05/08/2025
Originally published by HealthTech World.
In a major development for weight management drugs, Eli Lilly recently announced the successful completion of a Phase III clinical trial for orforglipron, a daily oral pill that could rival popular injectable drugs such as Ozempic and Wegovy.
Unlike these well-known treatments, orforglipron is a non-peptide small molecule. This is a key difference that could significantly expand access to obesity and diabetes care.
But how exactly does orforglipron work, and what sets it apart from its predecessors?
A familiar mechanism with a new twist
Orforglipron belongs to the class of drugs known as GLP-1 receptor agonists, the same class as semaglutide (active ingredient of Ozempic and Wegovy) and tirzepatide (active ingredient of Mounjaro and Zepbound). These drugs mimic the action of glucagon-like peptide-1 (GLP-1), a hormone that regulates blood sugar, by:
- Stimulating insulin secretion from pancreatic beta cells,
- Suppressing glucagon release, which lowers glucose production in the liver, and
- Slowing gastric emptying, promoting feelings of fullness and reducing appetite.
However, while semaglutide and tirzepatide are peptides, which must be injected, orforglipron is a non-peptide small molecule. This allows it to be formulated as a pill, making daily administration easier, more discreet, and potentially more accessible to a broader population.
The cost advantage of a pill
Peptide-based drugs are expensive and complex to manufacture, contributing to high price tags; Wegovy and Mounjaro cost patients over $1,000 per month in the US. They are also prone to supply shortages, which have limited access for patients.
In contrast, orforglipron’s non-peptide structure allows for simpler production and packaging, making it easier to scale. Whilst its list price hasn’t been set, it is expected to be significantly more affordable, potentially disrupting the current market dominated by injectables.
Clinical trial results
In Eli Lilly’s Phase III trial, more than 500 people with type 2 diabetes were studied over a period of 10 months. Participants receiving the highest dose of orforglipron lost an average of nearly 8% of their body weight; a result comparable to Wegovy over the same period.
Unlike injectable GLP-1 agonists, orforglipron can be taken at any time of day, without restrictions related to food or water—removing a significant barrier to daily compliance.
Not the first GLP-1 RA pill, but the first non-peptide one
Orforglipron is not the first GLP-1 receptor agonist pill. Rybelsus, developed by Novo Nordisk, is an oral GLP‑1 receptor agonist, and was approved by the FDA in 2019 for type 2 diabetes. It is peptide-based (semaglutide), which normally would degrade in the stomach, but Rybelsus uses an absorption enhancer (SNAC) to allow it to be taken orally.
However, it requires strict timing on an empty stomach with water only, and it delivers modest weight loss (3-5%) compared to injectables.
Orforglipron, on the other hand, appears to maintain high efficacy while avoiding the need for injection or high-dose administration.
Orforglipron is the first small molecule GLP‑1 receptor agonist to clear Phase III, placing it ahead of other oral candidates under development. Rivals like Pfizer’s danuglipron and lotiglipron either ran into toxicity issues (lotiglipron) or have not yet progressed to Phase III trials (danuglipron).
Patent protection and competitive landscape
Eli Lilly holds several patents covering orforglipron, covering the treatment of obesity, type 2 diabetes, and weight-related comorbidities through defined oral dosing regimens.
The first core compound patent for orforglipron— US20190225604A1—was filed in 2018. This means orforglipron is expected to remain under brand exclusivity well into the late 2030s, with likely market entry for generics or biosimilars not before 2038-2040, depending on regulatory data protection rights and patent term extensions. Additionally, it is likely that there will be a range of secondary patents, for example relating to different forms of the compound, medical uses and dosages, that effectively extend exclusivity beyond the initial 20 year patent term afforded by the initial compound patent.
Although companies like AstraZeneca, Structure Therapeutics, Viking Therapeutics, Roche, and Regor Therapeutics are developing similar oral GLP-1 candidates, orforglipron is the most advanced, placing Eli Lilly in a strong position to dominate the oral category initially.
What does this mean for Ozempic, Wegovy, and others?
Even with orforglipron’s introduction, existing injectable drugs like Ozempic, Wegovy, Mounjaro, and Zepbound are unlikely to lose relevance. Many patients prefer weekly injections over daily pills, particularly those who are already comfortable with their current regimens.
However, orforglipron is expected to expand the market by appealing to people who are injection-averse or looking for a more affordable alternative. As weight-loss treatments become increasingly mainstream, the availability of an effective oral option could help normalise and democratise access. Improved patient compliance and lower costs could also make such treatments especially appealing to the NHS and other centralised healthcare systems, which may well drive initial sales.
This article is for general information only. Its content is not a statement of the law on any subject and does not constitute advice. Please contact Reddie & Grose LLP for advice before taking any action in reliance on it.
