A Phase 1, Open-Label, Randomized Study With A 5-Period, 4-Sequence, Crossover Design to Compare the Single Dose Pharmacokinetics Between Immediate and Modified Release Formulations of Danuglipron Administered Orally to Healthy Adult Participants

The purpose of the study is to learn how different forms of a study medication called danuglipron are taken into the blood in healthy adults.

Start Date27 Nov 2023

Sponsor / Collaborator

Pfizer Inc.

NCT05093205 / CompletedPhase 1

A PHASE 1, OPEN-LABEL, TWO-PART STUDY TO EVALUATE THE EFFECT OF TWO STEADY-STATE DOSE LEVELS OF PF-06882961 ON THE PHARMACOKINETICS OF SINGLE ORAL DOSES OF ATORVASTATIN AND MIDAZOLAM IN HEALTHY ADULTS AND AN ORAL CONTRACEPTIVE IN HEALTHY POST-MENOPAUSAL FEMALES

The purpose of this study is to characterize the effect of PF-06882961, administered at 2 steady-state dose levels, on the PK of single doses of atorvastatin (20 mg) or midazolam (5 mg), administered separately, in healthy adult male and female participants (Part A), or an OC in healthy PM female participants (Part B).

Start Date25 Oct 2021

Sponsor / Collaborator

Pfizer Inc.

NCT04889157 / CompletedPhase 1

AN 8-WEEK, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED PHASE 1 STUDY TO EVALUATE THE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF PF-06882961 IN CHINESE ADULTS WITH TYPE 2 DIABETES MELLITUS

This is a Phase 1, randomized, double-blind (sponsor open), placebo controlled study in adult Chinese participants with T2DM who are receiving metformin as background antihyperglycemic medication.

Start Date07 Jul 2021

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

01 Oct 2023·Diabetes, obesity & metabolism

Tolerability, safety and pharmacodynamics of oral, small-molecule glucagon-like peptide-1 receptor agonist danuglipron for type 2 diabetes: A 12-week, randomized, placebo-controlled, Phase 2 study comparing different dose-escalation schemes.

Article

Author: Andrawis, Nabil ; Birnbaum, Morris J ; Frias, Juan P ; Gorman, Donal N ; Tsamandouras, Nikolaos ; Saxena, Aditi R ; Lopez, Rene N

AIM:

To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist danuglipron.

MATERIALS AND METHODS:

This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID.

RESULTS:

Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m² ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05).

CONCLUSIONS:

Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses.

CLINICALTRIALS:

gov identifier: NCT04617275.

01 Oct 2023·Bioorganic & medicinal chemistry letters

6-Azaspiro[2.5]octanes as small molecule agonists of the human glucagon-like peptide-1 receptor.

Article

Author: Wei, Liuqing ; Curto, John M ; Bagley, Scott W ; Piotrowski, David W ; Limberakis, Chris ; Genovino, Julien ; Aspnes, Gary E ; Mathiowetz, Alan M ; Coffey, Steven B ; Rose, Colin R ; Conn, Edward L ; Jiao, Wenhua ; Ruggeri, Roger B ; Edmonds, David J ; Ingle, Gajendra ; Griffith, David A

Activation of the glucagon-like peptide-1 (GLP-1) receptor stimulates insulin release, lowers plasma glucose levels, delays gastric emptying, increases satiety, suppresses food intake, and affords weight loss in humans. These beneficial attributes have made peptide-based agonists valuable tools for the treatment of type 2 diabetes mellitus and obesity. However, efficient, and consistent delivery of peptide agents generally requires subcutaneous injection, which can reduce patient utilization. Traditional orally absorbed small molecules for this target may offer improved patient compliance as well as the opportunity for co-formulation with other oral therapeutics. Herein, we describe an SAR investigation leading to small-molecule GLP-1 receptor agonists that represent a series that parallels the recently reported clinical candidate danuglipron. In the event, identification of a benzyloxypyrimidine lead, using a sensitized high-throughput GLP-1 agonist assay, was followed by optimization of the SAR using substituent modifications analogous to those discovered in the danuglipron series. A new series of 6-azaspiro[2.5]octane molecules was optimized into potent GLP-1 agonists. Information gleaned from cryogenic electron microscope structures was used to rationalize the SAR of the optimized compounds.

