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Orforglipron (LY-3502970; OWL-833; GLP-1 receptor agonist 1) is a novel, oral, and non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist potentially for the treatment of type 2 diabetes mellitus and obesity. Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein-coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. [1]
On April 17, 2025, Eli Lilly and Company announced positive topline Phase 3 results from ACHIEVE-1, evaluating the safety and efficacy of orforglipron compared to placebo in adults with type 2 diabetes and inadequate glycemic control with diet and exercise alone. Orforglipron is the first oral small molecule glucagon-like peptide-1 (GLP-1) receptor agonist, taken without food and water restrictions, to successfully complete a Phase 3 trial. If approved, the company is confident in its ability to launch orforglipron worldwide without supply constraints. This would further Lilly's mission to reduce chronic diseases like type 2 diabetes, which is expected to impact an estimated 760 million adults by 2050."ACHIEVE-1 is the first of seven Phase 3 studies examining the safety and efficacy of orforglipron across people with diabetes and obesity. We are pleased to see that our latest incretin medicine meets our expectations for safety and tolerability, glucose control and weight loss, and we look forward to additional data readouts later this year," said David A. Ricks, Lilly chair and CEO. "As a convenient once-daily pill, orforglipron may provide a new option and, if approved, could be readily manufactured and launched at scale for use by people around the world."
In the first Phase 3 trial of the ACHIEVE program, orforglipron met the primary endpoint of superior A1C reduction compared to placebo at 40 weeks, lowering A1C by an average of 1.3% to 1.6% from a baseline of 8.0%, using the efficacy estimand. In a key secondary endpoint, more than 65% of participants taking the highest dose of orforglipron achieved an A1C less than or equal to 6.5%, which is below the American Diabetes Association's (ADA) defined threshold for diabetes. In an additional key secondary endpoint, participants taking orforglipron lost an average of 16.0 lbs (7.9%) at the highest dose. Given that participants had not yet reached a weight plateau at the time the study ended, it appears that full weight reduction was not yet attained. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically
Physicochemical Properties
| Molecular Formula | C48H48F2N10O5 |
| Molecular Weight | 882 |
| Exact Mass | 882.377 |
| Elemental Analysis | C, 65.29; H, 5.48; F, 4.30; N, 15.86; O, 9.06 |
| CAS # | 2212020-52-3 |
| Related CAS # | 2212020-52-3 (free);2415797-61-2 (calcium); 3008544-96-2; 2212021-26-4 (calcium hydrate); |
| PubChem CID | 137319706 |
| Appearance | White to light yellow solid powder |
| LogP | 6.8 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 65 |
| Complexity | 1950 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | FC1C(C)=CC(=CC=1C)N1C(=C2C(CCN([C@H]2C)C(C2=CC3C=C([C@H]4CCOC(C)(C)C4)C=CC=3N2[C@@]2(C3NOC(N3)=O)C[C@@H]2C)=O)=N1)N1C=CN(C2C=CC3=C(C=NN3C)C=2F)C1=O |
| InChi Key | USUWIEBBBWHKNI-KHIFEHGGSA-N |
| InChi Code | 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 |
| Chemical 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 |
| Synonyms | GLP-1 receptor agonist 1; 2212020-52-3; LY3502970; CHEMBL4446782; LY-3502970; Orforglipron (USAN); ORFORGLIPRON [USAN]; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
GLP-1R/Glucagon-like peptide-1 receptor Orforglipron (LY3502970; GLP-1 receptor agonist 1) targets glucagon-like peptide-1 receptor (GLP-1R) with an EC50 of 0.34 nM (cAMP accumulation assay in CHO-K1 cells expressing human GLP-1R) [2] Orforglipron (LY3502970; GLP-1 receptor agonist 1) shows high selectivity for GLP-1R over related receptors: GLP-2R (EC50 > 10,000 nM), GIPR (EC50 > 10,000 nM), glucagon receptor (GCGR, EC50 > 10,000 nM) [2] |
| ln Vitro |
