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Orforglipron

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Orforglipron
Clinical data
Other namesLY-3502970
Routes of
administration		Oral
ATC code
  • None
Pharmacokinetic data
Elimination half-life29–49 hours
Identifiers
  • 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
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC48H48F2N10O5
Molar mass882.974 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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
  • Key: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.[1] It was discovered by Chugai Pharmaceutical Co., then was licensed to Lilly in 2018.[1]

Orforglipron is easier to produce than existing peptide GLP-1 agonists and is expected to be cheaper.[2]

Mechanism

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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.[1][3]

Research

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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.[4][5]

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.[3]

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.[6] The most common side effects of orforglipon are diarrhea, nausea, upset stomach, and constipation.[1][6]

The ability of orforglipron to reduce blood sugar levels and body weight was judged favorable compared to dulaglutide.[6]

Phase III ACHIEVE-1 trial

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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%.[1][7]

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.[1] People taking the highest dose of the pill lost 8% of their weight, or around 16 lb (7.3 kg), on average after 40 weeks.[1][8]

Side effects were similar to those seen with other GLP-1 agonists, and no significant liver problems were observed.[1]

See also

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References

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  1. ^ a b c d e f g h "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" (Press release). Eli Lilly. April 17, 2025. Retrieved April 18, 2025.
  2. ^ Sidik S (2023). "Beyond Ozempic: brand-new obesity drugs will be cheaper and more effective". Nature. 619 (7968): 19. Bibcode:2023Natur.619...19S. doi:10.1038/d41586-023-02092-9. PMID 37369789.
  3. ^ a b Kokkorakis M, Chakhtoura M, Rhayem C, et al. (January 2025). "Emerging pharmacotherapies for obesity: A systematic review". Pharmacological Reviews. 77 (1): 100002. doi:10.1124/pharmrev.123.001045. PMID 39952695.
  4. ^ Pratt E, Ma X, Liu R, et al. (June 2023). "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, Obesity & Metabolism. 25 (9): 2642–2649. doi:10.1111/dom.15150. PMID 37264711. S2CID 259022851.
  5. ^ Wharton S, Blevins T, Connery L, et al. (June 2023). "Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity". The New England Journal of Medicine. 389 (10): 877–888. doi:10.1056/NEJMoa2302392. PMID 37351564.
  6. ^ a b c Frias J, et al. (2023). "Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study". The Lancet. 402 (10400): 472-83.
  7. ^ Constantino AK (April 17, 2025). "Eli Lilly's weight loss pill succeeds in first late-stage trial on diabetes patients". CNBC. Retrieved April 17, 2025.
  8. ^ Kolata G (April 17, 2025). "Daily Pill May Work as Well as Ozempic for Weight Loss and Blood Sugar". The New York Times. ISSN 0362-4331. Retrieved April 17, 2025.
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