[Translation] Master protocol to evaluate the efficacy and safety of once-daily orforglipron in obese or overweight participants with obstructive sleep apnea: a randomized, double-blind, placebo-controlled trial (ATTAIN-OSA)

本研究的目的是评估试验药物在两组（接受PAP治疗和不愿意或者不能使用PAP治疗）肥胖或超重合并阻塞性睡眠呼吸暂停的患者中的有效性和安全性

[Translation]

The purpose of this study was to evaluate the efficacy and safety of the investigational drug in two groups of obese or overweight patients with obstructive sleep apnea (those who received PAP therapy and those who were unwilling or unable to use PAP therapy).

Start Date24 Dec 2024

Sponsor / Collaborator

Eli Lilly Suzhou Pharmaceutical Co. Ltd.

[+2]

NCT06692348

/ RecruitingPhase 1

A Phase 1, Open-Label, Multiple-Dose Study to Investigate the Comparability of the Pharmacokinetics of Orforglipron (LY3502970) Single Capsule and Multiple Capsules in Healthy Participants

The main purpose of this study is to assess and compare a single capsule and multiple capsules of Orforglipron based on the amount that gets into the blood stream and how long it takes the body to get rid of it, when given to healthy participants under fasted and fed conditions. How the body handles and eliminates the study drug after meals and on an empty stomach will be measured. Information about any adverse effects experienced will be collected and the safety and tolerability of Orforglipron will also be evaluated. The study will last approximately 21 weeks, including a screening period.

Start Date13 Dec 2024

Sponsor / Collaborator

Eli Lilly & Co.

NCT06704763

/ Not yet recruitingPhase 1

A Drug-Drug Interaction, Single-arm, Open-label Study to Assess the Effect of Quinidine on the Pharmacokinetics of Orforglipron in Healthy Participants

The purpose of this study is to determine the effect of quinidine on the levels of orforglipron in the blood stream and how long it takes the body to eliminate it, when administered orally in healthy participants.
The study will last up to approximately 8 weeks including screening.

Start Date01 Dec 2024

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with Orforglipron

100 Translational Medicine associated with Orforglipron

100 Patents (Medical) associated with Orforglipron

Literatures (Medical) associated with Orforglipron

01 Jan 2025·PHARMACOLOGICAL REVIEWS

Emerging pharmacotherapies for obesity: A systematic review

Article

Author: Al Rifai, Jana ; Valenzuela-Vallejo, Laura ; Rhayem, Caline ; Kokkorakis, Michail ; Mantzoros, Christos S. ; Mantzoros, Christos S ; Chakhtoura, Marlene ; Ghezzawi, Malak

The history of anti-obesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging anti-obesity drugs or combinations thereof and four withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide, survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4-24.2%. Almost half of the drugs undergoing phase 2 trials were incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on under-represented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. Significance Statement Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium. However, emerging alternatives of novel agents and combinations populate the obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.

18 Dec 2024·Science Translational Medicine

The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron

Article

Author: Willard, Francis S. ; Suter, Todd M. ; Emmerson, Paul J. ; Padgett, Leah R. ; O’Farrell, Libbey S. ; White, Alex ; Hewitt, Natalie ; Peterson, Jeffrey A. ; Sangwung, Panjamaporn ; Liu, Zhaomin ; Wainscott, David B. ; Coskun, Tamer ; Ruble, J. Craig ; Cox, Amy L. ; Sloop, Kyle W. ; Showalter, Aaron D. ; Snider, Brandy M. ; Dunbar, James D. ; Stutsman, Cynthia ; Coutant, David E. ; Woerly, Eric M. ; Ai, Minrong ; Droz, Brian A.

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [ 125 I]GLP-1(7-36)NH 2 or [ 3 H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant ( Ki ) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor Ki value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R ( Glp1r S33W ) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in Glp1r S33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.

01 Dec 2024·METABOLISM-CLINICAL AND EXPERIMENTAL

Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials

Review

Author: Li, Mengting ; Cao, Weiling ; Zheng, Guimei ; Xie, Zeyu ; Deng, Weishang ; Liang, Zhuoru

PURPOSE:

This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis.

METHODS:

Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software.