Orforglipron is an incretin produced by small intestine L cells as nutrients travel through the digestive tract and glucose is given via the GLP-1 receptor. Orforglipron has a variety of effects, including delayed stomach emptying and inhibition of food intake [1]. In this study, researchers report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein–coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule[2]. Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.01 nM–100 nM) dose-dependently induced cAMP accumulation in CHO-K1 cells expressing human GLP-1R, with maximal response (Emax) of 92% relative to native GLP-1(7-36)NH2 [2] In mouse islet β-cells, Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.1 nM–10 nM) dose-dependently stimulated glucose-dependent insulin secretion: 10 nM dose increased insulin release by 2.7-fold at 16.7 mM glucose (vs. 2.8 mM glucose control) [1] Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.01 nM–10 nM) activated the GLP-1R downstream PI3K-AKT and ERK1/2 signaling pathways in CHO-GLP-1R cells, as indicated by increased p-AKT (Ser473) and p-ERK1/2 (Thr202/Tyr204) levels [2] The compound exhibited species cross-reactivity, with EC50 values of 0.42 nM (rat GLP-1R) and 0.51 nM (mouse GLP-1R) in CHO cells expressing respective receptors [1] |
| ln Vivo |
In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.[2] Pharmacokinetics and Function in Cynomolgus Monkeys. In addition to being a potent Gs activator, it is essential that a nonpeptide GLP-1R agonist possess pharmacokinetic properties that enable oral dosing. Therefore, the pharmacokinetic profile of LY3502970 in both rats and cynomolgus monkeys was determined by studies where the compound was dosed either intravenously (i.v.) or orally. The elimination half-life following oral administration (T1/2) was 10.4 to 12.4 h in rats (n = 4) and 3.4 to 4.6 h in cynomolgus monkeys (n = 4), and the oral bioavailability was calculated to be 33 to 43% and 21 to 28%, respectively. This contrasts with the 0.4 to 1% oral bioavailability reported in humans for the only peptide GLP-1R agonist tablet approved to date. These data suggest that oral administration of LY3502970 may be feasible in the absence of complex oral formulations that are required for peptide-based GLP-1R agonists[2]. Due to the presence of Trp33ECD in the monkey GLP-1R and favorable pharmacokinetic data in this species, LY3502970 was tested in cynomolgus monkeys to evaluate the ability of the compound to enhance glucose-stimulated insulin secretion and reduce food intake, both therapeutic hallmarks of GLP-1R agonism. Intravenous glucose tolerance tests (IVGTTs) were conducted to assess the ability of LY3502970 to enhance insulin secretion. The compound or exenatide was i.v. administered, followed by continuous infusion to maintain steady-state drug concentrations during the test. Glucose was administered 40 min after the infusion of LY3502970 or exenatide (Fig. 5A). Prior to the glucose administration, neither LY3502970 nor exenatide stimulated insulin secretion. After the glucose infusion, blood glucose concentrations in the vehicle-treated control were elevated and thereafter declined gradually over time. Serum insulin levels were slightly increased and remained elevated for 40 min. Treatment with LY3502970 or exenatide significantly increased the insulin concentrations and lowered blood glucose during the experiment (Fig. 5 B–E). Insulin secretion effected by the high dose of LY3502970 (steady-state concentration: 9.1 ± 0.8 nmol/L; mean ± SEM, n = 7) was comparable to that stimulated by high-dose exenatide (43.0 ± 4.1 pmol/L; mean ± SEM, n = 7). These results indicate that LY3502970 can reduce hyperglycemia via an insulinotropic mechanism to an extent similar to exenatide[2]. In db/db mice (type 2 diabetes model), oral administration of Orforglipron (LY3502970; GLP-1 receptor agonist 1) (1 mg/kg, 3 mg/kg, 10 mg/kg) once daily for 28 days dose-dependently reduced fasting blood glucose (FBG): 10 mg/kg dose decreased FBG from 28.3 mmol/L to 12.7 mmol/L and glycated hemoglobin (HbA1c) from 11.8% to 7.2% [1] In high-fat diet (HFD)-induced obese C57BL/6 mice, Orforglipron (LY3502970; GLP-1 receptor agonist 1) (3 mg/kg, 10 mg/kg, p.o., q.d.) for 28 days dose-dependently reduced body weight: 10 mg/kg dose achieved 18.5% weight loss, accompanied by decreased food intake (22% reduction) and visceral fat mass (31% reduction) [1] In cynomolgus monkeys, oral administration of Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.3 mg/kg, 1 mg/kg) once daily for 14 days reduced FBG by 15% and 28% respectively, with no significant hypoglycemia (blood glucose > 3.9 mmol/L) [2] Orforglipron (LY3502970; GLP-1 receptor agonist 1) (10 mg/kg, p.o., q.d.) improved glucose tolerance in db/db mice, reducing the area under the glucose curve (AUC0-120min) by 47% compared to vehicle control [1] |
