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

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

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.

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, 2011. US Centers for Disease Control and Prevention (CDC). www.cdc.gov

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

Famous People with Diabetes

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

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. www.phrma.org/sites/default/files/pdf/diabetes 2014.pdf. Accessed on 4/16/15.

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®)

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

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

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 http://www.nature.com/nbt/journal/v25/n12/full/nbt1207-1331.html

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

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.

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

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.

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

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.

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

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

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

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

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.

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

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

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

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 http://diabetes.diabetesjournals.org/content/63/2/390/F1.expansion.html2014.

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 https://investor.lilly.com/releasedetail.cfm?ReleaseID=869098

PEGylated Lispro (LY2605541) 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

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

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

Phase II Data

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!!

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

Kinetics/Dynamics http://www.slideshare.net/Sanofi/201406-ir-diabetes

Insulin Glargine U300 (Toujeo®) http://www.slideshare.net/Sanofi/201406-ir-diabetes

Edition 1-3 Pooled Data http://www.slideshare.net/Sanofi/201406-ir-diabetes

Edition 3 Bolli GB. Diab Ob Metab 17:386-394, 2015.

Edition 3 Bolli GB. Diab Ob Metab 17:386-394, 2015.

Insulin Glargine U300 (Toujeo®) http://www.rxlist.com/toujeo-drug/medication-guide.htm

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

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

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

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;30:104-119.

Phase III A1C Reduction Diabet Metab Res Rev 2014;30:104-119.

Hypoglycemia Add hypoglycemia issues Diabet Metab Res Rev 2014;30:104-119.

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;30:104-119.

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

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

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

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

Questions?