For anti-diabetic agent, Ozempic has been known for clinical efficacy of diabetes and obesity [1]. Among them, weight reduction tends to be smaller in diabetic cases rather than non-diabetic cases. As an impressive topic, promising results of phase 3 trial for new oral anti-diabetic med was reported, which would be the rival Ozempic for weight control. The agent has been orforglipron (LY?3502970) that is oral form of GLP-1RA, which belongs to the same class in Ozempic.  Although Ozempic showed big waves for potential weight reduction, Orforglipron will become the large topic that could have similar beneficial efficacy as easier-to-swallow pill.

From historical point of view, orforglipron is not the first oral GLP-1RA [2]. Ozempic has formerly has an oral sibling agent, that is Rybelsus. It contains semaglutide, the active ingredient of Ozempic. As a matter of fact, Rybelsus has played a role for decreasing HbA1c value in T2D, rather than weight reduction. The reason would be that Rybelsus has enough efficacy for HbA1c decrease, but insufficient for weight reduction. The characteristic point of Orforglipron would be satisfactory clinical efficacy. They include 16 pounds weight reduction in average as well as decreasing HbA1c -1.6%. This would be pretty significant clinical efficacy for weight control and diabetic control. Eli Lilly plan to have FDA approval by 2025, and to have broader application approval for T2D by 2026.

Various types of phase 1-3 studies for orforglipron have been conducted across the world. Some main investigations would be described from 1 to 3 phases in the following. For phase 1 study, the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970) was investigated [3]. It was double-blind, placebo-controlled phase 1b study, for evaluating five different dosing regimens. Participants were provided orforglipron or placebo as 3:1 randomly for 12 weeks. Mean HbA1c change showed -1.5% to -1.8% for orforglipron doses, versus -0.4% with placebo.

As phase 2 test, multi-center project (n=45) was conducted in USA, Poland, Hungary, and Slovakia [4]. The applicants (aged>=18 years) were T2D cases, and the efficacy and safety of orforglipron vs placebo or dulaglutide were evaluated. Then, 383 participants were enrolled from 569 screened cases.  As a result, mean change in HbA1c at week 26 showed orforglipron -2.10%, vs placebo -0.43%, and dulaglutide -1.10%, respectively. Similarly, mean change in weight at week 26 showed orforglipron -10.1kg, vs placebo -2.2kg, and dulaglutide -3.9kg. From these data, orforglipron at doses of >= 12mg have shown significant reductions of HbA1c and weight in comparison with other 2 groups. For phase 2/3 test, randomized, double-blind trial was conducted for cases with obesity, overweight and >1 weight-related problems, and without diabetes [5]. Participants (n=272) were assigned randomly for 4 doses which were 12, 24, 36 and 45mg, placebo per day for 36 weeks. As a result, average BMI was 37.9 kg/m². Weight changes at 36 week was -9.4% to -14.7% for orforglipron, -2.3% for placebo. The ratio with > 10% reduction showed 46-75% for orforglipron, and 9% for placebo.

As phase 3 of  orforglipron, double-blind, placebo-controlled trial was performed as randomly assignment of 1:1:1:1 ratio for 3mg, 12mg, 36mg and placebo per day for 40 weeks [6]. The baseline HbA1c was 8.0% in average for n=559. As a result, HbA1c changes were -1.24% for 3mg, -1.47% for 12mg, -1.48% for 36mg, and -0.41% for placebo. Weight changes were -4.5% for 3mg, -5.8% for 12mg, -7.6% for 36mg, and -1.7% for placebo. Consequently, orforglipron showed significant reduction of HbA1c.

Two projects are currently underway for phase 3 controlled trials. One is a comparative study of orforglipron and rybelsus in patients with T2D. The study is titled "A Study of Orforglipron (LY3502970) Compared with Semaglutide in Participants with Type 2 Diabetes Inadequately Controlled with Metformin (NCT06045221)". It is scheduled to be completed in September 2025 [7]. The other is a Phase 3 trial in patients with obesity, overweight, and non-type 2 diabetes, including those with severe complications. The study is titled "A Study of orforglipron (LY3502970) in Participants with Obesity or Overweight and at Least One Weight-Related Comorbidity (NCT06972459)." The study will last approximately 18 months.

For basic information, orforglipron is characteristic for its small-molecule, and partial GLP-1RA affecting the activity of cAMP [8] (Figure 1). It was developed as a brand-new obesity agent that was more effective beyond Ozempic [9]. As latest report, a systematic review was summarized for pharmacotherapy for obesity. Among them, Orforglipron is effective GLP-1RA and evaluated as its effectiveness and economic benefit [10].

Figure 1: Molecular Construction of Orforglipron.

There have been 14 ongoing phase 3 trials on GLP-1RAs for orforglipron, ecnoglutide and TG103, GLP-1 RA/amylin agonist for CagriSema, GLP-1/glucagon RAs for survodutide and mazdutide, GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA for retatrutide, dapagliflozin and the combination of sibutramine/topiramate [10]. From previous data, phase 2 trials on incretin-based treatment were completed, in which mean weight reduction showed 7.4% to 24.2%. Eli Lilly and Company has been conducting phase 3 studies on orforglipron. The applicants include the patients with T2D and continuing weight management with at least 1 weight-related medical issue. In addition, possible treatment has been evaluated for obstructive sleep apnea (OSA) and hypertension among cases with obesity [11].  From medical market point of view, orforglipron will be probable less expensive than Ozempic (Novo Nordisk) or dulaglutide (currently available injectable GLP-1 drugs like semaglutide [12]. 

Consequently, Orforglipron has the potential to become a breakthrough drug with efficacy comparable to injectable GLP 1 drugs [13].  It will mainly apply for cases of diabetes and obesity [14]. Furthermore, it may offer broader applicability and lower cost in future medical practice.

The authors declare no conflict of interest.

Funding

There was no funding received for this paper.

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