A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE STUDY TO EVALUATE THE PHARMACOKINETIC INTERACTIONS BETWEEN PF-07976016 AND PF-06882961 IN OTHERWISE HEALTHY ADULT PARTICIPANTS WITH OVERWEIGHT OR OBESITY

The purpose of this study is to see how two study medicines, PF-07976016 and danuglipron, taken together affect the level of each other in the blood of participants who have overweight or obesity.
The total number of weeks of the study is up to approximately 22 weeks (5.5 months).

Start Date13 Mar 2025

Sponsor / Collaborator

Pfizer Inc.

NCT06541678

/ Active, not recruitingPhase 1

A Phase 1, Open-Label, Fixed-Sequence Study to Evaluate the Effect of Itraconazole and Cyclosporine on the Single-Dose Pharmacokinetics of Danuglipron in Healthy Adult Participants

The purpose of this study is to see how single dose of cyclosporine and multiple doses of itraconazole affect the level of the study medicine danuglipron in the blood of healthy adult participants. The information from this study may inform how danuglipron will be used in the future with medicines like cyclosporine and itraconazole.

Start Date23 Dec 2024

Sponsor / Collaborator

Pfizer Inc.

NCT06567327

/ Active, not recruitingPhase 1

A Two-Part Phase 1, Open-Label, Fixed-Sequence Study to Evaluate the Multiple Dose Pharmacokinetics of Danuglipron Following Oral Administration and The Effects of Steady-State Danuglipron on the Pharmacokinetics of Single Oral Dose of Atorvastatin and Rosuvastatin in Otherwise Healthy Adult Participants With Overweight or Obesity

The purpose of this study is to learn the following about the study medicine, danuglipron, after multiple days of dosing in healthy adults who are overweight or obese:
* how the study medicine, danuglipron, is taken up into the blood
* if the study medicine, danuglipron, changes how the body processes other study medicines (Atorvastatin and Rosuvastatin)
* about the safety and tolerability of danuglipron
The study will take place in 4 Cohorts (groups). The total number of weeks of the study is about 23 (about 6 months) for Cohort 1 and 22 weeks (about 5.5 months) for Cohort 2, 21 weeks (about 5 months) for Cohort 3 and 20 weeks (about 5 months) for Cohort 4.

Start Date28 Aug 2024

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with Danuglipron

100 Translational Medicine associated with Danuglipron

100 Patents (Medical) associated with Danuglipron

Literatures (Medical) associated with Danuglipron

03 May 2025·Journal of biomolecular structure & dynamics

Discovery of non-peptide GLP-1r natural agonists for enhancing coronary safety in type 2 diabetes patients

Article

Author: Iranshahi, Mehrdad ; Azimi, Sabikeh G. ; Sadeghi-Aliabadi, Hojjat ; Hadizadeh, Farzin ; Rajabian, Fatemeh ; Shakour, Neda ; Hoseinpoor, Saeideh

This study explores the computational discovery of non-peptide agonists targeting the Glucagon-Like Peptide-1 Receptor (GLP-1R) to enhance the safety of major coronary outcomes in individuals affected by Type 2 Diabetes. The objective is to identify novel compounds that can activate the GLP-1R pathway without the limitations associated with peptide agonists. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) and mortality, which is attributed to the accumulation of fat in organs, including the heart. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are frequently used to manage T2DM and could potentially offer cardiovascular benefits. Therefore, this study examines non-peptide agonists of GLP-1R to improve coronary safety in type 2 diabetes patients. After rigorous assessments, two standout candidates were identified, with natural compound 12 emerging as the most promising. This study represents a notable advancement in enhancing the management of coronary outcomes among individuals with type 2 diabetes. The computational methodology employed successfully pinpointed potential GLP-1R natural agonists, providing optimism for the development of safer and more effective therapeutic interventions. Although computational methodologies have provided crucial insights, realizing the full potential of these compounds requires extensive experimental investigations, crucial in advancing therapeutic strategies for this critical patient population.

