Dose-finding study: PCK9 MAb/GLP-1 analogue fusion molecule
Diabetes is without a doubt one of the fastest growing diseases in the world, even more so in low- and middle-income countries. A recent report by the International Diabetes Foundation (IDF Diabetes Atlas 2017, eighth edition 2017) indicates that about 425 million adults (ages 20 to 79) are living with diabetes and that this number will increase to 629 million by 2045. The report also states that diabetes caused 4 million deaths and at least $727 billion in health expenditures in 2017 alone. These are indeed alarming facts and figures, highlighting the obvious need to develop powerful new treatments.
Combining one hypocholesterolemic molecule controlling LDL-receptor activity, with another molecule that increases insulin secretion, shows potential as a therapeutic approach. PCSK9 inhibitors are used for managing dyslipidemia, and the GLP-1 agonist increases intracellular cyclic AMP (cAMP) in beta cells, leading to the release of glucose-dependent insulin. Both molecules already exist and can be combined during treatment. What if these two drugs could be combined into a single, more potent molecule? The result would be MEDI4166, an anti-peptide fusion molecule comprising a PCSK9 antibody linked with a GLP-1 analogue.
In this article, MedImmune’s Meena Jain describes how the MEDI4166 dose-finding study was designed before launching a full-phase Phase I study. The study’s design, participants’ basic demographic and physiological characteristics, safety data, and pharmacokinetic properties are all described in detail. Of course, before entering full clinical study in humans, the molecule’s potency was evaluated ex vivo on a GLP-1 receptor CHO cell line by measuring MEDI4166 mediated cAMP production.
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.
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/m2 to ≤42 kg/m2, and LDL-cholesterol levels ≥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 (AUC0-4h) post-mixed-meal tolerance test (MMTT) from baseline to day 36. The pharmacokinetics and immunogenicity of MEDI4166 were also evaluated.
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 AUC0-4h 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%.
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.
Diabetologia. 2019 Mar;62(3):373-386.