Adlyxin® - Lixisenatide Manufacturer: Sanofi FDA Approval Date: 07/2016 Robert Vincent, PharmD PGY-1

Adlyxin® - Lixisenatide Objectives At the end of this presentation participants will be able to: Appropriately recommend Adlyxin® - (Lixisenatide) Effectively educate patients on the purpose, proper use and potential adverse effects of Adlyxin® - (Lixisenatide)

Adlyxin® - Lixisenatide Clinical Application Indications: FDA Approved: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes Potential off-label use: Weight loss Place in therapy: 5th-in-class GLP-1 agonist without any currently known benefits over other agents in class Adlyxin [package insert].

Adlyxin® - Lixisenatide Clinical Application Contraindications: Hypersensitivity Type 1 diabetes Adlyxin [package insert].

Adlyxin® - Lixisenatide Clinical Application Precautions Anaphylaxis and severe hypersensitivity reactions Acute pancreatitis- discontinue if suspected; do not restart if confirmed. Avoid with history of pancreatitis Acute kidney injury- monitor renal function with renal impairment reporting severe GI reactions. Avoid in ESRD Gastroparesis- avoid use Hypoglycemia with concomitant use of sulfonylurea or basal insulin- consider dose reduction of basal insulin or sulfonylurea Immunogenicity- patients may develop antibodies to lixisenatide Adlyxin [package insert].

Adlyxin® - Lixisenatide Clinical Application Animal Toxicology: Thyroid C-cell tumor in rats (all doses) Pregnancy: Category C- Limited data in pregnant women. May be risks to fetus from exposure based on animal reproductive studies Lactation: No information regarding presence in human milk. Present in rat milk (9.4% transfer) Adlyxin [package insert].

Adlyxin® - Lixisenatide Drug Facts Pharmacology: GLP-1 Receptor agonist Increases glucose-dependent insulin release Decreases glucagon secretion Slows gastric emptying Adlyxin [package insert].

Adlyxin® - Lixisenatide Drug Facts Pharmacokinetics: A Tmax 1-3.5 after SQ injection D Vd≈100L M No significant metabolism E terminal half-life≈ 3 hours Adlyxin [package insert].

Adlyxin® - Lixisenatide Drug Interactions Drug Interactions – Object Drugs: Due to delayed gastric emptying, drug may impact absorption or orally administered medications (e.g. concentration-dependent antibiotics, narrow therapeutic index drugs, oral contraceptives) Advise patient to take these drugs 1 hour prior to injection or 11 hours post injection Adlyxin [package insert].

Adlyxin® - Lixisenatide Adverse Effects Adverse Effects: (drug%)[placebo%] Nausea (25%) [6%] Diarrhea (8%) [6%] Vomiting (10%) [2%] Headache (9%) [6%] Dizziness (7%) [4%] Injection site rxn (4%) [2%] Hypersensitivity (0.4%) [0.2%] Hypoglycemia-basal ± SU (47%) [22%] Pancreatitis (21 per 10,000 pt years) [14 per 10,000 pt years] Adlyxin [package insert].

Adlyxin® - Lixisenatide Monitoring Parameters Efficacy Monitoring: Average A1c reduction ≈ 0.8%-1.2% Toxicity Monitoring: GI-related symptoms (N/V/D) especially with reduced kidney function Adlyxin [package insert].

Adlyxin® - Lixisenatide Prescription Information Dosing: Initial: 10 mcg once daily x 14 days 1 hour prior to first meal Maint/Max: 20 mcg once daily 1 hour prior to first meal Brand - Generic Doses $ 30-day supply Adlyxin® - Lixisenatide 10 mcg pen Cost TBD 20 mcg pen Bydureon® - Exenatide 2 mg pen $692.00 (4 pens) Tanzeum® - Albiglutide 30/50mg pen $527.00 (4 pens) Trulicity® - Dulaglutide 0.75/1.5mg pen $690.00 (4 pens) Victoria® - Liraglutide 1.2mg dose pen $544.00 (2 pens) 1.8mg dose pen $831.00 (3 pens) Lexicomp® Copyright 2016, Wolters Kluwer.

Adlyxin® - Lixisenatide Literature Review 24 week study (n=323) with T2DM inadequately controlled with diet/exercise and metformin alone Intervention Lixisenatide 20mcg or placebo in addition to metformin ± SU Baseline -56.7 years old Characteristics -5.9 years from Dx (Mean) -A1c 8% -BMI 33 kg/m2 (89 kg) -1,955 mg metformin daily -90% CrCl > 60 mL/min Adlyxin [package insert]

Adlyxin® - Lixisenatide Literature Review Results A1c Lixisenatide n=161 Placebo n=162 Change from baseline -0.72 -0.26 Difference from placebo -0.46 (-0.64, -0.28) p<0.0001 Patients achieving A1c <7% 44% 22% Body weight (kg) -2.70 -1.71 Difference from placebo -1.00 (-0.29, -1.71) p=0.006 Significant reductions in A1c and bodyweight NO difference in bodyweight vs. placebo ALONE Adlyxin [package insert]

Adlyxin® - Lixisenatide Literature Review 24 week open label study (n=634) with T2DM inadequately controlled with diet/exercise and metformin alone Intervention Lixisenatide 20mcg or exenatide 10mcg BID in addition to metformin Baseline -57.4 years old Characteristics -6.8 years from Dx (Mean) -A1c 7.96% -BMI 34 kg/m2 (95 kg) -2,039 mg metformin daily -90% CrCl > 60 mL/min Adlyxin [package insert]

Adlyxin® - Lixisenatide Literature Review Results A1c Lixisenatide n=318 Exenatide n=316 Change from baseline -0.73 -0.90 Difference from exenatide 0.17 (0.03-0.31) p=0.0175 Patients achieving A1c <7% 43.1% 45.6% Body weight (kg) -2.74 -3.72 Difference from placebo 0.98 No difference? Non-inferiority to exenatide (0.4% margin) however, exenatide had significantly greater A1c reduction Adlyxin [package insert]

Adlyxin® - Lixisenatide Literature Review Lixisenatide in Patients with T2DM and ACS: ELIXA Study 6,068 patients with T2DM and ACS with past 6 months Maximum tolerated dose of Adlyxin vs. placebo Pfeffer, M.A., et al. N Engl J Med 2015; 373:2247-2257

Adlyxin® - Lixisenatide Literature Review Primary Composite Endpoint of CV death, non-fatal MI, non-fatal stroke, or hospitalization or unstable angina No difference from placebo in regard to cardiovascular outcomes Pfeffer, M.A., et al. N Engl J Med 2015; 373:2247-2257

Adlyxin® - Lixisenatide Summary New once daily GLP-1 agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes Starting dose of 10 mcg daily x 14 days with a maintenance dose of 20 mcg daily Dose NTI drugs, conc.- dependent ABX, and oral contraceptives 1 hour before or 11 hours after injection

Adlyxin® - Lixisenatide Summary Most common side effects are GI-related (N/V/D) Reduce dose of insulin or SU’s when initiating lixisenatide Avoid ESRD, gastroparesis, history of pancreatitis, or history of thyroid tumors Likely no better than others in class

Adlyxin® - Lixisenatide References http://www.sanofi.com Adlyxin® package insert. Sanofi-Aventis. August 2016. Pfeffer, M.A. et al.: Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015; 373:2247-2257