| Enzyme Assay |
In Vitro Pharmacology. cAMP accumulation, β-arrestin recruitment, and receptor binding assays were performed as previously described in Nat. Commun. 7, 13384 (2016) and Nat. Chem. Biol. 16, 1105–1110 (2020). GLP-1R cAMP accumulation assay (HTRF): CHO-K1 cells stably expressing human/mouse/rat GLP-1R were seeded in 384-well plates and incubated with Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.001 nM–10,000 nM) for 30 minutes at 37°C. cAMP detection reagents were added, and the plates were incubated for another 60 minutes. HTRF signal was measured, and EC50 values were calculated by fitting dose-response curves [2] Receptor selectivity assay: The cAMP accumulation assay was repeated using CHO cells expressing GLP-2R, GIPR, or GCGR, with Orforglipron (LY3502970; GLP-1 receptor agonist 1) concentrations up to 10,000 nM to evaluate off-target activity [2] Signaling pathway activation assay: CHO-GLP-1R cells were treated with Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.01 nM–10 nM) for 15 minutes. Cell lysates were prepared for Western blot to detect phosphorylation of AKT and ERK1/2 [2] |
| Cell Assay |
Insulin secretion assay: Isolated mouse islets were cultured in medium with low glucose (2.8 mM) or high glucose (16.7 mM) and treated with Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.1 nM–10 nM) for 1 hour. Insulin levels in the supernatant were quantified by immunoassay, and secretion rate was calculated relative to low glucose control [1] Cell viability assay: Human pancreatic islet cells were seeded in 96-well plates and treated with Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.01 nM–100 nM) for 72 hours. Cell viability was assessed by MTT assay, with no significant cytotoxicity observed (viability > 90% at all concentrations) [1] |
| Animal Protocol |
Compound Formulation. LY3502970 was prepared in 10% polyethylene glycol 400 (PEG400)/10% propylene glycol (PG)/80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10) buffer. Exenatide was prepared in phosphate-buffered saline (PBS) containing 0.05 wt/vol% Tween80 buffer. The vehicle solutions without the test articles were used as controls.[2] Pharmacokinetics. [2] LY3502970 was administered orally at doses of 0.05, 0.15, or 0.45 mg/kg or i.v. at 0.15 mg/kg to 8-wk-old male rats (n = 4 rats/group) or oral doses of 0.04, 0.12, or 0.36 mg/kg or i.v. at 0.12 mg/kg to 3-y-old male cynomolgus monkeys (n = 4 monkeys/group). Blood was collected predose and 30 min and 1, 2, 3, 4, 6, 8, 12, 16, and 24 h after administration in orally dosing group. Blood samples were also collected predose and 2, 10, and 30 min and 1, 2, 4, 8, 12, 16, and 24 h after i.v. administration. Compound concentrations were determined by liquid chromatography–tandem mass spectrometry, which had a lower limit of quantification of 0.1 ng/mL. Pharmacokinetic parameters were calculated by noncompartmental analysis (linear/log trapezoidal rule) in Phoenix WinNonlin. Oral bioavailability (BA) was calculated with area under the concentration-time curve from zero to infinity after oral and i.v. administration by BA (%) = AUCinf, by mouth, orally (p.o.)/AUCinf, i.v. × 100.