PMID- 30593607 OWN - NLM STAT- MEDLINE DCOM- 20190624 LR - 20200309 IS - 1432-0428 (Electronic) IS - 0012-186X (Linking) VI - 62 IP - 3 DP - 2019 Mar TI - Randomised, phase 1, dose-finding study of MEDI4166, a PCSK9 antibody and GLP-1 analogue fusion molecule, in overweight or obese patients with type 2 diabetes mellitus. PG - 373-386 LID - 10.1007/s00125-018-4789-6 [doi] AB - AIMS/HYPOTHESIS: Cardiovascular disease is the leading cause of morbidity and mortality in people with type 2 diabetes. MEDI4166 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and glucagon-like peptide-1 (GLP-1) analogue fusion molecule designed to treat patients with type 2 diabetes who are at risk for cardiovascular disease. In this completed, first-in-human study, we evaluated the safety and efficacy of single or multiple doses of MEDI4166 in participants with type 2 diabetes. METHODS: In this phase 1 study that was conducted across 11 clinics in the USA, eligible adults had type 2 diabetes, a BMI of >/=25 kg/m(2) to /=1.81 mmol/l. Participants were randomised 3:1 to receive MEDI4166 or placebo using an interactive voice/web response system, which blinded all participants, investigators and study site personnel to the study drug administered. In 'Part A' of the study, five cohorts of participants received a single s.c. injection of MEDI4166 at 10 mg, 30 mg, 100 mg, 200 mg or 400 mg, or placebo. 'Part B' of the study consisted of three cohorts of participants who received an s.c. dose of MEDI4166 once weekly for 5 weeks at 50 mg, 200 mg or 400 mg, or placebo. The primary endpoint in Part A was safety. The co-primary endpoints in Part B were change in LDL-cholesterol levels and area under the plasma glucose concentration-time curve (AUC(0-4h)) post-mixed-meal tolerance test (MMTT) from baseline to day 36. The pharmacokinetics and immunogenicity of MEDI4166 were also evaluated. RESULTS: MEDI4166 or placebo was administered to n = 30 or n = 10 participants, respectively, in Part A of the study, and n = 48 or n = 15 participants, respectively, in Part B. The incidence of treatment-emergent adverse events (TEAEs) were comparable between MEDI4166 and placebo in both Part A (60% vs 50%) and Part B (79% vs 87%) of the study. Common TEAEs with MEDI4166 included injection-site reactions, diarrhoea and headache; there was no evidence for dose-related increases in TEAEs. In Part B of the study, at all tested doses of MEDI4166, there was a significant decrease in LDL-cholesterol levels vs placebo (least squares mean [95% CI]; MEDI4166 50 mg, -1.25 [-1.66, -0.84]; MEDI4166 200 mg, -1.97 [-2.26, -1.68]; MEDI4166 400 mg, -1.96 [-2.23, -1.70]; placebo, -0.03 [-0.35, 0.28]; all p < 0.0001). However, there were no clinically relevant reductions or significant differences between MEDI4166 vs placebo in glucose AUC(0-4h) post-MMTT (least squares mean [95% CI]; MEDI4166 50 mg, -10.86 [-17.69, -4.02]; MEDI4166 200 mg, -4.23 [-8.73, 0.28]; MEDI4166 400 mg, -2.59 [-7.14, 1.95]; placebo, -4.84 [-9.95, 0.28]; all p > 0.05). MEDI4166 was associated with a pharmacokinetic profile supportive of weekly dosing and an overall treatment-induced anti-drug antibody-positive rate of 22%. CONCLUSIONS/INTERPRETATION: MEDI4166 was associated with an acceptable tolerability profile and significantly decreased LDL-cholesterol levels in a dose-dependent manner in overweight or obese patients with type 2 diabetes. However, there were no significant reductions in postprandial glucose levels at any dose of MEDI4166. TRIAL REGISTRATION: ClinicalTrials.gov NCT02524782 FUNDING: This study was funded by MedImmune LLC, Gaithersburg, MD, USA. FAU - Jain, Meena AU - Jain M AD - MedImmune Ltd, Milstein Building, Granta Park, Cambridge, CB21 6GH, UK. JainM@MedImmune.com. FAU - Carlson, Glenn AU - Carlson G AD - AstraZeneca, Gaithersburg, MD, USA. FAU - Cook, William AU - Cook W AD - MedImmune, Gaithersburg, MD, USA. FAU - Morrow, Linda AU - Morrow L AD - ProSciento Inc., Chula Vista, CA, USA. FAU - Petrone, Marcella AU - Petrone M AD - MedImmune Ltd, Milstein Building, Granta Park, Cambridge, CB21 6GH, UK. FAU - White, Nicholas E AU - White NE AD - MedImmune Ltd, Milstein Building, Granta Park, Cambridge, CB21 6GH, UK. FAU - Wang, Tao AU - Wang T AD - MedImmune, Gaithersburg, MD, USA. FAU - Naylor, Jacqueline AU - Naylor J AD - MedImmune Ltd, Milstein Building, Granta Park, Cambridge, CB21 6GH, UK. FAU - Ambery, Philip AU - Ambery P AD - MedImmune Ltd, Milstein Building, Granta Park, Cambridge, CB21 6GH, UK. FAU - Lee, Charles AU - Lee C AD - MedImmune, Gaithersburg, MD, USA. FAU - Hirshberg, Boaz AU - Hirshberg B AD - MedImmune, Gaithersburg, MD, USA. LA - eng SI - ClinicalTrials.gov/NCT02524782 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20181228 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Antibodies) RN - 0 (Hypoglycemic Agents) RN - EC 3.4.21.- (PCSK9 protein, human) RN - EC 3.4.21.- (Proprotein Convertase 9) SB - IM MH - Antibodies/*therapeutic use MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Double-Blind Method MH - Female MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - Male MH - Middle Aged MH - Obesity/complications/*drug therapy MH - Overweight/complications/*drug therapy MH - Proprotein Convertase 9/*immunology MH - Treatment Outcome OTO - NOTNLM OT - First-in-human study OT - Glucagon-like peptide-1 analogue OT - Glucose OT - Low-density lipoprotein cholesterol OT - Multiple ascending dose OT - Pharmacokinetics OT - Phase 1 OT - Proprotein convertase subtilisin/kexin type 9 antibody OT - Single ascending dose OT - Type 2 diabetes mellitus EDAT- 2018/12/30 06:00 MHDA- 2019/06/25 06:00 CRDT- 2018/12/30 06:00 PHST- 2018/06/08 00:00 [received] PHST- 2018/10/31 00:00 [accepted] PHST- 2018/12/30 06:00 [pubmed] PHST- 2019/06/25 06:00 [medline] PHST- 2018/12/30 06:00 [entrez] AID - 10.1007/s00125-018-4789-6 [pii] AID - 10.1007/s00125-018-4789-6 [doi] PST - ppublish SO - Diabetologia. 2019 Mar;62(3):373-386. doi: 10.1007/s00125-018-4789-6. Epub 2018 Dec 28.