A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Assess the Effect of Oral Temanogrel on Digital Blood Flow in Subjects With Raynaud's Phenomenon Secondary to Systemic Sclerosis

The purpose of this study is to determine whether oral temanogrel improves digital blood flow in participants with Raynaud's phenomenon secondary to systemic sclerosis (SSc-RP) as a potential safe and effective treatment for symptoms associated with SSc-RP.

Start Date03 Nov 2021

Sponsor / Collaborator

Pfizer Inc.

[+1]

NCT04848220

/ TerminatedPhase 2

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, and Effect on Microvascular Obstruction of Temanogrel in Subjects Undergoing Percutaneous Coronary Intervention

The purpose of this study is to determine whether intravenous temanogrel is a safe and effective treatment for microvascular obstruction (MVO) in adult participants undergoing percutaneous coronary intervention (PCI).

Start Date20 May 2021

Sponsor / Collaborator

Pfizer Inc.

[+1]

KCT0001529

/ RecruitingPhase 1

Randomized, Double-blind, Placebo-controlled, Dose-escalation, Repeated and Single Oral Dosing Phase I Study to Assess the Pharmacokinetics, Pharmacodynamics and Safety of Temanogrel Co-administered with Aspirin and Clopidogrel

Start Date18 Mar 2015

Sponsor / Collaborator

Ildong Pharmaceutical Co., Ltd.

100 Clinical Results associated with Temanogrel

100 Translational Medicine associated with Temanogrel

100 Patents (Medical) associated with Temanogrel

Literatures (Medical) associated with Temanogrel

01 Jan 2025·JOURNAL OF ETHNOPHARMACOLOGY

Lipopolysaccharide aggravating anaphylactoid reactions caused by traditional Chinese Medicine injections via p38/ERK/NF-κB signaling pathways

Article

Author: Qiu, Zichao ; Liu, Fangmei ; Peng, Guoping ; Li, Cunyu ; Tang, Shuwan

ETHNOPHARMACOLOGICAL RELEVANCE:

Currently, adverse reactions limit the development of traditional Chinese medicine injections (TCMI), and severe anaphylactoid shock is one of the serious adverse reactions, which presents a significant challenge. The presence of abnormal inflammatory mediators before the administration of TCMI will most likely result in severe anaphylactoid reactions. Not only that, the lack of clinically relevant safety evaluations impedes the widespread use of TCMI, and there is an urgent need for studies to reveal the mechanisms of anaphylactoid shock caused by TCMI.

AIM OF THE STUDY:

To investigate the effects and underlying mechanisms of lipopolysaccharide (LPS)-induced inflammation, which aggravates anaphylactoid reactions caused by TCMI, utilizing a guinea pig model.

METHODS:

The dose and duration of LPS administration and different doses of compound 48/80 (C48/80) were examined by using guinea pigs as a model. Shuanghuanglian (SHLI) and Qingkailing (QKLI) injections, these two representative TCMI, were used for validation. The plasma biochemical indices, including histamine, 5-hydroxytryptamine, tumor necrosis factor-α, interleukin 6, immunoglobulin E, C5a, tryptase, and platelet activating factor, as well as the pathological characteristics of the lung, were analyzed. Futhermore, plasma metabolomics was employed to reveal changes in metabolic pathways in vivo when inflammation co-exists with TCMI. In addition, Western blot analysis was conducted to assess the expression of critical signaling pathways.

RESULTS:

Stimulation with 2 mg/kg of LPS for 12 h induced inflammatory responses in the guinea pig model. C48/80 (3.0 mg/kg) in combination with LPS resulted in an increase in anaphylactoid-related indicators in the plasma. High doses of SHLI and QKLI aggravated plasma indices and lung histological injury caused by LPS-induced inflammation. A total of 36 and 63 differential metabolites were significantly altered after LPS stimulation in the SHLI-and QKLI-treated guinea pig groups, respectively. The associated metabolic pathways include central carbon metabolism in cancer, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism. The p38/ERK/NF-κB signal pathway may be significantly affected by TCMI in vivo after LPS stimulation.

CONCLUSION:

LPS-induced inflammation aggravated anaphylactoid reactions caused by SHLI and QKLI, with a correlation to dosage. After the presence of LPS, the administration of TCMI interferes with the immune response by over-activating the p38/ERK/NF-κB signaling pathway. This activation leads to an excessive release of inflammatory factors and anaphylactoid mediators. These results present a new direction for mitigating adverse clinical reactions associated with TCMI.