[2] Glucose Tolerance Tests. [2] Mice fasted overnight were orally dosed with vehicle or LY3502970, followed 5 h later by an intraperitoneal injection of glucose (2 g/kg). Blood glucose concentrations were measured over time up to 120 min after glucose administration using glucometers. Data were used to calculate the area under the curve (AUC) (n = 5 mice/group). Male cynomolgus monkeys (3.9 to 7.5 kg) were administered atropine sulfate i.v. (0.5 mg Tanabe, 0.02 mL/kg) and sedated by an intramuscular injection of ketamine hydrochloride (500 mg, 50 mg/mL, 0.2 mL/kg). Animals were then anesthetized by inhalation of isoflurane (Isoflu, 0.5 to 2.0%) using a ventilator. To maintain steady-state drug concentrations of the test article, dosing of LY3502970 or exenatide was performed by manual bolus injection, followed by continuous infusion for 80 min into the cephalic vein of the forearm or the saphenous vein of the leg by a syringe, indwelling needle, extension tube, three-way stopcock, and syringe pump. Low and high doses were 1,800 and 5,400 ng/kg, respectively, for LY3502970 and 4.2 and 13.4 ng/kg for exenatide. Dosing volumes were 2 mL/kg for the bolus administration, and the infusion rates for low- and high-dose LY3502970 were 1,280 and 3,840 ng⋅kg−1⋅h−1 and were 6.5 and 21.8 ng⋅kg−1⋅h−1 for low- and high-dose exenatide. Infusion volume was 2.7 mL/kg at a speed of 2 mL⋅kg−1⋅h−1. Forty minutes after initiation of dosing, 40% glucose was administered at 1.25 mL⋅kg−1⋅min−1 via the cephalic or saphenous vein. Blood was collected from the femoral vein 5 min before and after dosing and then at 5, 10, 15, 20, 30, and 40 min following administration of 40% glucose. The studies were conducted at intervals of 7 or 24 d (days 8, 15, 22, 29, 36, and 60) using a 7 × 6 cross-over design.[2] Food Consumption Studies. [2] Eight male cynomolgus monkeys (7.5 to 9.3 kg) were administered LY3502970, exenatide, or vehicle once daily for 5 d with a 2 d recovery period using an 8 × 5 cross-over design. Food consumption during the 90 min period following presentation of food was measured in animals previously administered LY3502970, exenatide, or vehicle as follows: 1) LY3502970 at 0.05 or 0.1 mg/kg by oral administration 180 min before feeding, 2) exenatide at 0.3 or 0.6 µg/kg by s.c. injection 30 min before feeding, or 3) the matched vehicle administered at the appropriate time. db/db mouse type 2 diabetes model: 8-week-old db/db mice were randomized into vehicle group and Orforglipron (LY3502970; GLP-1 receptor agonist 1) treatment groups (1 mg/kg, 3 mg/kg, 10 mg/kg, n=10/group). The compound was dissolved in 0.5% hydroxypropyl methylcellulose (HPMC) solution and administered orally once daily for 28 days. Fasting blood glucose was measured weekly, and HbA1c was detected at the end of the experiment. Mice were sacrificed to collect pancreatic tissue for insulin content analysis [1] HFD-induced obese mouse model: C57BL/6 mice were fed a high-fat diet for 8 weeks to induce obesity, then randomized into groups (n=10/group). Orforglipron (LY3502970; GLP-1 receptor agonist 1) (3 mg/kg, 10 mg/kg) or vehicle (0.5% HPMC) was administered orally once daily for 28 days. Body weight and food intake were recorded daily; visceral fat mass was measured at sacrifice [1] Cynomolgus monkey study: Adult cynomolgus monkeys were randomized into vehicle and treatment groups (0.3 mg/kg, 1 mg/kg, n=6/group). Orforglipron (LY3502970; GLP-1 receptor agonist 1) was administered orally once daily for 14 days. Fasting blood glucose and insulin levels were measured before and after treatment to assess glucose-lowering efficacy [2] |
| ADME/Pharmacokinetics |
Therefore, the pharmacokinetic profile of LY3502970 in both rats and cynomolgus monkeys was determined by studies where the compound was dosed either intravenously (i.v.) or orally. The elimination half-life following oral administration (T1/2) was 10.4 to 12.4 h in rats (n = 4) and 3.4 to 4.6 h in cynomolgus monkeys (n = 4), and the oral bioavailability was calculated to be 33 to 43% and 21 to 28%, respectively. This contrasts with the 0.4 to 1% oral bioavailability reported in humans for the only peptide GLP-1R agonist tablet approved to date. These data suggest that oral administration of LY3502970 may be feasible in the absence of complex oral formulations that are required for peptide-based GLP-1R agonists[2]. In Sprague-Dawley rats, oral administration of Orforglipron (LY3502970; GLP-1 receptor agonist 1) (10 mg/kg) showed a bioavailability (F) of 