Main Research Findings

1) Treatment with Orforglipron resulted in decreased body weight and HbA1c levels.

2) Administration of Orforglipron led to improvements in weight related and cardiometabolic measures.

 

Selected Data

1) This study performed by Pratt et al outlines the methodologies employed in a multicenter, blinded, placebo-controlled, randomized, multiple-ascending-dose clinical trial to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of orforglipron (LY3502970), a novel oral non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D). The trial was structured as a multiple-ascending-dose study across five different dosing regimens. An initial cohort established the tolerability of weekly dose escalation, which then informed the parallel-arm design for subsequent cohorts. Participants were randomized in a 3:1 ratio to receive either orforglipron or placebo for 12 weeks [1].

Inclusion criteria for participants with T2D included age between 18 and 70 years, a T2D diagnosis for at least 6 months, treatment with diet and exercise alone or a stable dose of metformin for at least 3 months, and baseline HbA1c levels between 7.0% (53.0 mmol/mol) and 10.5% (91.3 mmol/mol). Body Mass Index (BMI) was required to be between 18.5 and 45 kg/m², and participants needed a stable body weight (less than 5% change) for three months prior to screening. Exclusion criteria were designed to mitigate confounding factors and ensure patient safety. These included episodes of ketoacidosis or hyperosmolar state requiring hospitalization in the 6 months prior, severe or progressive diabetic retinopathy, specified cardiovascular events within the past 6 months, or known allergies to the test compound. All participants provided written informed consent [1].

Orforglipron was administered orally as capsules of different dose strengths, prepared extemporaneously, once daily. The dosing strategy involved an initial cohort starting with 3 mg, escalating weekly to 6, 12, and then 21 mg over a 4-week period, with this 21 mg dose maintained for the remainder of the 12 weeks. Based on the safety, tolerability, and PK/PD responses from this initial cohort, subsequent dose escalation schemes were determined for the other groups. These groups also started at 3 mg and escalated weekly to achieve final treatment dose levels of 9, 15, 27, and 45 mg within 4 to 6 weeks. Randomization was implemented in a 3:1 (orforglipron:placebo) ratio within each of the five orforglipron groups. A double-blind approach was maintained throughout the study: participants, investigators, and all study site personnel were blinded to the treatment allocation.

Safety and tolerability were primary objectives. This involved recording all treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), with investigators assessing their potential relatedness to the study drug. Blood pressure (systolic and diastolic) and pulse rate were measured after a 5-minute rest period. Pharmacokinetic (PK) assessments aimed to characterize orforglipron’s absorption, distribution, metabolism, and excretion after multiple oral doses. Primary PK variables included maximum observed drug concentration (Cmax) and area under the concentration curve (AUC) [1].

Pharmacodynamic (PD) endpoints focused on the drug’s effects on glucose metabolism and body weight. Changes from baseline to Week 12 were measured for fasting plasma glucose, fasting insulin, HbA1c, and body weight. Exploratory PD objectives included changes in C-peptide, glucose and insulin levels during a mixed-meal tolerance test (MMTT), visual analogue scale (VAS) scores for appetite, and lipid profiles. The MMTT involved administering acetaminophen to assess gastric emptying, with tmax used as a proxy for gastric emptying delay.

TEAEs were summarized by treatment group, severity, and relatedness to the study drug. PK variables were analyzed using standard noncompartmental methods and descriptive statistics. Dose proportionality for Cmax and AUC was assessed using a power model with log-transformed values. For changes from baseline in vital signs and PD characteristics, a linear mixed-effect repeated-measures model was fitted, incorporating treatment, time, and treatment-by-time interaction as fixed effects, and baseline as a covariate. Participants were included as a random effect. PD parameters were log-transformed as necessary. Placebo data from all parts of the study were pooled for the final analysis. Overall appetite was quantified using a validated 0-100 mm VAS [1].

2) This randomized, double-blind, placebo-controlled, parallel-group trial performed by researchers Wharton et al investigated the efficacy and safety of daily oral orforglipron for weight reduction in adults with obesity. Adults aged 18 to 75 years were eligible for inclusion. Key eligibility criteria required participants to have either obesity, defined as a body-mass index (BMI) ≥30, or overweight (BMI 27 to <30) accompanied by at least one weight-related coexisting condition. These coexisting conditions included hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea. Crucially, all participants were required to be free of diabetes, evidenced by a glycated hemoglobin level of <6.5% (48 mmol per mole). Participants also needed a stable body weight (≤5% gain or loss) for the 3 months prior to randomization [2].