10 Apr 2025·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of New Difluorocyclobutyl Derivatives as Effective Glucagon-Like Peptide-1 Receptor Agonists with Reduced hERG Inhibitory Activities

Article

Author: Zhang, Jinzhu ; Wang, Jianghai ; Shao, Shuai ; Zhong, Yongqing ; Wang, Guojian ; Huang, Yun ; Tang, Xinyi ; Ma, Zhongjun ; Ding, Wanjing ; Lou, Jinfang ; Li, Yuanyuan ; Miao, Lei ; Xu, Sicong ; Lei, Shaowei

Danuglipron (PF-06882961), a small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) developed by Pfizer, has shown significant potential to reduce blood glucose levels and weight in patients with type 2 diabetes mellitus. However, it has moderate hERG inhibitory activities (IC₅₀ = 4.3 μM), potentially conferring a risk for cardiac toxicity. Here, we report a new class of difluorocyclobutyl derivatives that can be used to reduce the potential hERG inhibition caused by the piperidine ring of danuglipron. After in vitro and in vivo screening, compound 73 was found to be the most potent GLP-1R agonist, with an EC₅₀ of 0.048 nM. Furthermore, compound 73 showed preferable absorption and excellent β-arrestin pathway selectivity compared with danuglipron. In the glucose tolerance test, compound 73 effectively inhibited elevated blood glucose levels. These results indicate that compound 73 is a promising GLP-1R agonist.

01 Mar 2025·JOURNAL OF CELLULAR AND MOLECULAR MEDICINE

Danuglipron Ameliorates Pressure Overload‐Induced Cardiac Remodelling Through the AMPK Pathway

Article

Author: Zhang, Xin‐Ru ; Yang, Zheng ; Ma, Yu‐Lan ; Wang, Ming‐Yu ; Kong, Chun‐Yan ; Guo, Zhen ; Wang, Pan

ABSTRACT:

Cardiac remodelling, a pathological process induced by various cardiovascular diseases, remains a significant challenge in clinical practice. Here, we investigate the potential of Danuglipron (PF‐06882961, PF), a novel oral glucagon‐like peptide‐1 (GLP‐1) receptor agonist, in alleviating pressure overload (PO)‐induced cardiac hypertrophy and fibrosis. Using both in vivo and in vitro models, we demonstrate that PF treatment (1 mg/kg/day, orally for 8 weeks) significantly attenuates aortic banding‐induced cardiac dysfunction and pathological remodelling in mice. Mechanistically, we show that PF mitigates apoptotic responses and enhances autophagy by promoting AMPK phosphorylation and increasing HSP70 expression. Notably, the cardioprotective effects of PF are abolished in AMPKα2 knockout mice, with no observable increase in HSP70 levels. Our findings reveal a previously unrecognised role of PF in cardiac protection, mediated through the AMPKα‐HSP70 signalling pathway, and suggest its potential as a therapeutic strategy for PO‐induced cardiac remodelling.

News (Medical) associated with Danuglipron

17 Apr 2025

·www.biopharmadive.com

Lilly’s obesity pill scores in large diabetes trial

Dive Brief:Eli Lillys weight loss pill orforglipron succeeded in a Phase 3 clinical trial in diabetes, helping study participants control their blood sugar while hinting at weight loss that might be comparable to injectable obesity medicines. Enrollees in the 40-week trial saw their blood sugar levels reduced by up to 1.6 percentage points, with 65% achieving healthy levels, the company said Thursday. Notably, the drug spurred an average of up to 8% weight loss, or about 16 pounds, at the highest dose, indicating that the effects will be even greater in Lillys longer Phase 3 trial in obesity. Lilly said trial participants had not yet reached a weight plateau when the diabetes study ended.A pill with similar weight loss effects to injectable GLP-1 therapies like Novo Nordisks Wegovy or Lillys own Zepbound could change the dynamics of the lucrative market for obesity drugs. As a small molecule, or chemical, drug, orforglipron would also be easier to manufacture than its injectable counterparts, which have faced production constraints that have limited uptake.Dive Insight:Orforglipron is one of the most closely watched drugs in the pharmaceutical industry. If successful in additional late-stage trials, it could offer people with diabetes or obesity a convenient, oral alternative to injectable therapies and quickly be scaled into mass production.The drug could also give Lilly a bigger share of a market estimated to top $100 billion annually by next decade. Lillys already made significant inroads on that front, with Zepbound outperforming Wegovy in a head-to-head trial. It could further press its top rival with orforglipron, which is expected to produce Phase 3 results in obesity later this year and could be submitted to regulators afterwards. Novo, by comparison, hasnt sought approval in obesity for an oral peptide drug called Rybelsus thats shown it can stimulate weight loss.One of Lillys top competitors, Pfizer, also suffered a significant setback earlier this week, when it abandoned development of a rival pill called danuglipron.The diabetes trial toplined Thursday, Achieve-1, enrolled 559 people with Type 2 diabetes and randomized them to receive one of three daily doses of orforglipron or a placebo. The people in the drug arms started with just a 1 milligram dose of orforglipron and gradually increased to their assigned dose of 3, 12 or 36 milligrams.Blood sugar reductions, from 8% on average at the studys start,were 1.3, 1.6 and 1.5 percentage points respectively in the 3, 12 and 36 mg groups, compared to a 0.1 percentage point reduction in the placebo group. Trial participants, who had a baseline mean body weight of 199 pounds, lost 4.7%, 6.1% and 7.9% of their weight on the three doses, versus 1.6% in those receiving a placebo.Orforglipron was associated with the same gastrointestinal side effects commonly seen with GLP-1 therapies. Notably, though, the rates of such side effects appear to be lower than what Lilly observed in earlier testing, which could be attributed to the gradual dosing increase in the Phase 3 study, wrote Evercore ISI analyst Umer Raffat.Elevated liver enzymes, a sign of possible organ damage, had also been seen in earlier testing. Though Lilly didnt provide specific details, it did say Thursday that no hepatic safety signal was observed.In a separate research note, Leerink Partners analyst David Risinger called the results picture perfect. Though the data are from a shorter trial in diabetes, the drugs safety and efficacy appear comparable to Novos drug, Risinger wrote. Multiple analysts had a similarly positive take, arguing orforglipron could set the standard for oral obesity drugs.The results have implications for others following with such medicines. Structure Therapeutics is developing a small molecule GLP-1 pill, while Viking Therapeutics and Zealand Pharma have peptide counterparts that could be at a disadvantage. And Novo, without a viable oral drug, may start facing tougher competition next year should orforglipron get to market for obesity and diabetes, Jefferies analyst Benjamin Jackson wrote.Lilly shares rose nearly 15% in morning trading, swelling its market value by more than $100 billion. '