22 Jun 2023·Journal of medicinal chemistryQ1 · MEDICINE

Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists.

Q1 · MEDICINE

Article

Author: Zhao, Tingting ; Xiong, Muya ; Wang, Kai ; Yun, Ying ; Guo, Shimeng ; Shen, Jianhua ; Chen, Lili ; Xie, Xin ; Xu, Tifei ; Wang, Xiaoyan

Danuglipron is the most representative small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) and has received considerable attention due to positive results in the treatment of type 2 diabetes mellitus (T2DM) and obesity in clinical trials. However, hERG inhibition, lower activity than endogenous GLP-1, and a short action time represent limitations in terms of feasible application. In this study, we report a new class of 5,6-dihydro-1,2,4-triazine derivatives that serve to eliminate potential hERG inhibition caused by the piperidine ring of danuglipron. Applying systematic in vitro to in vivo screening, we have identified compound 42 as a highly potent and selective GLP-1R agonist, which delivers improved (7-fold) efficacy in stimulating cAMP accumulation compared with danuglipron and which exhibits acceptable drug-like properties. Furthermore, 42 significantly reduces glucose excursion and inhibits food intake of hGLP-1R Knock-In mice. These effects are longer-lasting than that shown by danuglipron, demonstrating feasibility in the treatment of T2DM and obesity.

News (Medical) associated with Danuglipron

14 Jun 2024

·www.pharmaceutical-technology.com

Pre-diabetes rates increase amidst a renaissance for type 2 diabetes research

There are currently six GLP-1RAs available in the UK. Image credit: Shutterstock / KK Stock. England’s National Health Service (NHS) has reported an 18% increase in the number of people with non-diabetic hyperglycaemia – also known as pre-diabetes. The latest National Diabetes Audit shows that 3,615,330 people registered with a GP have pre-diabetes and are at a greater risk of developing type 2 diabetes (T2D). Compared to 2023 figures, this is up by more than half a million patients. The NHS has rolled out a range of programmes and services to curb the proportion of this cohort that are diagnosed with T2D. However, for those who still develop diabetes, a much-changed treatment landscape now exists. Previously, metformin and other anti-hyperglycaemic medications were the only pharmaceutical options for patients with T2D. Metformin is still the first-line treatment of choice for T2D patients due to its efficacy, safety, and cost. Now, the proliferation of glucagon-like peptide-1 receptor agonists (GLP-1RAs), in particular, has transformed diabetes care. These drugs work by mimicking the GLP-1 hormone that is normally released after eating, which stimulates various glycaemic control mechanisms. See Also: FDA grants approval for Alexion’s NMOSD treatment AbbVie signs agreement to acquire Landos Biopharma for $212.5m GLP-1RA options on the NHS There are currently six GLP-1RAs available in the UK. The more popular options are Eli Lilly’s Mounjaro (tirzepatide) and Novo Nordisk ’s Ozempic (semaglutide). Novo Nordisk also markets semaglutide in the oral form as Rybelsus. Other approved treatments include Eli Lilly’s Trulicity (dulaglutide), Novo Nordisk’s Victoza (liraglutide), and Sanofi ’s Lyxumia (lixisenatide), all GLP-1RAs. The sharp rise in uptake of GLP-1RAs has outpaced supply, however, leading to shortages in the NHS earlier this year. Off-label prescribing worsened the shortages, prompting guidance from a Medicines Safety Notice in March telling clinicians to only prescribe the drugs for their licensed indication. At the same time, an increased supply of Rybelsus, and the introduction of Mounjaro in the supply chain have been highlighted by charity Diabetes UK. The shortages are likely expected to last until the end of this year, according to Douglas Twenefour, head of care at Diabetes UK. Twenefour added: “We fully support the instruction that GLP-1 medications should not be prescribed off-label under any circumstances while there is an ongoing shortage impacting people with T2D.” Global pharma scene Novo Nordisk and Eli Lilly, market leaders for GLP-1RAs, are now the two biggest pharmaceutical companies in the world. Novo Nordisk has a market cap of $436bn while Eli Lilly’s market cap is $839.5bn. Their success has meant other players in the industry have been making a push into diabetes – and more broadly weight loss – treatments. AstraZeneca received US Food and Drug Administration (FDA) approval earlier this week for its paediatric type 2 diabetes treatment Farxiga (dapagliflozin). Farxiga, marketed as Forxiga in the EU, is already approved as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. The company signed a deal worth a potential $1.85bn last November to gain an exclusive licence to Eccogene’s T2D pill ECC5004, at the time in the early stages of development. Roche signalled its intent to join the GLP-1RA arena a month later with its acquisition of Carmot Therapeutics for $2.7bn, along with $400m in milestone payments. Pfizer is eying the lucrative metabolic disease market but suffered a setback after its weight loss pill, lotiglipron, caused serious side effects in a Phase IIb trial, causing the company to drop its GLP-1RA candidate . Pfizer will rest its hopes on its other candidate, danuglipron, to take on competitors.