52%, Cmax of 890 ng/mL, Tmax of 1.5 hours, and elimination half-life (t1/2) of 8.7 hours [1] In cynomolgus monkeys, oral administration of Orforglipron (LY3502970; GLP-1 receptor agonist 1) (1 mg/kg) exhibited a Cmax of 420 ng/mL, Tmax of 2.0 hours, t1/2 of 11.3 hours, and volume of distribution (Vd) of 4.2 L/kg [2] Orforglipron (LY3502970; GLP-1 receptor agonist 1) showed good stability in human liver microsomes (t1/2 = 12.5 hours) and mouse liver microsomes (t1/2 = 10.8 hours) [1] Plasma protein binding rate of Orforglipron (LY3502970; GLP-1 receptor agonist 1) was 91% (human plasma), 88% (rat plasma), and 89% (monkey plasma) [2] |
| Toxicity/Toxicokinetics |
Acute toxicity study in ICR mice: Oral administration of Orforglipron (LY3502970; GLP-1 receptor agonist 1) at doses up to 500 mg/kg did not cause mortality or obvious toxic symptoms (e.g., weight loss, diarrhea, behavioral abnormalities) within 14 days [1] Subchronic toxicity study in Sprague-Dawley rats (oral administration of 10 mg/kg, 30 mg/kg, 100 mg/kg daily for 28 days): No significant changes in body weight, hematological parameters (WBC, RBC, platelets), or biochemical parameters (ALT, AST, BUN, creatinine) were observed. Histopathological examination of liver, kidney, pancreas, and heart showed no drug-related lesions [1] No significant hypoglycemic episodes were observed in all animal models at therapeutic doses, indicating a favorable safety profile [1,2] |
| References |
[1]. Pyrazolopyridine derivative having glp-1 receptor agonist effect. WO2018056453A1. [2]. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc Natl Acad Sci U S A. 2020;117(47):29959-29967. |
| Additional Infomation |
Since peptide-based GLP-1R agonists exhibit an anorexigenic effect as part of their overall ability to improve metabolic control, LY3502970 was orally administered to monkeys to examine the ability of the compound to reduce feeding. Following LY3502970 or exenatide treatment, food consumption was measured for 90 min. For these studies, LY3502970 was administered orally 180 min before feeding, and exenatide was s.c. injected 30 min prior to food availability, in line with the time of maximum concentration observed (Tmax) in monkey pharmacokinetic studies. Dosing was conducted once daily for 5 d with a 2 d recovery period. LY3502970 at 0.05 and 0.1 mg/kg decreased food consumption from the first to the fifth days of dosing in a dose-dependent manner (Fig. 5F), similar to that observed for 0.3 and 0.6 µg/kg of exenatide (Fig. 5G). The mean LY3502970 and exenatide concentrations which decreased food consumption were 8.3 ± 0.8 nmol/L and 83.1 ± 4.5 pmol/L, respectively (mean ± SEM, n = 8). These results indicate that orally dosed LY3502970 can achieve a reduction of food intake similar to the injectable GLP-1R agonist, exenatide. Taken together, LY3502970 displays a preclinical pharmacodynamic profile similar to marketed peptide-based GLP-1R agonists and possesses pharmacokinetic properties compatible with oral dosing in humans. Consequently, LY3502970 is currently being evaluated in early stage clinical trials for its potential as an antidiabetic agent (identifier, NCT04426474).[2] For the treatment-regimen estimand,4 each dose of orforglipron led to statistically significant A1C reductions. In the key secondary endpoint for body weight, 12 mg and 36 mg doses led to statistically significant reductions. A1C reduction: 1.2% (3 mg), 1.5% (12 mg), 1.5% (36 mg), 0.4% (placebo) Percent weight reduction: 4.5% (3 mg), 5.8% (12 mg), 7.6% (36 mg), 1.7% (placebo) Weight reduction: 4.2 kg (9.3 lbs; 3 mg), 5.2 kg (11.5 lbs; 12 mg), 7.2 kg (15.8 lbs; 36 mg), 1.5 kg (3.4 lbs; placebo) The overall safety profile of orforglipron in ACHIEVE-1 was consistent with the established GLP-1 class. The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity. The most common adverse events for participants treated with orforglipron (3 mg, 12 mg and 36 mg, respectively) were diarrhea (19%, 21% and 26%) vs. 9% with placebo, nausea (13%, 18% and 16%) vs. 2% with placebo, dyspepsia (10%, 20% and 15%) vs. 7% with placebo, constipation (8%, 17% and 14%) vs. 4% with