Efficacy and safety of once-weekly efpeglenatide in people with suboptimally controlled type 2 diabetes: The AMPLITUDE-D, AMPLITUDE-L and AMPLITUDE-S randomized controlled trials.

AIM: To evaluate the efficacy and safety of once-weekly (QW) efpeglenatide in people with type 2 diabetes (T2D) suboptimally controlled with oral glucose-lowering drugs and/or basal insulin (BI). MATERIALS AND METHODS: Three phase 3, multicentre, randomized controlled trials compared the efficacy and safety of QW efpeglenatide versus dulaglutide when added to metformin (AMPLITUDE-D), efpeglenatide versus placebo when added to BI ± oral glucose-lowering drugs (AMPLITUDE-L) or metformin ± sulphonylurea (AMPLITUDE-S). All trials were terminated early by the sponsor because of funding rather than safety or efficacy concerns. RESULTS: In AMPLITUDE-D, non-inferiority of efpeglenatide to dulaglutide 1.5 mg was shown in HbA1c reduction from baseline to week 56, least squares mean treatment difference (95% CI): 4 mg, -0.03% (-0.20%, 0.14%)/-0.35 mmol/mol (-2.20, 1.49); 6 mg, -0.08% (-0.25%, 0.09%)/-0.90 mmol/mol (-2.76, 0.96). The reductions in body weight (approximately 3 kg) from baseline to week 56 were similar across all treatment groups. In AMPLITUDE-L and AMPLITUDE-S, numerically greater reduction in HbA1c and body weight were observed at all doses of efpeglenatide than placebo. American Diabetes Association level 2 hypoglycaemia (< 54 mg/dL [< 3.0 mmol/L]) was reported in few participants across all treatment groups (AMPLITUDE-D, ≤ 1%; AMPLITUDE-L, ≤ 10%; and AMPLITUDE-S, ≤ 4%). The adverse events profile was consistent with other glucagon-like peptide-1 receptor agonists (GLP-1 RAs); gastrointestinal adverse events were most frequent in all three studies. CONCLUSIONS: In people with T2D suboptimally controlled with oral glucose-lowering drugs and/or BI, QW efpeglenatide was non-inferior to dulaglutide in terms of HbA1c reduction and showed numerically greater improvements than placebo in glycaemic control and body weight, with safety consistent with the GLP-1 RA class.

A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis - Study design and rationale of HM-TRIA-201 study.

Non-alcoholic steatohepatitis (NASH) is a multifactorial disease with an increasing prevalence worldwide due to the obesity pandemic. HM15211 (efocipegtrutide), a novel, long-acting glucagon-like peptide-1/glucagon/glucose-dependent insulinotropic polypeptide triple incretin agonist has shown promising efficacy in in vitro, preclinical rodent models of NASH and phase 1 studies with manageable toxicity. Though liver biopsy is recommended for grading and staging of NASH, its invasive nature necessitates innovative approaches in clinical trials that decrease the burden of patients otherwise subjected to this invasive procedure. We report an innovative study design of phase 2 study of HM15211. METHODS: HM-TRIA-201 is a multicenter, randomized, double-blind, 52-week, placebo-controlled, parallel-group adaptive design study of 217 patients with biopsy-proven NASH. The primary endpoint is the proportion of patients with complete resolution of steatohepatitis (defined as Non-alcoholic fatty liver disease Activity Score of 0-1 for inflammation, 0 for ballooning, and any other value for steatosis) on overall histopathological reading and no worsening of liver fibrosis on NASH Clinical Research Network fibrosis score. An interim analysis is planned after 15 patients/group complete 26 weeks of treatment, after which one HM15211 dose group will be discontinued based on safety and efficacy risk-to-benefit analysis; patients of the dropped dosing arm will be re-randomized into 2 remaining HM15211 groups. CONCLUSION: The adaptive design study of HM15211 minimizes the number of patients to be exposed to a liver biopsy while optimizing the sample size of patients exposed to safe and effective doses of HM15211 to inform ideal dose for further clinical development in NASH.

Efficacy and Safety of Once-Weekly Efpeglenatide Monotherapy Versus Placebo in Type 2 Diabetes: The AMPLITUDE-M Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy and safety of the glucagon-like peptide 1 receptor agonist (GLP-1 RA) efpeglenatide versus placebo in patients with type 2 diabetes inadequately controlled with diet and exercise alone. RESEARCH DESIGN AND METHODS: AMPLITUDE-M was a phase 3, double-blind, placebo-controlled, multicenter trial that randomized adults with type 2 diabetes suboptimally controlled with diet and exercise alone to once-weekly efpeglenatide (2, 4, or 6 mg) or placebo for up to 56 weeks. The primary objective was to demonstrate the superiority of efpeglenatide versus placebo for HbA1c reduction at week 30. Secondary objectives included changes in other measures of glycemic control and body weight at weeks 30 and 56. RESULTS: At week 30, HbA1c was reduced from a baseline of 8.1% (65 mmol/mol) to 6.9% (52 mmol/mol), 6.6% (49 mmol/mol), and 6.4% (47 mmol/mol) with efpeglenatide 2, 4, and 6 mg, respectively. Least squares mean HbA1c reductions from baseline were statistically superior for each efpeglenatide dose versus placebo (2 mg, -0.5% [95% CI -0.9, -0.2; P = 0.0054]; 4 mg, -0.8% [-1.2, -0.5; P < 0.0001]; 6 mg, -1.0% [-1.4, -0.7; P < 0.0001]). A greater proportion of efpeglenatide-treated patients (all doses) achieved HbA1c <7% (53 mmol/mol) versus placebo by week 30 (P < 0.0001 for all), and significant reductions in body weight and fasting plasma glucose were also observed for efpeglenatide (4 and 6 mg doses) versus placebo at week 30 (P < 0.05 for all). Consistent with the GLP-1 RA class, gastrointestinal adverse events were most commonly reported; these were generally transient and mild/moderate in severity. Few patients reported hypoglycemia. CONCLUSIONS: As monotherapy in patients with type 2 diabetes, once-weekly efpeglenatide significantly improved glycemic control and body weight with a safety and tolerability profile similar to that of other GLP-1 RAs.