Phase 3Clinical Result

17 Apr 2025

·www.pharmaceutical-technology.com

Eli Lilly’s shares up as oral GLP-1RA scores in first Phase III trial

Baqsimi was launched as an option to provide rescue treatment for diabetes patients who take insulin. Credit: Diabetesmagazijn.nl on Unsplash. Eli Lilly’s Phase III trial with its oral weight loss pill, orforglipron, has met its primary endpoint, reducing A1C levels by up to 1.6%. In the first of several readouts expected from a Phase III programme, Lilly said its oral glucagon-like peptide-1 receptor agonist (GLP-1RA) demonstrated significant efficacy while maintaining a safety profile consistent with subcutaneously delivered GLP-1RA drugs. Eli Lilly’s stock jumped up by 13.8% at market open today (17 April). The company has a market cap of $659.93bn. This news comes just days after Pfizer culled its second obesity pill due to a liver injury incident in a patient . The manageable safety profile of Lilly’s drug marks an important development in the field of oral GLP-1RAs . Based on this update and other trials from the programme that are due to read out later this year, Lilly expects to submit an approval application for orforglipron as a weight management treatment to global regulatory agencies by the end of this year, with the submission for the treatment of type 2 diabetes (T2D) anticipated in 2026. If it gains market approval, GlobalData predicts sales of orforglipron to reach $11.8bn in 2030. The global GLP-1RA market is experiencing substantial growth and is projected to reach $125bn by 2033. GlobalData is the parent company of Clinical Trials Arena . Efficacy and safety proven in first study In the randomised, placebo-controlled, double-blind ACHIEVE-1 trial (NCT05971940), the efficacy and safety of three doses – 3mg, 12mg and 36mg – of orforglipron were evaluated in adults with T2D and inadequate glycemic control with diet and exercise alone. The drug reduced A1C levels by an average of 1.3% to 1.6% from a baseline of 8.0% after 40 weeks. It also scored in a key secondary endpoint, with more than 65% of participants taking the highest dose of orforglipron achieving an A1C less than or equal to 6.5%, which is below the American Diabetes Association’s (ADA) defined threshold for diabetes. Finally, there was significant weight loss achieved in the study, with patients losing an average of 16lb (7.9%) in the highest dose cohort. This weight loss had not plateaued, indicating potential further weight loss could be possible with further dosing. Meanwhile, the placebo cohort saw an average weight loss of 3.4lb. In addition to the efficacy, Lilly has also touted that orforglipron’s safety profile in ACHIEVE-1 and said it was consistent with the established GLP-1RA class, with the most commonly reported adverse events (AEs) being gastrointestinal-related and generally mild to moderate in severity. No hepatic safety signal was observed. Treatment discontinuation rates due to AEs were 6% in the low-dose group, 4% in the medium-dose cohort and 8% in the high-dose group compared to 1% with placebo. A Bank of America Securities report said that the four main parameters for assessing orforglipron were weight loss, blood sugar control, tolerability and safety, describing the data for all these as “solid”. This data readout was viewed as a closely watched event, and all eyes are now on Novo Nordisk’s oral GLP-1RA drug Rybelsus, which is approved for T2D, but not for weight management. The report said Rybelsus is a peptide with certain limitations, while orforglipron, being a small-molecule drug, could be easy to scale and produce. Eli Lilly’s CEO David Ricks said: “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. We look forward to additional data readouts later this year.” Lilly states that orforglipron is the first oral small molecule GLP-1RA, taken without food and water restrictions, to successfully complete a Phase III trial. If approved, the company is confident in its ability to launch orforglipron worldwide without supply constraints, something that until recently has plagued the GLP-1RA market . Data is set to be presented at ADA’s 85th Scientific Sessions in June 2025 and published in a peer-reviewed journal. Lilly already a powerhouse in the weight loss space Eli Lilly has already cemented its name in the GLP-1RA space with its subcutaneous therapy, tirzepatide, which is marketed as Mounjaro for T2D and Zepbound for obesity. GlobalData predicts a global sales forecast for tirzepatide of $26.75bn in 2030. Its main competitor in the space currently is Novo Nordisk, which is also a high flier with its GLP-1RA semaglutide, marketed as Ozempic for T2D and Wegovy for weight loss. Other companies are trying to break into the space, including Viking Therapeutics, which is set to initiate trials of VK2735, with the subcutaneous formulation set to enter a Phase III trial in Q2 2025 and the oral version in an ongoing Phase II study (NCT06828055). While Pfizer pulled its oral candidate, danuglipron, from development earlier this week, the company does have another obesity pill – PF-07976016, which is in a Phase IIa trial.