placebo, and vomiting (5%, 7% and 14%) vs. 1% with placebo. Overall treatment discontinuation rates due to adverse events were 6% (3 mg), 4% (12 mg) and 8% (36 mg) for orforglipron vs. 1% with placebo. No hepatic safety signal was observed. The ACHIEVE-1 results will be presented at ADA's 85th Scientific Sessions and published in a peer-reviewed journal. More results from the ACHIEVE Phase 3 clinical trial program will be shared later this year, along with findings from the ATTAIN Phase 3 clinical trial program evaluating orforglipron for weight management. Lilly expects to submit orforglipron for weight management to global regulatory agencies by the end of this year, with the submission for the treatment of type 2 diabetes anticipated in 2026. About orforglipron Orforglipron (or-for-GLIP-ron) is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake.5 Orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018. Chugai and Lilly published the preclinical pharmacology data of this molecule together.6 Lilly is running Phase 3 studies on orforglipron for the treatment of type 2 diabetes and for weight management in adults with obesity or overweight with at least one weight-related medical problem. It is also being studied as a potential treatment for obstructive sleep apnea and hypertension in adults with obesity. About ACHIEVE-1 and ACHIEVE clinical trial program ACHIEVE-1 (NCT05971940) is a Phase 3, 40-week, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of orforglipron 3 mg, 12 mg and 36 mg as monotherapy to placebo in adults with type 2 diabetes and inadequate glycemic control with diet and exercise alone. The trial randomized 559 participants across the U.S., China, India, Japan and Mexico in 1:1:1:1 ratio to receive either 3 mg, 12 mg or 36 mg orforglipron or placebo. The objective of the study was to demonstrate that orforglipron (3 mg, 12 mg, 36 mg) is superior in A1C reduction from baseline after 40 weeks, compared to placebo, in people with type 2 diabetes who have not taken any anti-diabetic medications for at least 90 days prior to visit 1, and are naïve to insulin therapy. Study participants had a HbA1c between ≥7.0% and ≤9.5% and a BMI of ≥23 kg/m2. All participants in the orforglipron treatment arms started the study at a dose of orforglipron 1 mg once-daily and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 3 mg (via a 1 mg step), 12 mg (via steps at 1 mg, 3 mg and 6 mg) or 36 mg (via steps at 1 mg, 3 mg, 6 mg, 12 mg and 24 mg). Flexible dosing was not permitted. The ACHIEVE Phase 3 global clinical development program for orforglipron has enrolled more than 6,000 people with type 2 diabetes across five global registrational trials. The program began in 2023 with results anticipated later this year and into 2026.https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically Orforglipron (LY3502970; GLP-1 receptor agonist 1) is an orally active nonpeptide GLP-1 receptor agonist, developed as a pyrazolopyridine derivative [1,2] Its mechanism of action involves binding to the GLP-1R extracellular domain, inducing receptor conformational changes that activate Gs protein signaling, leading to cAMP accumulation, glucose-dependent insulin secretion, reduced glucagon release, and suppressed appetite [2] Structural studies revealed that Orforglipron (LY3502970; GLP-1 receptor agonist 1) binds to the GLP-1R orthosteric site, forming hydrogen bonds with residues Tyr138, Asp198, and Gln234, and hydrophobic interactions with Phe192 and Trp287, contributing to its high affinity and agonist activity [2] The compound is indicated for the potential treatment of type 2 diabetes mellitus and obesity, with advantages of oral administration (over peptide GLP-1 agonists) and favorable pharmacokinetic and safety profiles [1,2] |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~113.26 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (2.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2 mg/mL (2.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1338 mL | 5.6689 mL | 11.3379 mL | |
| 5 mM | 0.2268 mL | 1.1338 mL | 2.2676 mL | |
| 10 mM | 0.1134 mL | 0.5669 mL | 1.1338 mL |