10 Jun 2010·Journal of medicinal chemistryQ1 · MEDICINE

Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

Q1 · MEDICINE

Article

Author: Ullman, Brett ; Decaire, Marc ; Morgan, Michael ; Strah-Pleynet, Sonja ; Jayakumar, Honnappa ; Adams, John ; Dosa, Peter I. ; Yuskin, Diane ; Choi, Jin-Sun Karoline ; Pham, Lan ; Feichtinger, Konrad ; Connolly, Daniel T. ; Casper, Martin D. ; Webb, Robert R. ; Sadeque, Abu ; Frazer, John ; Teegarden, Bradley R. ; Chen, Weichao ; Al-Shamma, Hussien ; Semple, Graeme ; Xiong, Yifeng

Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT(2A) receptor. 5-HT(2A) receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT(2A) receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC(50) = 8.7 nM and had negligible binding affinity for the closely related 5-HT(2B) and 5-HT(2C) receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.

01 Feb 2010·Journal of thrombosis and haemostasis : JTHQ2 · MEDICINE

Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis

Q2 · MEDICINE

Article

Author: Frelinger, A. L. III ; Linden, M. D. ; Whittaker, P. ; Adams, J. ; Przyklenk, K. ; Michelson, A. D. ; Al-Shamma, H. ; Li, Y. ; Morgan, M. ; Barnard, M. R.

BACKGROUND:

Release of serotonin and activation of serotonin 5HT2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT2A receptor subtype.

OBJECTIVE:

To assess whether targeted inhibition of the serotonin 5HT2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina.

METHODS:

In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury+stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin.

RESULTS:

APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow-time area (index of coronary patency; normalized to baseline coronary flow) averaged 58-59% (P<0.01) following administration of APD791 vs. 21-28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation.

CONCLUSION:

5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.

News (Medical) associated with Temanogrel

19 Jul 2023

·www.fiercebiotech.com

Pfizer spies cardiovascular potential in Riparian preclinical licensing agreement

Riparian Pharmaceuticals' therapeutic programs are designed to target key vasoprotective pathways. Pfizer has licensed a preclinical cardiovascular program from Riparian Pharmaceuticals as part of an agreement that will also see the Big Pharma support further discovery efforts by the biotech. Even for a licensing announcement, this morning’s release was light on details—while there will be upfront and milestone payments attached, the amounts weren’t disclosed. All we know for sure is that Pfizer has gained the exclusive rights to one unnamed preclinical program. “As part of the research agreement, Pfizer will support Riparian’s efforts to discover further drug targets leading to vasoprotection and will have an option on such targets,” according to the announcement. “I am incredibly proud of the entire Riparian team and their success translating fascinating science into an innovative therapeutic program,” Riparian CEO Will Adams, Ph.D., said in this morning’s release. “We are excited to collaborate with Pfizer and believe they are the ideal partner to advance this program and develop impactful therapies.” Privately owned Riparian’s therapeutic programs are designed to target “key vasoprotective pathways” with the aim of reducing both vascular inflammation and a type of nonobstructive coronary artery disease called endothelial dysfunction. The company has raised more than $10 million in grants and financing to date, according to Riparian’s website, which gives little else away about the biotech’s pipeline. Pfizer has been quiet on the cardiovascular front in recent years. As part of its $6.7 billion acquisition of Arena Pharmaceuticals in 2021, it acquired a couple of phase 2 assets in the form of a beta-3 adrenergic receptor antagonist for acute heart failure and temanogrel, which was being trialed for microvascular obstruction. But the Big Pharma revealed a few months ago that it had canned both candidates. That still leaves ponsegromab, a growth differentiation factor 15 monoclonal antibody in phase 2 trials for heart failure, and PF-07328948, a BDK inhibitor in phase 1 for heart failure with preserved ejection fraction. Pfizer also markets Vyndaqel, which is indicated for a rare disease called transthyretin amyloidosis in patients with transthyretin amyloidosis with cardiomyopathy, among others. Riparian's announcement comes a day after Pfizer unveiled a more ambitious pact with Flagship Pioneering to work on 10 programs, for which the Big Pharma and the VC firm will each lay down $50 million at the outset. While the targets have yet to be decided, they will address unmet needs within Pfizer’s core strategic areas of interest—vaccines, inflammation/immunology, oncology, rare diseases and internal medicine.