Phase 3Clinical ResultPhase 2Drug Approval

15 Apr 2025

·pipelinereview.com

Pfizer Provides Update on Oral GLP-1 Receptor Agonist Danuglipron

NEW YORK, NY, USA I April 14, 2025 I Pfizer Inc. (NYSE: PFE) today announced the decision to discontinue development of danuglipron (PF-06882961), an oral glucagon-like peptide-1 (GLP-1) receptor agonist, which was being investigated for chronic weight management. Pfizer’s dose-optimization studies of once-daily formulations of danuglipron ( NCT06567327 and NCT06568731 ) met key pharmacokinetic objectives and confirmed a formulation and dose with the potential to deliver a competitive efficacy and tolerability profile in Phase 3 testing, based on earlier studies of twice-daily danuglipron. While the overall frequency of liver enzyme elevations across the over 1,400 participant safety database of danuglipron is in-line with approved agents in the class, a single asymptomatic participant in one of the dose-optimization studies experienced potential drug-induced liver injury which resolved after discontinuation of danuglipron. After a review of the totality of information, including all clinical data generated to date for danuglipron and recent input from regulators, Pfizer has decided to discontinue development of the molecule. “Cardiovascular and metabolic diseases including obesity remain important areas of unmet medical need, and we plan to continue applying our global capabilities to advance a pipeline of investigational treatments that have the potential to fill critical gaps in patient care, including continued development of our oral GIPR antagonist candidate and other earlier obesity programs,” said Chris Boshoff, MD, PhD, Chief Scientific Officer and President, Research and Development at Pfizer. “While we are disappointed to discontinue the development of danuglipron, we remain committed to evaluating and advancing promising programs in an effort to bring innovative new medicines to patients.” Data from the danuglipron clinical development program will be presented at a scientific forum or submitted for publication in a peer-reviewed journal in the future. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com . In addition, to learn more, please visit us on www.Pfizer.com and follow us on X at @Pfizer and @Pfizer News , LinkedIn , YouTube and like us on Facebook at Facebook.com/Pfizer . SOURCE: Pfizer

Phase 3

100 Deals associated with Danuglipron

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KEGG	Wiki	ATC	Drug Bank
D11910	-	-	DB16043

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Phase 2	United States	Pfizer Inc.	06 Jan 2021
Diabetes Mellitus, Type 2	Phase 2	United States	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	Bulgaria	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	Canada	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	Hungary	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	Poland	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	Slovakia	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	South Korea	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	Taiwan Province	Pfizer Inc.	15 Oct 2019
Liver Injury	Phase 1	United States	Pfizer Inc.	30 Dec 2020

