Dulaglutide: designed with patients in mind

Transcription

1 31 st Panhellenic Annual Congress of the Hellenic Association for the Study & Education of Diabetes Mellitus Thessaloniki 11 th, November 2017 Dulaglutide: designed with patients in mind Imre Pavo MD PhD Eli Lilly Diabetes Medical Research

2 Disclosures Imre Pavo is full time employee and shareholder of Eli Lilly and Co.

3 GLP-1 Has a Broad Range of Biological Activity Cardiovascular System 1 Cardiovascular risk factors Weight Blood pressure Lipid profile Intestine Brain Appetite 1 Satiety 2 Stomach Gastric emptying 1 Liver Glucose production 2 GLP-1 Direct actions Indirect actions Muscle and Adipose Tissue Glucose uptake 2 Pancreas Insulin secretion 1 Glucagon secretion 3 1. Smilowitz et al. Circulation. 2014;129(22): Gupta. Indian J Endocrinol Metab. 2013;17(3): Kalra S, et al. Indian J Endocrinol Metab. 2016;20(2):

4 GLP-1 RAs: Key Efficacy and Safety GLP-1 RAs HbA 1c Effective in lowering HbA 1c 1,2,3 Weight Potential for weight loss 1,2,3 Hypoglycaemia Low potential for incidents 1,2 GI adverse events Nausea, diarrhoea, and vomiting that are mild to moderate in severity and transient in nature 2,4 1. Karagiannis T, et al. Diabetes Obes Metab. 2015;17(11): Liu FP, et al. J Diabetes. 2015;7(3): Singh S, et al. Diabetes Obes Metab. 2017;19(2): Prasad-Reddy L, et al. Drugs Context. 2015;9(4). DOI: /dic

5 Comparison of Human GLP-1 and Exendin-4 Backbone GLP-1 Analog Human GLP-1 His Ala Glu Gly Thr Phe Thr Ser Asp Val 7 9 Ser Lys Glu Ala Ala Gln Gly Glu Leu Tyr Ser Phe 36 Ile Ala Trp Leu Val Lys Gly Arg 53% homology His Gly Glu Gly Thr Phe Thr Ser Asp Leu Exendin-4 backbone (Exenatide) GLP-1=glucagon-like peptide-1 1. Baggio et al. Gastroenterol 2007;132: Eng et al. J Biol Chem 1992;267: Ser Arg Leu Val Ala Glu Glu Glu Met Gln Lys Phe Ile Glu Trp Leu Lys Asn Lys Gly Gly Pro Ser Ser Gly Ser Pro Pro Pro Ala

6 Overview of Approved GLP 1 Receptor Agonists GLP-1 receptor agonists subcutaneously administered peptides Human GLP-1 backbone Exendin-4 backbone Weekly Once daily Weekly Once daily or Twice daily Albiglutide Liraglutide Exenatide Exenatide Twice daily Dulaglutide Lixisenatide Once daily GLP-1=glucagon-like peptide-1 Madsbad et al. Diabetes Obes Metab 2011;13(5):

7 Approved GLP-1 RAs Structure and Half-life Exenatide BID Liraglutide Exenatide QW Lixisenatide Albiglutide Dulaglutide DPP-4 Resistant to DPP-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS DPP-4 HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG C-16 free fatty acid derivative Albumin via a glutamoyl spacer DPP-4 DPP-4 Partial resistant to DPP-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS Resistant to DPP-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK DPP-4 Resistant to DPP-4 Poly (D,L lactic-co-glycolic acid) microspheres Resistant to DPP-4 HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR DPP-4 Resistant to DPP-4 HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG Recombinant fusion protein linked to human albumin Albumin Modified IgG4 Fc domain Modified IgG4 Fc domain t 1/2 = hours and renal filtration t 1/2 = hours and multiple organ filtration Steady state over 6-7 weeks and renal filtration t 1/2 = ~3 hours and renal filtration t 1/2 = ~ 5 days and multiple organ filtration t 1/2 = ~5 days

