of the new medications being developed and approved for the treatment of diabetes.
List the potential benefits of treating diabetes with the diabetes medications in development.
List the drawbacks to treating diabetes with the diabetes medications in development.

4. Diabetes (DM) Impact Almost 26 million Americans are affected by DM
Seven million Americans are unaware they have DM
79 million people may have pre-diabetes
Per the CDC, DM is the 7th leading cause of death in the US
Over 75,000 deaths in the US per year
Death rates have fallen by up to 40% since 1997
New DM diagnosis has more than tripled since 1980
National Diabetes Fact Sheet, US Centers for Disease Control and Prevention (CDC).

5. Economic Impact Cost of diabetes in 2012: $245 billion
Direct medical costs: $176 billion
Reduced productivity: $69 billion
Increase in 41% since 2007
Average medical expenses are 2.3x higher in patients with diabetes
Economic costs of diabetes in the US in 2012, American Diabetes Association (ADA), www. Diabetes.org

6. Famous People with Diabetes

7. Insulin Facts Discovered in 1921
One of the most studied molecules in history
First hormone to be cloned and produced via DNA technology
Made insulin supply unlimited
Full therapeutic potential is still not optimized

8. Diabetes: Medicines in Development
New medications in development for DM or related diseases: 180
128 for DM
52 for related diseases
Clinical trials: 200
140 recruiting patients
60 active trials
Medicines in Development-2014 report. Pharmaceutical Research and Manufacturers of America pdf. Accessed on 4/16/15.

9. Outline Short-acting Insulin Long-acting Insulin
Inhaled Insulin (Afrezza®)
Long-acting Insulin
PEGylated lispro insulin
Insulin glargine 300 Units/mL (Toujeo®)
Insulin degludec (Tresiba®)

10. Insulin Delivery Methods
Oral
Buccal
Nasal
Ocular
Transdermal
Rectal
Uterine
Vaginal
Most modalities failed due to lack of bioavailability from small surface areas.

11. Inhaled Insulin Novel drug delivery First investigated in 1924
Large surface tissue area
Alveolar deposition

12. Exubera® Marketed in 2006 Removed from the market in 2007
Disappointing profit margin
Dosed in mg vs units
Available in 2 strengths
Large device
Small decrease in FEV1
FDA-warning regarding lung cancer

13. Inhaled Insulin (Afrezza®)
Approved July 2014
Dry powder, human, regular insulin
Adsorbed onto technosphere microparticles (TI-technosphere insulin)
Carrier is fumaryl diketopiperazine (FDKP)
Inert excipient
Dissolves immediately when inhaled

14. Inhaled Insulin (Afrezza®)
Ultra rapid acting insulin
Peak-15 minutes
“Regular” insulin
Bioavailability varies depending on inhaler technique (21-30% of SubQ)
Cartridges of 4 units or 8 units
Afrezza(R) [package insert]. Danbury, CT: MannKind Corporation; 2014.

15. Dosing Insulin naïve On mealtime insulin
4 units Afrezza with each meal
On mealtime insulin
Use chart
Afrezzapro.com

16. Clinical Trials Affinity 1 Affinity 2 DM1 Basal insulin present
Compared to SubQ aspart
Verified efficacy of Dreamboat inhaler
Change in A1C met noninferiority, but favored aspart
More patients in aspart group achieved A1C <7%
Affinity 2
DM2
Oral agents present
Compared to placebo
No basal insulin
Change in A1C favored Afrezza
More patients in Afrezza group achieved A1C<7%
Bode BW. Diabetes 2014;63:A33-4
Rosenstock J. Diabetes 2014;63:A34.

17. Adverse Events Hypoglycemia Pulmonary
Similar or lower than SubQ insulin
Pulmonary
Contraindicated in chronic lung disease (bronchospasm)
COPD, Asthma
Decline in FEV1
Small
Within first 3 months, then persisting
Studies suggest decline is reversible upon discontinuation
Lung cancer
2 cases seen in studies
Both patients with history of heavy smoking

18. Black Box Warning/REMS
REMS Required due to bronchospasm risk
Labeling recommends baseline spirometry, after 6 months, then annually
Afrezza(R) [package insert]. Danbury, CT: MannKind Corporation; 2014.

19. Inhaled Insulin (Afrezza®)
“Dreamboat” inhaler
Step 1: Select Cartridge
Step 2: Load cartridge into inhaler
Step 3: Inhale

20. Steps for Use Open device and snap in cartridge
Afrezza(R) [package insert]. Danbury, CT: MannKind Corporation; 2014.

21. Steps for Use
Afrezza(R) [package insert]. Danbury, CT: MannKind Corporation; 2014.

22. Inhaled Insulin (Afrezza®)
Afrezza(R) [package insert]. Danbury, CT: MannKind Corporation; 2014.

23. Storage Store in refrigerator
Inhaler good for 15 days from date of first use – then discard and replace with new inhaler
Afrezza(R) [package insert]. Danbury, CT: MannKind Corporation; 2014.