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04889157 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	20	Placebo	ayslnftecg = zzodtgdmdy hmypasmfza (gdjnfljwvc, lzqhgpghvs - rwohhwdlpw) View more	-	01 Oct 2024
NCT04616027 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	42	PF-06882961 (Healthy and Normal Renal Function)	ickmavewpi(zfexodutyo) = jqwpgmueui ajcendxulp (hkioiduaqf, 28) View more	-	10 May 2024
				PF-06882961 (T2DM Normal Renal Function)	ickmavewpi(zfexodutyo) = dmouywubor ajcendxulp (hkioiduaqf, 58) View more
NCT04604496 (CTgov)	Phase 1	Liver Injury	24	PF-06882961 (Without Hepatic Impairment)	utnsmuicpo(hcwdcwhgrr) = ispkgbxuce sqaegqqjjx (yiuqagndhn, 50) View more	-	21 Mar 2024
				PF-06882961 (Mild Hepatic Impairment)	utnsmuicpo(hcwdcwhgrr) = kdoplvjidm sqaegqqjjx (yiuqagndhn, 33) View more
NCT04707313 (Corporate Publications) Manual	Phase 2	Obesity	-	Danuglipron	sbvwcxmowr(cpcoggomyy) = cmbatquprr rsikdprggn (rowcxhftie ) View more	Negative	01 Dec 2023
				Placebo	sbvwcxmowr(cpcoggomyy) = lhgbhzkxwj rsikdprggn (rowcxhftie ) View more
NCT04621227 (CTgov)	Phase 1	Obesity	16	Rosuvastatin (Rosuvastatin 10mg (Period 1))	jojyorypfs(awagpoqvol) = fypqjhcpeh prpvfjubnn (pcnpcynolo, 43) View more	-	01 Dec 2023
				Rosuvastatin+PF-06882961 (PF-06882961 120mg BID + Rosuvastatin 10mg (Period 4))	jojyorypfs(awagpoqvol) = cvsgquyoyn prpvfjubnn (pcnpcynolo, 50) View more
NCT04617275 (Pubmed)	Phase 2	Diabetes Mellitus, Type 2	151	Placebo	knhrhcmwfh(chrjgsenqv) = lmogozsmlv yggcrfzwxz (neodefbngo ) View more	-	13 Jun 2023
				Danuglipron low starting dose (5-mg)	knhrhcmwfh(chrjgsenqv) = ldimtaktjc yggcrfzwxz (neodefbngo ) View more
NCT03985293 (Literature) Manual	Phase 2	Diabetes Mellitus, Type 2	411	Danuglipron 2.5 mg	kjteuhsovc(bgoayqmlhk) = ewkcpzoixg ixxmycdqvu (opxhgobjfo, -0.70 to to 0.28) View more	Positive	22 May 2023
				Danuglipron 10 mg	kjteuhsovc(bgoayqmlhk) = udwzbslgpi ixxmycdqvu (opxhgobjfo, -1.11 to to 0.72) View more
NCT03985293 (Pubmed)	Phase 2	Diabetes Mellitus, Type 2	411	Danuglipron 2.5 mg	phrfxxtvco(rsgfcttati) = wgmojapsof lhpotfskph (sfmfvmdner, -1.47 to -0.86) View more	Positive	01 May 2023
				Danuglipron 80 mg	jvkcdluqlq(vmelitdyvr) = lokjovwvyy trlxkugknq (vnjguagwmy, -3.01 to -1.07)
NCT04617275 (CTgov)	Phase 2	Diabetes Mellitus, Type 2 \| Obesity	151	Placebo (Placebo (T2DM))	yrlkyuretf = krvubrtwbh iazpmfaszu (sfkvdrcwja, pexqrgecfr - hfiqfecydm) View more	-	08 Dec 2022
				PF-06882961 (PF-06882961 80 mg BID Low, Slow (T2DM))	yrlkyuretf = shfmptgalo iazpmfaszu (sfkvdrcwja, almprdxsmb - mablzkmupb) View more
NCT04552470 (Pubmed) Manual	Phase 1	Diabetes Mellitus, Type 2	37	danuglipron	uszasfslli(qkqpsiprpr) = Most treatment-emergent adverse events were of mild or moderate intensity. dqsksewxqu (bpffexxunw )	Positive	26 Nov 2022
				Placebo

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