8 Topics Dulaglutide molecule Overview of dulaglutide PK / PD and clinical pharmacology Overview of AWARD trials AWARD-5: an adaptive seamless dose finding study

9 Dulaglutide: A GLP-1 IgG Fusion Protein A GLP-1 analog Heavy chain Light chain Antigen binding site Linker Fab domain Modified IgG4 Fc domain Fc domain B NH 2 G 8 IgG 22 H G E G T F T S D V S S Y L E E Q 36 G G G G G G K V L W A I F E K A A S G G G G S G G G G S A Modified IgG4 Color code in B is representative of region color in A 1. Umpierrez et al. Diabetes Obes Metab 2011;13: Kuritzky et al. Postgrad Med 2014;126: Glaesner et al. Diabetes Metab Res Rev 2010;26: Fc domain COOH

10 Dulaglutide has Extended Activity 1 Allows once-weekly administration 1,2 Removed and replaced alanine at position 8 with glycine resulting in resistance to DPP-4 degradation 3 Fused 2 GLP-1 analogues to the Fc portion of an IgG4 antibody resulting in decreased renal clearance and increased time-action profile 4-5 Inserted optimized amino acid linker resulting in improved binding 1,4 Linker GLP-1 analogue Modified IgG4 Fc domain Fc-fusion protein molecules are used currently to treat a wide range of disease states, such as rheumatoid arthritis, organ rejection, and macular degeneration 6 1. Data on file, Eli Lilly and Company and/or one of its subsidiaries 2. Sivaraman et al. Br J Diabetes Vasc Dis 2013;13: Umpierrez et al. Diabetes Obes Metab 2011;13: Pabreja et al. Br J Pharmacol 2014;171: Madsbad et al. Diabetes Obes Metab 2011;13: Glaesner et al. Diabetes Metab Res Rev 2010;26:287-96

11 Dulaglutide is Soluble Eliminates the need for reconstitution and allows delivery via a small-gauge needle (29G) 1 Fc fusion-enhanced solubility 2 In addition to other changes, modified glycine at position 22 in the GLP-1 analogue to glutamic acid results in further enhanced solubility 3 Linker GLP-1 analogue Modified IgG4 Fc domain 1. Matfin et al. J Diabetes Sci Technol 2015;9: Czajkowsky et al. EMBO Mol Med 2012;4:

12 Dulaglutide has Low Potential for Immunogenicity 1 IgG4 selected to minimize potential for cell-mediated toxicity 1,2 Mutations inserted into the IgG4 to minimize potential cytotoxicity 1 Replacing an arginine residue with glycine in the GLP-1 analogue eliminate a potential T-cell epitope 1 Linker GLP-1 analogue Modified IgG4 Fc domain 1. Data on file, Eli Lilly and Company and/or one of its subsidiaries 2. Glaesner et al. Diabetes Metab Res Rev 2010;26: Nirula et al. Current Opin Rheumatol 2011;23:119-24

13 Schematic Presentation of Dulaglutide Structure Dulaglutide is a recombinant GLP-1 Fc fusion protein consisting of 2 identical chains, each containing a human GLP-1 analog sequence linked to a modified human immunoglobulin G4 (IgG4) heavy chain by a small peptide linker 1,2 GLP-1 Analog It is approved for the treatment of type 2 diabetes and its main features are: Linker Extended plasma half-life (~5 days) 3,4 Minimal renal clearance Low immunogenic potential Once weekly dosing Solution injection: no reconstitution needed Modified IgG4 Fc Domain 1. Glaesner et al. Diabetes Metab Res Rev 2010;26: Kuritzky et al. Postgrad Med 2014; Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; Trulicity [Summary of Product Characteristics]. Houten, The Netherlands: Eli Lilly and Company; 2016