Participants were randomly assigned to receive daily oral doses of orforglipron or a matching placebo for a total of 36 weeks. Four distinct orforglipron dose cohorts were established: 12 mg, 24 mg, 36 mg, and 45 mg. The 36-mg and 45-mg dose cohorts were further divided into two subcohorts each, featuring different starting doses and dose-escalation schemes to explore optimal titration strategies. The randomization ratio was complex, involving a 5:5:3:3:3:3:5 scheme across the placebo and various orforglipron subcohorts [2].

Orforglipron or matching placebo was administered once daily via oral capsules in the morning, without any restrictions regarding meal timing. This oral, non-peptide formulation aimed to provide a convenient treatment option. Throughout the trial, all participants received education on healthy eating and exercise from the trial personnel. The total trial period encompassed a 2-week screening and lead-in phase, followed by a 36-week treatment period, and concluded with a 2-week follow-up period. During the treatment period, dose escalation was implemented across all orforglipron dose cohorts. The duration of this dose-escalation phase varied up to 16 weeks, depending on the specific dose cohort. Starting doses were either 2 mg or 3 mg, with subsequent dose-escalation steps tailored to each cohort to reach the target maintenance dose.

The primary efficacy endpoint measured in this study was the percentage change from baseline in body weight at week 26. Secondary endpoints included the percentage change from baseline in body weight at week 36, absolute changes from baseline in body weight, BMI, and waist circumference at both week 26 and week 36. Additionally, the study assessed the proportion of participants achieving weight reductions of at least 5% and at least 10% by week 26 and week 36. Additional exploratory endpoints included weight reductions of at least 15% by week 26 and week 36. Comprehensive safety assessments included recording all adverse events (AEs), monitoring blood pressure and pulse, evaluating safety-related laboratory measures, and collecting pharmacokinetic (PK) measures. Participant-reported outcomes were also gathered. A complete list of all end points was detailed in the study protocol [2].

The study aimed for a sample size of 270 participants, calculated to provide at least 90% power for demonstrating the superiority of orforglipron over placebo with respect to the primary endpoint. Efficacy analyses for continuous outcomes utilized a mixed model for repeated measures, with potential missing data after intercurrent events imputed implicitly. For binary efficacy outcomes, logistic regression was used, and missing values were handled with multiple imputation. No multiplicity adjustments were applied for type 1 error rate in this early-stage study. For the 36-mg and 45-mg doses, data were pooled across subcohorts. Safety analyses were conducted on all randomized participants who received at least one dose of the assigned treatment, regardless of adherence [2].

 

Discussion

1) The Phase 1b clinical trial of orforglipron (LY3502970) in patients with type 2 diabetes (T2D) successfully demonstrated its safety, tolerability, and promising efficacy in improving glycemic control and reducing body weight, with an adverse event profile consistent with other GLP-1RAs. A total of 69 participants with T2D were enrolled, with 68 receiving at least one dose of the study drug. This included 17 assigned to placebo and 51 assigned to various orforglipron dose groups including 9 mg, 15 mg, 21 mg, 27 mg, 45 mg. Among the orforglipron-treated participants, 7 completed the study. Baseline characteristics were generally comparable between groups, though some variations existed due to small sample sizes. Mean baseline HbA1c was 8.1% (8.03% in orforglipron) and mean body weight was around 90 kg (88.4 kg in orforglipron) [1].

Orforglipron was found to be generally well-tolerated. Eleven participants discontinued the study due to AEs, with COVID-19 infection being the most common reason for discontinuation (three participants). No serious adverse events (SAEs), deaths, or TEAEs of special interest (cardiovascular, hypoglycemic, or hepatic events) were reported, indicating a favorable safety profile. Two orforglipron-treated participants experienced elevated amylase and lipase levels, deemed clinically significant by the investigator, but these were mild to moderate and did not suggest widespread pancreatic issues .

The PK profile of orforglipron demonstrated dose-proportional increases in Cmax and AUC across the 9 to 45 mg dose range at Week 12. The median tmax ranged from 4 to 8 hours across all doses, and the mean half-life (t1/2) ranged from 28.7 to 49.3 hours. This prolonged half-life supports once-daily oral dosing. Orforglipron treatment led to significant and clinically meaningful improvements in glycemic control and body weight. All orforglipron groups showed significant reductions in HbA1c from baseline to Week 12. Mean FPG levels at Week 12 were significantly decreased in the 9-mg and 15-mg dose groups compared to placebo. A significant reduction in body weight from baseline compared to placebo was observed across all orforglipron dose groups, except for the 21-mg group, which had a small sample size and higher variability. Glucose concentrations following a mixed-meal tolerance test (MMTT) were consistently lower in orforglipron-treated participants compared to placebo at Week 12. A consistent decrease in AUC for glucose was observed across all orforglipron groups. Overall appetite VAS scores generally indicated decreased appetite across all treatment groups, though not statistically significant. Prospective food consumption and hunger scores generally decreased from baseline, while fullness and satiety scores increased. Orforglipron also induced a delay in gastric emptying, as indicated by a 1 to 3.5 hour delay in acetaminophen tmax on Day 1, which reduced towards baseline with multiple dosing [1].