RESULTS:

Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (-22.10 % in body weight and - 17.00 cm in waist circumference), retatrutide 8 mg (-20.70 % and - 15.90 cm), and tirzepatide 15 mg (-16.53 % and - 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable.

CONCLUSION:

Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.

News (Medical) associated with Orforglipron

15 Jan 2025

·medcitynews.com

At JPM, Eli Lilly’s CEO Explains Why Mounjaro, Zepbound Sales Were Lower Than Expected - MedCity News

Only in the crazy sector of metabolic medicines can 32% revenue growth be considered a disappointment. That’s how much Eli Lilly’s revenue grew in 2024, but it was still not as much as the company or investors expected, which had CEO David Ricks trying to assuage investors. Lilly on Tuesday revised its revenue guidance for the fourth quarter to about $13.5 billion, which is about $400 million less than the company’s previous revenue projection. The company attributed the revision to lower-than-expected sales of tirzepatide, marketed as Mounjaro for type 2 diabetes and Zepbound for obesity. “It’s always disappointing to miss your own expectations,” Ricks said during a presentation Tuesday at the annual J.P. Morgan Healthcare Conference in San Francisco. “We own that, it’s our job to give good guidance to the street, and we aim to land within that guidance normally. That said, we’re dealing with a business year that is pretty unprecedented in our sector, in terms of size, and scale and growth rate.” presented by Sponsored Post 3D Medical Animation Services: A Revolution in Healthcare Education and Marketing 3D medical animation services have emerged as a groundbreaking tool in the healthcare industry, revolutionizing the way medical concepts are taught, understood, and marketed. By Start Grid The Lilly metabolic medicines are still tremendous drivers of revenue. The company expects Mounjaro will tally about $3.5 billion in sales for the fourth quarter of 2024 while Zepbound revenue will be about $1.9 billion. The company’s previous fourth quarter revenue guidance was based on expectations of faster revenue growth for the period. Ricks cited several reasons for the lower-than-expected sales of the incretin mimetics, engineered peptides that work by mimicking gut hormones. December sales usually outperform the rest of the fourth quarter. That did not happen last month for Mounjaro and Zepbound. Ricks said the difference could be changes in Medicare Part D and insurance, keeping patients from doing two prescriptions in the same month. The company also had lower-than-expected amount of the drugs in stock at the end of the year. Ricks dismissed suggestions that the missed guidance indicates a slowdown in adoption of the metabolic medicines. “We think we’re in the early innings of this,” he said. “There is limits on demand for each category. I think the incretin story, the tirzepatide story, is going to be about unlocking new categories over and over again.” Beyond revenue growth in diabetes and obesity, Lilly’s strategy includes expanding use of tirzepatide to other indications. In late December, the FDA approved Zepbound as a treatment for obstructive sleep apnea, which represents another potential blockbuster market. Lilly is also studying tirzepatide in cardiovascular indications and the fatty liver disease MASH. Sponsored Post The Funding Model for Cancer Innovation is Broken — We Can Fix It Closing cancer health equity gaps require medical breakthroughs made possible by new funding approaches. By Eve McDavid - CEO of Mission-Driven Tech Leerink Partners analyst David Risinger said in a research note that despite the second straight quarter of lower-than-expected revenue figures, he expects Lilly’s 2025 financial performance and pipeline news — specifically the Phase 3 results for oral GLP-1 drug orforglipron — will be encouraging.