14 Dulaglutide Is Delivered via a Ready-to-Use Pen Characteristics of the ready-to-use pen Steps to use: uncap, place and unlock, press and hold 1 Provides dose confirmation 1 Dose delivery (5-10 seconds) 1 Automatically retracts needle following injection 1 Small (29G, 5 mm injection depth 2 ), hidden needle 1 In a Phase 3 study, 99% of people found the pen easy to use 2 1. Trulicity [Summary of Product Characteristics]. Houten, The Netherlands: Eli Lilly and Company; Matfin et al. J Diabetes Sci Technol 2015;9:1071-9

15 Topics Dulaglutide molecule Overview of dulaglutide PK / PD and clinical pharmacology Overview of AWARD trials AWARD-5: an adaptive seamless dose finding study

16 Dulaglutide Pharmacokinetics Summary Steady-state plasma concentrations were achieved between 2 to 4 weeks after onceweekly administration 1,2 Elimination half-life of 4.5 to 4.7 days for both doses makes dulaglutide suitable for onceweekly administration 1,2 Renal impairment USPI: no dose adjustment of dulaglutide is needed 1 SmPC: no dosage adjustment is required in patients with mild/moderate renal impairment 2. Not recommended in patients with severe renal impairment (egfr [by CKD-EPI] < 30 ml/min/1.73 m 2 ) or end-stage renal disease 2 Hepatic impairment: no dose adjustment of dulaglutide is needed 2, however needs to be used with caution 1 No dosage adjustment recommended based on PK for co-administration with 2 lisinopril ethinylestradiol S-warfarin metoprolol atorvastatin R-warfarin digoxin metformin sitagliptin norelgestromin acetaminophen 1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; Trulicity [Summary of Product Characteristics]. Houten, The Netherlands: Eli Lilly and Company; 2016

17 Dulaglutide Pharmacodynamics Summary Dulaglutide increases first-and second-phase insulin secretion in patients with type 2 diabetes compared with placebo Dulaglutide stimulates glucose-dependent insulin secretion and reduces glucagon secretion Dulaglutide causes a delay of gastric emptying. The delay is largest after the first dose and diminishes with subsequent doses In a thorough QTc study, dulaglutide did not produce QTc prolongation at supratherapeutic doses of 4 and 7 mg Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2017

18 Topics Dulaglutide molecule Overview of dulaglutide PK / PD and clinical pharmacology Overview of AWARD trials AWARD-5: an adaptive seamless dose finding study

19 Dulaglutide Clinical Trial Program Monotherapy 2-Drug Combinations 1st Injectable Therapy 3-Drug Combinations More Complex Strategies Combination With Insulin AWARD-3 3 vs metformin Drug-naïve or washout from 1 OAM AWARD-5 5,6,7 vs sitagliptin Add-on to metformin AWARD-6 8 vs liraglutide Add-on to metformin AWARD-8 10 vs placebo Add-on to SU AWARD-1 1 vs exenatide BID Add-on to metformin and TZD AWARD-2 2 vs insulin glargine Add-on to metformin and SU AWARD-10 9 vs placebo Add-on to SGLT2i with or without metformin AWARD-4 4 vs insulin glargine Both with mealtime insulin lispro with or without metformin AWARD-7 9 vs insulin glargine in CKD Both with mealtime insulin lispro AWARD-9 11 vs placebo Both with titrated insulin glargine with or without metformin More than 5000 patients have been enrolled in Phase 3 clinical trials The AWARD program spans the continuum of care One additional study (long-term cardiovascular outcomes), REWIND, is ongoing 1. Wysham et al. Diabetes Care 2014;37: Giorgino et al. Diabetes Care 2014;38: Umpierrez et al. Diabetes Care 2014;37: Blonde et al. Lancet 2015;385: Nauck et al. Diabetes Care 2014;37: Weinstock et al. Diabetes Obes Metab 2015;17: Skrivanek et al. Diabetes Obes Metab 2014;16(8): Dungan et al. Lancet 2014;384: Data on file. Dulaglutide Clinical Overview. 10. Dungan et al. Diabetes Obes Metab 2016;18: Pozzilli et al. Diabetes Obes Metab Mar 14. doi: /dom [Epub ahead of print]