A Randomized, Double-Blind, Placebo- and Active-Controlled, Escalating Single-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Subcutaneous Eflapegrastim in Healthy Japanese and Caucasian Subjects.

BACKGROUND: Eflapegrastim (Rolontis®) is a novel long-acting pegylated recombinant human granulocyte colony-stimulating factor (G-CSF). Eflapegrastim has been developed to reduce the duration and incidence of chemotherapy-induced neutropenia in cancer patients using patient-friendly, less-frequent administration. OBJECTIVE: This phase I study aimed to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of eflapegrastim following a single subcutaneous administration to healthy Japanese and Caucasian subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted in healthy Japanese and Caucasian subjects. Eligible subjects randomly received a single subcutaneous administration of eflapegrastim (1.1, 3.3, 10, 45, 135, and 270 µg/kg), pegfilgrastim 6 mg, or placebo in a ratio of 6:2:2 (Cohorts 1-2, Caucasian subjects only) or 12:2:2 (Cohorts 3-6, Japanese and Caucasian subjects). Safety and tolerability were assessed throughout the study. Serial blood samples were collected predose and up to day 22 postdose for PK and PD analyses. PK assessments were performed in the 45, 135, and 270 µg/kg dose groups. Antidrug antibodies to eflapegrastim were determined at baseline up to day 42 after the first dose for immunogenicity. RESULTS: A total of 84 subjects (42 males and 42 females) were enrolled, and 78 (31 Japanese and 47 Caucasian subjects) completed the study as planned. Japanese and Caucasian subjects showed similar PK and PD profiles. In the 45, 135, and 270 µg/kg dose groups, the maximum serum concentration (Cmax) of eflapegrastim exhibited a dose-proportional increase, whereas its exposure increased greater than dose proportional in both ethnic groups. The mean area under the effect-time curve (AUEClast) and maximum serum concentration of both absolute neutrophil count (ANCmax) and CD34+ cell count (CD34+max) increased in a dose-dependent manner. There were no significant adverse events attributable to eflapegrastim or pegfilgrastim in both Japanese and Caucasian subjects. No neutralizing antibodies against G-CSF were detected. CONCLUSIONS: Eflapegrastim was safe and well tolerated at doses up to 270 µg/kg in healthy Japanese and Caucasian subjects. In both ethnic groups, eflapegrastim showed dose-dependent PK and the exposure to eflapegrastim was positively correlated with ANC and CD34+ cell count. The comparable PK and PD profiles of eflapegrastim in Japanese and Caucasian subjects may indicate the same dosage regimen is acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01037543 (23 December 2009).

A double-blind, placebo-controlled, single-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue, in healthy subjects.

AIM: To evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue under development, in healthy males and females presenting with no childbearing potential. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, single-ascending dose study was conducted in 56 subjects who randomly received a single subcutaneous dose of HM15136 or its matching placebo at a ratio of 6:2 at 10, 20, 30, 50, 80, 100, and 120 µg/kg. RESULTS: All adverse events were mild and transient. Neither serious adverse events nor discontinuation as a result of adverse events occurred. The most frequent adverse drug reaction was nausea (5.3%, only in the 100- and 120-µg/kg groups). HM15136, particularly at doses of 50 µg/kg or higher, increased fasting blood glucose, with a maximum increase and area under the curve of 1.5 mmol/L at day 10 (P = .006) and 166.3 day·mmol/L (P = .022) at the dose of 80 µg/kg, while suppressing the secretion of endogenous glucagon, which continued until day 17. HM15136 also significantly reduced gluconeogenic and ketogenic amino acids. Compensatory changes in endogenous insulin and incretin hormones by HM15136 were not apparent. HM15136 was slowly but steadily absorbed and reached a peak concentration at 46-68 hours after a single subcutaneous injection. HM15136 was eliminated with a terminal phase half-life of 77.1-101.1 hours. CONCLUSIONS: A single subcutaneous dose of HM15136 at 10-120 µg/kg was safe and well tolerated. The long half-life of HM15136, coupled with an increase in blood glucose for ~2 weeks, may warrant a weekly dosing regimen.