Phase 3Drug Approval

14 Jan 2025

·endpts.com

Eli Lilly misses 2024 revenue expectations, stock dips 7%

Eli Lilly expects to miss its recent revenue estimate for 2024 by about $400 million, according to a preliminary report. The company’s estimates have varied widely this year. Lilly raised its 2024 revenue projections multiple times before tempering those expectations in the third quarter. Now executives are saying the actual figure will be around $45 billion, which is $400 million below the low end of its third-quarter projection, but still above the midpoint of its first-time estimate. Investors sent Lilly’s stock $LLY down 7% on Tuesday afternoon, following the announcement . David Risinger, an analyst with the investment bank Leerink Partners, said in a note to investors that this is the “second quarter in a row of disappointing results” for Lilly. However, he added that the company’s financial and R&D prospects in 2025 and beyond are “encouraging,” specifically Lilly’s Phase 3 oral GLP-1 candidate for weight loss and diabetes, orforglipron. Lilly anticipates 2025 sales to come in between $58 billion and $61 billion. Lilly CEO David Ricks cited “lower-than-expected channel inventory” as a continuing challenge that contributed to lower-than-expected fourth-quarter sales. In the first half of the year, when supply was tight for incretin products such as Lilly’s blockbuster Zepbound and Mounjaro, wholesalers kept higher levels of inventory “to manage uncertainty,” a Lilly spokesperson told Endpoints News . As supply improved and became more reliable, wholesalers ended the year with less inventory than Lilly expected. “We’re growing a pharmaceutical product at a rate and a scale that really is new for us and new for the industry,” Ricks said in a Tuesday interview with CNBC. “We’re going to get some things wrong, and we have. We saw de-stocking in the channel in the second half. We’ve put that into our forward outlook.” Nonetheless, Ricks touted “robust sales growth” for both Zepbound and Mounjaro in Lilly’s announcement on Tuesday. He said in the CNBC interview that Lilly is now the market leader for new patients starting on diabetes and weight loss products, adding that the company is in a “good position on supply.” “We finished the fourth quarter with every dose in stock and available the whole time,” he said. Lilly recently resolved its shortage of tirzepatide, though it continues to fight compounders producing their own, often cheaper, versions of GLP-1 drugs. In its Tuesday announcement, Lilly said it plans to add manufacturing capacity to produce “at least 60% more salable doses of incretins in the first half of the year” compared to the same period in 2024.

Phase 3

03 Jan 2025

·endpts.com

After CagriSema, eyes are on Lilly’s oral GLP-1 as next key obesity play

With the disappointment of Novo Nordisk’s injected CagriSema in obesity at the end of 2024, there are questions around how much more injected next-gen weight loss drugs can deliver above what’s already in the market. Consequently, there is heightened anticipation around oral products. And Eli Lilly, Novo’s main rival, has a major late-stage trial readout coming up. Lilly’s orforglipron, a GLP-1 agonist, is in various Phase 3 trials in patients with type 2 diabetes, obesity and both. But one study in patients with obesity but not diabetes, dubbed ATTAIN-1, will be watched particularly closely when data come in the second half of 2025. It is clear what the drug will have to achieve. Novo already has an oral GLP-1 on the market — Rybelsus, a once-daily pill formulation of semaglutide — though it’s only for diabetes so far. In its first Phase 3 trial in obesity, Rybelsus cut patients’ body weight by 15.1% after 68 weeks versus 2.4% with placebo. Following the release of these data in mid-2023, Novo said it would wait for results from another late-stage obesity trial before seeking approval for oral semaglutide in the condition. And those data arrived at the ObesityWeek meeting in November, with the pill allowing an average weight loss of 13.6% at 64 weeks compared with 2.2% for placebo. Novo has not said whether it has yet to file oral semaglutide for obesity. Whether orforglipron can exceed these two benchmarks when ATTAIN-1 reports its 72-week data later in 2025 remains to be seen. In the drug’s Phase 2 obesity trial, patients taking the highest dose at 45 mg once daily lost 14.7% of their weight, against 2.3% with placebo. But this was at 36 weeks, and if the effect deepens over time, it is possible that orforglipron could outdo oral semaglutide. Lilly has never explicitly said why it opted to develop an oral GLP-1 product over an oral form of tirzepatide, the subcutaneous blockbuster GIP/GLP-1 agonist sold as Zepbound for obesity. It is possible that the higher dose required for oral delivery could mean unmanageable side effects. Other possible explanations could be a simpler or cheaper manufacturing process for orforglipron than tirzepatide. The orforglipron readout will affect another company, too. The drug was licensed from Roche’s subsidiary Chugai, so the Swiss giant — which has a separate oral obesity candidate in early trials — could also see a return if orforglipron succeeds.