20 Topics Dulaglutide molecule Overview of dulaglutide PK / PD and clinical pharmacology Overview of AWARD trials AWARD-5: an adaptive seamless dose finding study

21 AWARD-5 Study Design: Dose-Finding to 104 Weeks Safety Follow-up Key inclusion criteria T2D ( 6 months) HbA1c >8.0% (64 mmol/mol) and 9.5% (80 mmol/mol) on diet and exercise alone or HbA1c 7.0% (53 mmol/mol) and 9.5% (80 mmol/mol) on OAM monotherapy or combination therapy (metformin plus another OAM) Metformin a Lead Study in period week -11b 0 Dose finding c Dulaglutide 0.25 mg Dulaglutide 0.5 mg Dulaglutide 1.0 mg Dulaglutide 2.0 mg Dulaglutide 3.0 mg Placebo d 52-Week Analysis Dulaglutide 0.75 mg once weekly Dulaglutide 1.5 mg once weekly 104-Week Analysis Sitagliptin 100 mg once daily Sitagliptin 100 mg once daily Treatment period Randomization Primary Time Point Final Time Point Stage 1 Stage 2 a Metformin background concomitant therapy from lead-in period through treatment period ( 1500 mg/day); b Lead-in period lasted from 2 weeks up to 11 weeks; c The dose-finding period (indicated by the pink area) ended at the Decision Point (April 29, 2009) resulting in different exposures within and across treatment groups. All patients on non-selected arms were discontinued regardless of length of participation in the study; d After 26 weeks, patients in the placebo arm transitioned to Sitagliptin (100 mg/day) in a blinded fashion 1. Skrivanek et al. Diabetes Obes Metab 2014;16(8): Geiger et al. J Diabetes Sci Technol 2012;6: Skrivanek et al. J Diabetes Sci Technol 2012; 6:

22 AWARD-5 Dose Finding Stage 1-3 Objective: identify a dulaglutide dose with an optimal efficacy and safety profile, and possibly one lower dose a using an adaptive design Patients were adaptively randomized to dulaglutide doses and evaluated biweekly based on predefined dose decision rules Adaptive randomization and dose selection was facilitated by a clinical utility index (CUI) of HbA1c vs sitagliptin at 52 weeks and weight, pulse rate and diastolic blood pressure vs placebo at 26 weeks The decisions made by the algorithm were based on the posterior probability distributions of the CUI; with an adaptive potential decision point a In case of an observed, unforeseen safety signal with the optimal dose during subsequent clinical development 1. Skrivanek et al. Diabetes Obes Metab 2014;16: Nauck et al. Diabetes Care 2014;37: Weinstock et al. Diabetes Obes Metab 2015;17:849-58

23 Dose-Response Model and CUI ΘPR (bpm) Clinical Utility Index Skrivanek et al. Diabetes Obes Metab 2014;16:748-56

24 Summary and Conclusions for the Dose Finding Stage of AWARD-5 Efficacy Optimal dose: Dulaglutide 1.5 mg Second dose: Dulaglutide 0.75 mg This second dose was the next highest dose with an acceptable CUI 0.6 and 50% of the maximum utility dose to ensure minimal overlap of dulaglutide exposure Safety GI adverse events (nausea, diarrhea, and vomiting) and urinary tract infection were the most common adverse events reported Conclusions This adaptive design successfully identified safe and efficacious doses, once weekly dulaglutide 1.5 mg and 0.75 mg, that were selected for further investigation in the Phase 3 program with a relatively small sample size and limited exposure to make the dose decision Skrivanek et al. Diabetes Obes Metab 2014;16:748-56