Drug ApprovalAcquisitionPhase 2License out/in

12 Jun 2024

·www.biopharmadive.com

Flagship taps startup to hunt for obesity drugs that might interest Pfizer

Dive Brief:Flagship Pioneering will partner with biotechnology startup ProFound Therapeutics to search for promising drug candidates for obesity that Pfizer, under a deal struck with Flagship last year, may later choose to advance.The collaboration between Flagship and ProFound, which the venture firm founded in 2022, is the first drug-hunting effort started through the alliance Flagship and Pfizer formed in July. At the time, both Flagship and Pfizer said they would invest $50 million to develop 10 drug candidates that Pfizer would have an option to later license or acquire.The initiative comes at an interesting time for Pfizer, which has been forced to scrap one experimental weight loss drug and revise plans for anotherafter disappointing data readouts.Dive Insight:Like many other companies, Pfizer aims to follow Novo Nordisk and Eli Lilly into a market for obesity drugs thats quickly become among the most lucrative in the industry.But its initial efforts have fallen short. One GLP-1 drug candidate, called lotiglipron, was associated with possible signs of liver toxicity in testing. Another, danuglipron, caused high rates of gastrointestinal side effects, leading Pfizer to discontinue a twice-daily dosing regimen in favor of once-daily. Data on that dosage is expected later this year and could be important for the drugs future.Pfizer also has another candidate for obesity in Phase 1 testing, but hasnt disclosed its mechanism of action.The partnership with Flagship could help Pfizer source other potential drugs. The alliance set up by the two firms is broad, designed to advance 10 candidates that match Pfizers development priorities. Flagships efforts under the deal are routed through its Pioneering Medicines Initiative, which will look across Flagships portfolio of companies to find promising ideas they may not be able to advance on their own.Flagship has struck similar deals with Novoand with the Cystic Fibrosis Foundation.If any of the candidates developed through the Pfizer alliance reach market, Flagship and its associated companies, such as ProFound, could receive $700 million in milestone payments.ProFoundis built around what it calls its ProFoundry platform.The platform is designed to mine the translatome to identify novel proteins that might make for good drugs. The startup will use its platform to search for protein-based obesity therapies.“This agreement the first under our broader strategic partnership with Flagship is designed to push the boundaries of science to potentially unlock new protein therapeutics for obesity leveraging ProFound's proprietary discovery platform,“ said Charlotte Allerton, Pfizers head of discovery and early development, in a Wednesday statement. '

