Eli Lilly Initiates Global Phase III ACHIEVE-4 Trial of Orforglipron, the First Oral Small-Molecule GLP-1 Receptor Agonist

On April 7, Eli Lilly registered a Phase III clinical trial (ACHIEVE-4) on the ClinicalTrials.gov website, aiming to evaluate the safety and efficacy of LY3502970 (incremental doses, once daily) compared with insulin glargine (personalized doses, once daily) in adult patients with type 2 diabetes at increased cardiovascular risk and in adult patients with obesity or overweight.

This study is a global, multicenter, randomized, open-label, active-controlled clinical trial, planning to enroll 2,620 adult participants with a body mass index (BMI) ≥27 kg/m² and type 2 diabetes. Additionally, enrolled participants must have conditions that increase the risk of cardiovascular events, including coronary artery disease, peripheral artery disease inferred to be caused by atherosclerosis, cerebrovascular disease, chronic kidney disease (CKD), and congestive heart failure (CHF) classified as New York Heart Association (NYHA) functional class II to III.

The primary endpoint of the study was the time to the first occurrence of any major adverse cardiovascular event (MACE-4) within 104 weeks, where MACE-4 includes myocardial infarction (MI), stroke, hospitalization for unstable angina, or cardiovascular (CV) death. Secondary endpoints included the time to the first occurrence of MACE-3 (MI, stroke, CV death) within 104 weeks, the change in glycated hemoglobin (HbA1c) at week 52 compared to baseline, the change in fasting blood glucose levels at week 52, and the change in body weight at week 52 compared to baseline, among others.

LY3502970 (Orforglipron) is an orally available, non-peptide glucagon-like peptide-1 receptor (GLP-1R) agonist developed by Chugai Pharmaceutical. In September 2018, Eli Lilly and Company entered into a licensing agreement with Chugai Pharmaceutical, securing global development and commercialization rights for the product in exchange for a $50 million upfront payment. The product was submitted for clinical trials in China this past March (see: ).

Preclinical studies have shown that the glucose-lowering effect of LY3502970 is comparable to that of exenatide. Pharmacokinetic experiments conducted in cynomolgus monkeys indicated that the half-life of orally administered LY3502970 was 3.4-4.6 hours, with an oral bioavailability of 21%-28%.

Structure and partial preclinical data of LY3502970 (Source: PNAS)

Results from a Phase I study (N=68) conducted in patients with type 2 diabetes showed that at week 12 of treatment, the maximum blood concentration range for patients in different dose groups of LY3502970 was 60-236 ng/mL, with a median time to peak concentration of 4-8 hours. Additionally, reductions in HbA1c levels were 1.5%-1.8% across the different dose groups of LY3502970 (compared to a 0.4% reduction in the placebo group), and weight loss ranged from 1.6-5.0 kg (compared to a 0.5 kg weight gain in the placebo group).

Partial Phase I Study Data of LY3502970 (Source: Eli Lilly and Company Press Release)

In terms of safety, the most commonly reported treatment-emergent adverse events in the LY3502970 group were nausea (47.1%), decreased appetite (45.1%), and vomiting (43.1%).

In addition to lowering blood sugar, Eli Lilly has also conducted clinical trials of LY3502970 for weight loss. A Phase II clinical trial (NCT05051579) targeting overweight or obese patients with weight-related complications was completed in November 2022.

Copyright © 2023 PHARMCUBE. All Rights Reserved.

Welcome to forward, share, and reasonably cite. When citing, please clearly indicate the source of the article in a prominent position; if you need to reproduce it, please leave a message or send a notification to the WeChat Official Account backend, and include the name and ID of the official account.

Disclaimer: The information in this WeChat article is for general reference only and should not be used directly as decision-making content. PharmaCube assumes no responsibility for any loss incurred by any party due to the use of the content herein.

Wonderful Live Broadcast

CUBE LIVE

PharmaCube Reader Survey Questionnaire

Thank you for your companionship. Looking forward to your feedback.

Scan the QR code to provide valuable suggestions