 

Figure 1: Changes from baseline in A) HbA1c levels, B) fasting plasma glucose levels, and C) body weight across experimental treatment groups receiving, 9 mg, 15 mg, 21 mg, 27 mg, or 45 mg of orforglipron, compared to the placebo

Fasting insulin levels were not significantly different from placebo. Orforglipron had little effect on lipid variables, with no significant or time-dependent trends in triglyceride, LDL, or HDL cholesterol. Pulse rate increased compared to placebo across all dose groups (4 to 10 beats/min change from baseline), but not in a dose-dependent manner. No significant changes were noted in blood pressure. In conclusion, orforglipron treatment achieved significant reductions in HbA1c and body weight, with an AE profile consistent with other GLP-1RAs. Its once-daily oral administration without food or water restrictions, coupled with a half-life supporting this regimen, positions orforglipron as a promising and convenient alternative to injectable or peptide-based oral GLP-1RAs for T2D management and chronic weight control [1].

2) This randomized, double-blind, placebo-controlled trial performed by Wharton et al demonstrated that daily oral orforglipron is an effective and well-tolerated treatment for weight reduction in adults with obesity. The results underscore its potential as a convenient oral alternative within the GLP-1 receptor agonist class.

A total of 272 participants underwent randomization between September 2021 and November 2022. The baseline demographics were well-balanced across all trial groups, reflecting the planned randomization ratio. The mean age of participants was 54.2 years, with a majority being female (59%) and White (91%). The mean baseline body weight was 108.7 kg, and the mean BMI was 37.9, confirming an obese study population. The completion rate was high, with 86% of participants completing the trial, and 76% completing the assigned treatment [2].

Orforglipron demonstrated significant and dose-dependent weight reduction. The primary endpoint measured at week 26 exhibited a mean change from baseline in body weight ranging from -8.6%, for 12 mg dose, to -12.6%, for 45 mg dose, across the orforglipron cohorts, compared to -2.0% in the placebo group. This represented a placebo-corrected percentage change ranging from -6.5% to -10.6% across dose cohorts. The secondary endpoint measured at week 36 emphasized that weight reduction continued to improve with a mean change from baseline ranging from -9.4% for the 12 mg group to -14.7% for the 45 mg group receiving orforglipron, versus -2.3% with placebo. At week 36, absolute weight loss ranged from -7.4 kg to -13.0 kg with orforglipron, compared to -2.4 kg with placebo. A weight reduction of at least 10% by week 36 was achieved by 46% to 75% of participants on orforglipron, significantly higher than the 9% in the placebo group. Even a ≥15% weight reduction, an exploratory endpoint, was achieved by 22% to 48% of orforglipron-treated participants, compared to 1% in the placebo group [2].

 

Figure 2: A) Percentage change in body weight, B) absolute change in body weight, C) weight reduction by week 26, and D) weight reduction by week 36 across experimental treatment groups receiving 12 mg, 24 mg, 36 mg, or 45 mg of orforglipron, compared to the placebo group.

Orforglipron led to a continuous, dose-dependent decrease in both BMI and waist circumference from baseline through week 36. Placebo-corrected changes ranged from -2.4 to -3.9 for BMI and -4.4 cm to -8.7 cm for waist circumference at week 26, further improving at week 36. Orforglipron treatment resulted in clinically meaningful improvements in cardiometabolic measures. Participants receiving orforglipron experienced a mean reduction in systolic blood pressure of up to -10.5 mm Hg at both week 26 and week 36, compared to -3.6 mm Hg and -1.8 mm Hg in the placebo group, respectively. While diastolic blood pressure showed no clinically meaningful change, orforglipron demonstrated beneficial effects on fasting lipid levels, including triglycerides, total cholesterol, HDL, non-HDL, LDL, and very-LDL cholesterol, contributing to a favorable cardiometabolic profile [2].

In conclusion, daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, significantly reduced body weight in adults with obesity, maintained continuous weight loss without plateauing, and improved cardiometabolic measures. Its safety profile was consistent with the GLP-1RA class, with GI events being the most common adverse effects, primarily during dose escalation. These findings position orforglipron as a promising oral treatment for obesity [2] .

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Pratt E, Ma X, Liu R, et al. Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes. Diabetes Obes Metab. 2023;25(9):2642-2649. doi:10.1111/dom.15150

[2] Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med. 2023;389(10):877-888. doi:10.1056/NEJMoa2302392

 

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