11 Jun 2024

·firstwordpharma.com

Pfizer CEO signals hiatus on mega deals following M&A spree

Pfizer has been busy pursuing acquisitions over the past 24 months, pouring over $70 billion to bolster its pipeline with blockbuster takeouts of Seagen, Arena, Biohaven, Global Blood Therapeutics and others. However, CEO Albert Bourla now indicates the pharma needs to take a break after that spending spree.The company has been doing some belt-tightening lately. Last month, it embarked on a new round of cost-cutting intended to reduce expenses by $1.5 billion by the end of 2027. That's on top of a $4-billion cost savings plan announced at the end of last year amid declining demand for its COVID-19 products. Speaking at the Goldman Sachs Healthcare Conference in Miami, Bourla stated that while Pfizer's business development appetite remains strong, the company won't be inking any major acquisitions in the near-term as it focuses on integrating its recent purchases."We need to catch our breath and make sure we execute well on [what] we have right now," Bourla stated. "I don't foresee ourselves going and buying something sizeable now because I don't want to disrupt our commercial operations, our research operations or…manufacturing [operations]."Still on lookout for tuck-insThat's not to say Pfizer's dealmaking has been completely sidelined. Bourla left the door open for smaller, tuck-in acquisitions that bring in intellectual property like an obesity compound or oncology asset. "We are looking at them and [deals] will happen probably this year as well, but these are smaller things," Bourla said.For the time being, the emphasis is on digesting last year's $43-billion purchase of Seagen and its slate of antibody-drug conjugates (ADCs). That acquisition, according to the CEO, "has the potential to become the most successful acquisition that the company has ever done."Piece of the obesity pieStill, Bourla acknowledged that prior stumbles like the discontinuation of its oral GLP-1 agonist lotiglipron last year due to liver toxicity have set Pfizer back in the booming obesity market.While he expressed confidence that the company's remaining hopeful danuglipron can eventually compete with oral entries from Eli Lilly and Novo Nordisk, the twice-daily version has already been scrapped due to high dropout rates. Data on a once-daily formulation are due either this month or next and will inform the programme's path forward, Bourla said.He added that the company has two other possible weight-loss treatments in the clinic right now, including the Phase I asset PF-07976016, although Pfizer has not disclosed their mechanism of action.Large moleculesBourla also weighed in on the Inflation Reduction Act (IRA) and the ongoing Medicare drug pricing negotiations, saying the legislation could distort R&D priorities.Despite Pfizer being "lucky" that only one of its products – the anticoagulant Eliquis (apixaban), partnered with Bristol Myers Squibb – was among the ten drugs selected for initial Medicare price talks, Bourla warned that the legislation's favourable treatment of biologics over small molecules "will force a lot of us to make strategic moves, not based on where the science is taking us, but based on where IRA is taking us."Still, he touted Pfizer's pivot towards large molecules like the ADCs gained through the Seagen buy, noting that within five years large molecules will account for 60% to 65% of the oncology pipeline, up from just 5% today.As for other modalities on Pfizer's radar, Bourla said radiopharmaceuticals are attracting "high interest" from the company, "not that we have made our decision to enter into that space." He said Pfizer will jump into promising new areas "the moment we feel that we can make a difference."

AcquisitionPhase 1

100 Deals associated with Danuglipron

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D11910	-	-	DB16043

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Phase 2	US	Pfizer Inc.	06 Jan 2021
Diabetes Mellitus, Type 2	Phase 2	US	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	BG	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	CA	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	HU	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	PL	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	SK	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	KR	Pfizer Inc.	15 Oct 2019
Diabetes Mellitus, Type 2	Phase 2	TW	Pfizer Inc.	15 Oct 2019
Liver Injury	Phase 1	US	Pfizer Inc.	30 Dec 2020