Phase 3Phase 2Clinical Result

100 Deals associated with Orforglipron

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Sleep Apnea, Obstructive	Phase 3	US	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	CN	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	JP	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	AR	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	BR	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	CZ	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	DE	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	IN	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	MX	Eli Lilly & Co.	22 Oct 2024
Sleep Apnea, Obstructive	Phase 3	TW	Eli Lilly & Co.	22 Oct 2024

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05051579 (EASD2023)	Phase 2	Overweight \| Obesity	272	Orforglipron (OFG) 12 mg	vobfccrekt(waliildfzc) = rpfuwqycqy szkulfgvii (bplvwnonzb ) View more	Positive	03 Oct 2023
				Orforglipron (OFG) 24 mg	vobfccrekt(waliildfzc) = neprlipgqb szkulfgvii (bplvwnonzb ) View more
NCT05051579 (GZGI, CTgov)	Phase 2	Obesity	272	LY3502970 (24 mg LY3502970)	xzykecljai(jsavjbvrfo) = hwvtairlny femzagjgho (mlrtfyhmsq, ewembiadpc - pxjrhcxlje) View more	-	13 Sep 2023
				Placebo (Placebo)	xzykecljai(jsavjbvrfo) = jjdkmhjtvm femzagjgho (mlrtfyhmsq, ytzarwkuae - fhnpbmmukk) View more
NCT05048719 (ADA 12023 \| ADA 22023) Manual	Phase 2	Diabetes Mellitus, Type 2	383	Orforglipron 3 mg	gtkbsunije(lamluvswmy) = jqrddxabbt vwmjepinen (obbnhudtzr ) View more	Positive	25 Jun 2023
				Orforglipron 12 mg	gtkbsunije(lamluvswmy) = aylzggekcl vwmjepinen (obbnhudtzr ) View more
NCT05048719 (Literature \| Pubmed \| Lancet) Manual	Phase 2	Diabetes Mellitus, Type 2	303	orforglipron	sncznqukbm(yramtlhqak) = rvfamnrwte rdpwaqfjwp (beakaxfpfv ) View more	Positive	23 Jun 2023
				Dulaglutide	sncznqukbm(yramtlhqak) = jzjiutoojx rdpwaqfjwp (beakaxfpfv ) View more
NCT05051579 (ADA 12023 \| ADA 22023) Manual	Phase 2	Overweight \| Obesity	272	Orforglipron 12 mg	fatmxmlpuj(uvkebimtrr) = twzplbjxxy mwhlhklmtx (oktqckeucb ) View more	Positive	23 Jun 2023
				Orforglipron 24 mg	fatmxmlpuj(uvkebimtrr) = lsrmyctjyi mwhlhklmtx (oktqckeucb ) View more
NCT05051579 (GZGI, Pubmed)	Phase 2	Obesity	272	Orforglipron 12 mg	zsireefjnv(kbuezblxpr) = iwcjgirkop coonmcirkd (elanyyezon )	-	23 Jun 2023
				Orforglipron 24 mg	zsireefjnv(kbuezblxpr) = vedgymrvxr coonmcirkd (elanyyezon )
ADA 12023 \| ADA 22023 Manual	Phase 1	-	46	Orforglipron 3mg (fasted)	gpzgsmhakr(lxjzgpvepq) = srngkitlxr glckmuhmui (ubjiiiiisb ) View more	Positive	20 Jun 2023
				Orforglipron 3mg (fed)	gpzgsmhakr(lxjzgpvepq) = olaeffsksq glckmuhmui (ubjiiiiisb ) View more
NCT04426474 (NEWS) Manual	Phase 1	Diabetes Mellitus, Type 2	68	LY3502970	heytbykrji(trguxiiwri) = vphymtcpkx gmkqzwaqpj (tjoqcclnby ) View more	Positive	13 Oct 2022
				Placebo	ysowqszewh(nzoxormmvq) = tdodxcpfnv cgvwlbksgl (iteuicpayt ) View more
NCT04426474 (EASD2022)	Phase 1	Diabetes Mellitus, Type 2 HbA1c	51	LY3502970	yoztkwapje(xowhxutang) = One patient reported 2 severe gastrointestinal events (1 each of nausea and vomiting); all other events were mild or moderate hlcvgxldql (ssxcnuzlmu )	Positive	20 Sep 2022
				Placebo
NCT03929744 (ADA2022)	Phase 1	-	133	LY3502970	mjewiactza(tkzebtzmzl) = occurring in ≥3 subjects vlammlincb (hhsgcgafww ) View more	-	01 Jun 2022

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