24. Cost & Conclusions 4 unit (90): $271.27 4 and 8 unit (90): $302.80
Niche product for patients who want to decrease their number of injections
Most likely still will need to inject basal
Fascinating delivery

25. Future of Afrezza Change the mouthpiece by 2016
Choking hazard
Perform pediatric studies
Safety study
5 year
To assess lung malignancy risk and pulmonary function changes

26. New Basal Insulins Necessary?
ADA/AACE recommend basal initiation first when insulin is necessary
Long-acting analogs have decreased nocturnal hypoglycemia over NPH
New basals even better?
Fear of hypoglycemia delays insulin initiation
Likelihood of good glycemic control is currently low
Copying of endogenous insulin secretion still not optimal

27. PEGylated Lispro (LY2605541) Insulin lispro PEGylated at lysine B28
Slowed SubQ absorption rate
Reduced clearance
Decreased rate of protein breakdown
Increased half-life (24-48 hrs)
Duration-at least 36 hrs
4 times larger than lispro
Hydrodynamic diameter

28. PEGylated Lispro (LY2605541) Phase II trials published
Phase III trials
Imagine 1-7: Press release
Eli Lilly delayed submission to the FDA until 2016
Further studies on liver effects

29. PEGylated Lispro (LY )
Imagine-6 Phase III, 26 week, open-label study designed to compare PegLispro (n=428) with NPH insulin (n=213) in insulin naïve patients with type 2 diabetes
Imagine 7 is a Phase III, 36 week, randomized, cross-over study designed to compare PegLispro (n-182) administered once daily at a fixed time with PegLispro administered at a variable time of day in patients with type 1 diabetes

30. PEGylated Lispro (LY2605541) Imagine 1 and Imagine 3 Type 1 DM
Compared to glargine
Primary endpoint met: HbA1C noninferiority
Superiority demonstrated
Significantly more patients with HbA1C <7%
Peglispro group
Nocturnal hypoglycemia significantly less in PegLispro group
Daytime hypoglycemia increased
Severe hypoglycemia increased in Imagine 1

31. PEGylated Lispro (LY2605541) Imagine 1 and Imagine 3 Imagine 3
Weight loss seen
Increase in triglycerides (small but stat. sign.)
No difference in cardiac events
Increase in ALT (3x upper limit or normal)
No incidence of liver failure
Imagine 3
Increase LDL
Decrease in HDL (small but stat. sign.)
Increase in SBP/DBP

32. Phase II Data

33. PEGylated Lispro (LY2605541) Conclusions
Potential better blood glucose control
Potential weight loss vs. weight gain
Hypoglycemia risk
Potential lipid panel changes
Increase in triglycerides/LDL
Potential transaminase elevation
Liver dysfunction?
STAY TUNED!!

34. Insulin Glargine U300 (Toujeo®)
Concentrated 300 units/mL
Forms a compact, subcutaneous depot
Smaller surface area
More gradual and prolonged release
Marketed ONLY in Solostar pen
80 units per dose
450 units/pen

35. Kinetics/Dynamics

36. Insulin Glargine U300 (Toujeo®)

37. Edition 1-3 Pooled Data

38. Edition 3
Bolli GB. Diab Ob Metab 17: , 2015.

39. Edition 3
Bolli GB. Diab Ob Metab 17: , 2015.

40. Insulin Glargine U300 (Toujeo®)

41. Cost and Conclusions Toujeo® Solostar®: $134.19
$0.29/unit
Lantus® Solostar®: $89.46

42. Insulin Degludec Long-acting insulin Half-life ~25 hours
Usually dosed at dinner
Half-life ~25 hours
Duration exceeding 42 hours
Degludec (Tresiba®)
Possibly produced as U100 and U200
Can give up to 160 units/dose
Degludec/aspart (Ryzodeg®)
Novo

43. Insulin Degludec New Drug Application filed with FDA
September 2011
FDA requested further cardiovascular data
February 2013
“Potential cardiovascular signal of uncertain origin that appeared in analysis”
Degludec cardiovascular outcomes trial (Devote) to be completed
Late 2016
FDA will review interim Devote data
Approved in Europe and Japan
Europe concluded-no increased cardiovascular risk

44. Insulin Degludec Phase III trials
17 completed (along with degludec/aspart)
Degludec alone: 3-DM1, 8-DM2
Most trials non-inferiority studies vs. glargine
Once daily dosing
Three times weekly: 2 trials
Flexible dosing (q8-40 hrs): 2 trials
Primary outcome: Change in A1C
Non-inferiority confirmed in 5 trials
Three times weekly-reduced efficacy/increased hypoglycemia
Maiorine MI et al. Expert Opin Biol Ther (2014)14(6).
Diabet Metab Res Rev 2014;30:

45. Phase III A1C Reduction
Diabet Metab Res Rev 2014;30:

46. Hypoglycemia Add hypoglycemia issues
Diabet Metab Res Rev 2014;30:

47. Degludec Cardiovascular Risk
MACE=Major cardiac events
CV death, non-fatal MI, non-fatal stroke
Evaluation required by FDA
Potential mechanism unknown
Diabet Metab Res Rev 2014;30:

48. Conclusions No definitive advantage over existing agents
Unclear place in clinical practice
Lack of consistency for hypoglycemia reduction
Potential cardiovascular risk

49. Insulin glargine-Basaglar
Lilly product
Presented at 2014 ADA
Not biosimilar due to regulatory pathway
Provisional FDA approval
Patent litigation occurring

50. U500 News
Lilly is working to develop a prefilled pen designed to deliver Humulin R U-500
Lilly is working with a development partner on the design of a dedicated U-500 insulin syringe

51. A cure for Diabetes? Harvard Stem Cell Institute
Hormone discovered that can simulate production of insulin-secreting pancreas beta-cells (mouse)
London’s Imperial College
Turned patients own stem cells into insulin-secreting cells
Inject patients with the cells yearly
Type I DM vaccine
Stanford University
Shuts down immune system

52. Questions?