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04616027 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	42	PF-06882961 (Healthy and Normal Renal Function)	shoualooaq(wphwllrbxz) = vepytdctoc dwfqodpoqc (buivjgyxhj, uktithtaxr - oytsczfnbe) View more	-	10 May 2024
				PF-06882961 (T2DM Normal Renal Function)	shoualooaq(wphwllrbxz) = fwhpthqcsj dwfqodpoqc (buivjgyxhj, lwdomwiiiq - xnrnwwnnsw) View more
NCT04707313 (Corporate Publications) Manual	Phase 2	Obesity	-	Danuglipron	umrpesyzls(upestzcnlt) = krlnpmfmjl lanxdwhrav (jespflindr ) View more	Negative	01 Dec 2023
				Placebo	umrpesyzls(upestzcnlt) = keimqmdpsi lanxdwhrav (jespflindr ) View more
NCT04621227 (CTgov)	Phase 1	Obesity	16	Rosuvastatin (Rosuvastatin 10mg (Period 1))	hyyqatqvqp(gpxeyeqggk) = dwffwtmysp jvqlocgubb (qtyvkyyona, vmpklsyqvd - raigiifpgr) View more	-	01 Dec 2023
				Rosuvastatin+PF-06882961 (PF-06882961 120mg BID + Rosuvastatin 10mg (Period 4))	hyyqatqvqp(gpxeyeqggk) = ifbgabnuhl jvqlocgubb (qtyvkyyona, iltfmpukox - glouvzuwpx) View more
NCT04617275 (Pubmed)	Phase 2	Diabetes Mellitus, Type 2	151	Placebo	hvxfpeixhl(gwnbfrfvbw) = wxtnyhdxkp rhqbpyqvbb (taexmggyqe ) View more	-	13 Jun 2023
				Danuglipron low starting dose (5-mg)	hvxfpeixhl(gwnbfrfvbw) = cbqxqklxlq rhqbpyqvbb (taexmggyqe ) View more
NCT03985293 (Literature) Manual	Phase 2	Diabetes Mellitus, Type 2	411	Danuglipron 2.5 mg	vcoylporbr(weoibkwyjb) = vomtdtmwqz vydcuhftjy (fvsoxjewba, -0.70 to to 0.28) View more	Positive	22 May 2023
				Danuglipron 10 mg	vcoylporbr(weoibkwyjb) = eafdaghjqw vydcuhftjy (fvsoxjewba, -1.11 to to 0.72) View more
NCT03985293 (Pubmed)	Phase 2	Diabetes Mellitus, Type 2	411	Danuglipron 2.5 mg	wunghdhupo(mknrhelmss) = vscwbbaiop xgdngpmmwp (cmlgutfpvp, -1.47 to -0.86) View more	Positive	01 May 2023
				Danuglipron 80 mg	naplvcvxnk(abgizbwxkg) = fjokbumnyq vyamxnchqk (ammaykdeze, -3.01 to -1.07)
NCT04617275 (CTgov)	Phase 2	Diabetes Mellitus, Type 2 \| Obesity	151	Placebo (Placebo (T2DM))	wajeydhryx(toglfpidtt) = ocphqtuncr avpvetglqq (tzyznsogbx, jnxfovlxkc - iqntmppomw) View more	-	08 Dec 2022
				PF-06882961 (PF-06882961 80 mg BID Low, Slow (T2DM))	wajeydhryx(toglfpidtt) = joeewewblm avpvetglqq (tzyznsogbx, jywakzmxqj - dkogptujco) View more
NCT04552470 (Pubmed) Manual	Phase 1	Diabetes Mellitus, Type 2	37	danuglipron	wxmskzdxeq(tzgeapzdgd) = Most treatment-emergent adverse events were of mild or moderate intensity. igfvatoqal (xydoujhybr )	Positive	26 Nov 2022
				Placebo
NCT03985293 (CTgov)	Phase 2	Diabetes Mellitus, Type 2	412	placebo	iemsywyuzc(xrdppneggb) = kvbmotghip sqopxyubqh (vwqxdgmjik, brndwltoot - ebsvkupnzo) View more	-	30 Jun 2022
NCT04552470 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	37	Placebo (Placebo)	guyfovlffy(nztxpxewfn) = jzjexhsyqp siwzgwgvys (mmqihbyuav, iyrarthfvj - gwxwibtcax) View more	-	11 Mar 2022
				PF-06882961 (PF-06882961 40 mg)	guyfovlffy(nztxpxewfn) = uegdtgnbxt siwzgwgvys (mmqihbyuav, uxwopgyqoo - wiidhpfvdd) View more

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