orforglipron
{{Short description|Experimental drug for weight loss}}
{{Use American English|date=April 2025}}
{{Use mdy dates|date=April 2025}}
{{cs1 config|name-list-style=vanc|display-authors=3}}
{{infobox drug
| drug_name = Orforglipron
| image = Orforglipron.svg
| width = 280
| caption = Above: molecular structure of orforglipron
Below: 3D representation of an orforglipron molecule
| image2 = Orforglipron 3D.png
| routes_of_administration = Oral
| legal_UK =
| legal_US =
| legal_DE =
| C = 48
| H = 48
| F = 2
| N = 10
| O = 5
| IUPAC_name = 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
| elimination_half-life = 29–49 hours
| CAS_number = 2212020-52-3
| ChemSpiderID = 71117507
| ATC_prefix = None
| PubChem = 137319706
| UNII = 7ZW40D021M
| ChEMBL = 4446782
| synonyms = LY-3502970
| smiles = C[C@H]1C[C@]1(C2=NOC(=O)N2)N3C4=C(C=C(C=C4)[C@H]5CCOC(C5)(C)C)C=C3C(=O)N6CCC7=NN(C(=C7[C@@H]6C)N8C=CN(C8=O)C9=C(C1=C(C=C9)N(N=C1)C)F)C1=CC(=C(C(=C1)C)F)C
| StdInChI = 1S/C48H48F2N10O5/c1-25-18-32(19-26(2)40(25)49)60-42(58-16-15-57(46(58)63)37-11-10-36-33(41(37)50)24-51-55(36)7)39-28(4)56(14-12-34(39)53-60)43(61)38-21-31-20-29(30-13-17-64-47(5,6)23-30)8-9-35(31)59(38)48(22-27(48)3)44-52-45(62)65-54-44/h8-11,15-16,18-21,24,27-28,30H,12-14,17,22-23H2,1-7H3,(H,52,54,62)/t27-,28-,30-,48-/m0/s1
| StdInChIKey = USUWIEBBBWHKNI-KHIFEHGGSA-N
}}
Orforglipron (LY-3502970) is an oral, non-peptide, small-molecule GLP-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company.{{cite press release|url=https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically |title=Lilly's oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial|publisher=Eli Lilly|date=April 17, 2025|access-date=April 18, 2025}} It was discovered by Chugai Pharmaceutical Co., then was licensed to Lilly in 2018.
Orforglipron is easier to produce than existing peptide GLP-1 agonists and is expected to be cheaper.{{cite journal |last1=Sidik |first1=Saima |title=Beyond Ozempic: brand-new obesity drugs will be cheaper and more effective |journal=Nature |date=2023 |volume=619 |issue=7968 |pages=19 |doi=10.1038/d41586-023-02092-9 |pmid=37369789 |bibcode=2023Natur.619...19S |url=https://www.nature.com/articles/d41586-023-02092-9 |language=en|url-access=subscription }}
Mechanism
Orforglipron is a small-molecule, partial GLP-1 receptor agonist affecting the activity of cyclic adenosine monophosphate (cAMP); its effects are similar to the actions of glucagon-like peptide-1 (GLP-1) for reducing food intake and lowering blood glucose levels.{{cite journal |vauthors=Kokkorakis M, Chakhtoura M, Rhayem C, Al Rifai J, Ghezzawi M, Valenzuela-Vallejo L, Mantzoros CS |title=Emerging pharmacotherapies for obesity: A systematic review |journal=Pharmacological Reviews |volume=77 |issue=1 |pages=100002 |date=January 2025 |pmid=39952695 |doi=10.1124/pharmrev.123.001045 |url=https://pharmrev.aspetjournals.org/article/S0031-6997(24)00002-4/fulltext|doi-access=free |url-access=subscription }}
Clinical trials
The results of Phase I safety and Phase II ascending-dose clinical trials enrolling people with obesity or type 2 diabetes were published in 2023.{{cite journal | vauthors = Pratt E, Ma X, Liu R, Robins D, Coskun T, Sloop KW, Haupt A, Benson C | title = 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 | journal = Diabetes, Obesity & Metabolism | date = June 2023 | volume = 25 | issue = 9 | pages = 2642–2649 | doi = 10.1111/dom.15150 | pmid = 37264711 | s2cid = 259022851 | doi-access = free }}{{cite journal | vauthors = Wharton S, Blevins T, Connery L, Rosenstock J, Raha S, Liu R, Ma X, Mather KJ, Haupt A, Robins D, Pratt E, Kazda C, Konig M| title = Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity | journal = The New England Journal of Medicine | date = June 2023 | volume = 389 | issue = 10 | pages = 877–888 | doi = 10.1056/NEJMoa2302392 | pmid = 37351564 }}
Orforglipron has a half-life of 29 to 49 hours across the doses tested and is taken once per day by mouth without food or water restrictions.
Safety and dosing trials showed that the incidence of adverse events in orforglipron-treated participants was 62–89%, mostly from gastrointestinal discomfort (44–70% with orforglipron, 18% with placebo) having mild to moderate severity.{{cite journal |vauthors=Frias J, et al |title=Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study |journal=The Lancet |date=2023 |volume=402 |issue=10400 |page=472–83| url=https://www.sciencedirect.com/science/article/abs/pii/S0140673623013028}} The most common side effects of orforglipon are diarrhea, nausea, upset stomach, and constipation.
The ability of orforglipron to reduce blood sugar levels and body weight was judged favorable compared to dulaglutide.
= Phase III ACHIEVE-1 trial=
In April 2025, results from a Phase III clinical trial involving 559 people with type 2 diabetes who took an oral orforglipron pill, injectable dulaglutide or a placebo daily for 40 weeks showed that orforglipron produced a reduction in blood glucose levels by 1.3 to 1.6 percentage points from a starting level of 8%.{{Cite news |last=Constantino |first=Annika Kim |date=2025-04-17 |title=Eli Lilly's weight loss pill succeeds in first late-stage trial on diabetes patients |url=https://www.cnbc.com/2025/04/17/eli-lilly-weight-loss-pill-orforglipron-clears-first-late-stage-trial.html |access-date=2025-04-17 |work=CNBC |language=en}}
More than 65% of participants taking the highest dose of orforglipron achieved a reduction of hemoglobin A1C level by more than or equal to 1.5 percentage points, bringing them into the non-diabetic range as defined by the American Diabetes Association. People taking the highest dose of the pill lost 8% of their weight, or around {{cvt|16|lb}}, on average after 40 weeks.{{Cite news |last=Kolata |first=Gina |date=2025-04-17 |title=Daily Pill May Work as Well as Ozempic for Weight Loss and Blood Sugar |url=https://www.nytimes.com/2025/04/17/health/pill-glp-1-eli-lilly.html|access-date=2025-04-17 |work=The New York Times |language=en-US |issn=0362-4331}}
Side effects were similar to those seen with other GLP-1 agonists, and no significant liver problems were observed.
See also
References
{{reflist}}
External links
- [https://www.nytimes.com/2025/04/17/health/weight-loss-pill-eli-lilly.html What to Know About Eli Lilly’s Daily Pill for Weight Loss], The New York Times, April 17, 2025
{{Oral hypoglycemics and insulin analogs}}
Category:Experimental anti-obesity drugs