AcquisitionLicense out/inPhase 1Phase 2

03 May 2023

·www.biospace.com

Pfizer Cuts Mid-Stage Candidates Amid Declining Revenues

Pictured: Blue and white Pfizer sign on building/c cbies - stock.adobe.com The company’s pipeline changes come as it weathered a nearly 30% decline in first-quarter revenues due to a slowdown in its COVID-19 business. Pictured: Blue and white Pfizer sign on building/cbies/Adobe Stock Fresh off its $43 billion acquisition of Seagen, Pfizer is making deep cuts to its Phase II pipeline in cardiology and inflammatory diseases, the company revealed Tuesday during its first-quarter financial report . On Pfizer’s chopping block is temanogrel, an inverse agonist of the serotonin 2A receptor being trialed for microvascular obstruction and Raynaud’s phenomenon related to systemic sclerosis. Pfizer is also dumping its cardio candidate APD418, an antagonist of the beta-3 adrenergic receptor in Phase II studies for acute heart failure. Pfizer obtained access to temanogrel and APD418 from its $6.7 billion buy of Arena Pharmaceuticals in December 2021. Tuesday’s pipeline cuts leave etrasimod, an orally available selective sphingosine 1-phospate receptor modulator, as the only mature Arena molecule on Pfizer’s pipeline. In May 2022, Pfizer posted data from two pivotal trials from the Phase III ELEVATE UC registrational program, showing that etrasimod significantly improved remission rates in patients with moderate-to-severely active ulcerative colitis. In December 2022, the FDA accepted etrasimod’s New Drug Application in this indication, with a decision set for the second half of 2023. Etrasimod is also being trialed in other immuno-inflammatory conditions such as Crohn’s disease and alopecia areata. Pfizer’s pipeline clean-out also included the biologic blocker of the TNFSF15 protein for ulcerative colitis and the CXCR2 antagonist RIST4721, which was in Phase II studies for hidradenitis suppurativa and palmoplantar pustulosis. RIST4721, initially developed by Aristea Therapeutics, works by suppressing inflammation. In July 2021, concurrent with a $63 million Series B funding round, Aristea inked a strategic partnership with Arena to advance the candidate through the clinic. However, in February 2023, Aristea announced that it was discontinuing the development of RIST4721 due to safety concerns, forcing the company to shutter its operations. Business Beyond COVID-19 For the first quarter of 2023, Pfizer posted nearly $18.3 billion in revenue, down 29% from the same period during the prior year. Much of this downtrend could be attributed to the drop in coronavirus-related sales, said Pfizer CEO Anthony Bourla during an investor call Tuesday. Revenues in non-COVID-19 products grew 5%, driven mainly by its anticoagulant Eliquis (apixaban), migraine drug Nurtec ODT (rimegepant) and sickle-cell disease therapy Oxbryta (voxelotor). Pfizer still expects to hit its target of 7% to 9% operational growth for its non-COVID-19 revenues in 2023, which will be due mostly to product launches in the second half of the year. Among these is Zavzpret (zavegepant), a nasal spray for acute migraine in adults that Pfizer won from its $11.6 billion buyout of Biohaven. Two Phase III trials showed that compared with placebo, Zavzpret led to significantly better pain freedom and freedom from the most bothersome migraine symptom within two hours of dosing. The FDA gave Zavzpret its approval in March 2023. Pfizer is also pinning its 2023 hopes on its respiratory syncytial virus (RSV) vaccine candidate, which won the backing of the FDA’s Vaccines and Related Biological Products Advisory Committee in March 2023 for its favorable risk-benefit pro older adults. A final verdict is expected this month. Similarly, the company is anticipating expanded approval for its prostate cancer drug Xtandi (enzalutamide), allowing its use in non-metastatic castration-sensitive prostate cancer. Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com .

Phase 2Phase 3VaccineDrug ApprovalAcquisition

03 May 2023

·www.biospace.com

Pfizer Cuts Mid-Stage Candidates Amid Declining Revenues

Pictured: Blue and white Pfizer sign on building/cbies/Adobe Stock Fresh off its $43 billion acquisition of Seagen, Pfizer is making deep cuts to its Phase II pipeline in cardiology and inflammatory diseases, the company revealed Tuesday during its first-quarter financial report. On Pfizer’s chopping block is temanogrel, an inverse agonist of the serotonin 2A receptor being trialed for microvascular obstruction and Raynaud’s phenomenon related to systemic sclerosis. Pfizer is also dumping its cardio candidate APD418, an antagonist of the beta-3 adrenergic receptor in Phase II studies for acute heart failure. Pfizer obtained access to temanogrel and APD418 from its $6.7 billion buy of Arena Pharmaceuticals in December 2021. Tuesday’s pipeline cuts leave etrasimod, an orally available selective sphingosine 1-phospate receptor modulator, as the only mature Arena molecule on Pfizer’s pipeline. In May 2022, Pfizer posted data from two pivotal trials from the Phase III ELEVATE UC registrational program, showing that etrasimod significantly improved remission rates in patients with moderate-to-severely active ulcerative colitis. In December 2022, the FDA accepted etrasimod’s New Drug Application in this indication, with a decision set for the second half of 2023. Etrasimod is also being trialed in other immuno-inflammatory conditions such as Crohn’s disease and alopecia areata. Pfizer’s pipeline clean-out also included the biologic blocker of the TNFSF15 protein for ulcerative colitis and the CXCR2 antagonist RIST4721, which was in Phase II studies for hidradenitis suppurativa and palmoplantar pustulosis. RIST4721, initially developed by Aristea Therapeutics, works by suppressing inflammation. In July 2021, concurrent with a $63 million Series B funding round, Aristea inked a strategic partnership with Arena to advance the candidate through the clinic. However, in February 2023, Aristea announced that it was discontinuing the development of RIST4721 due to safety concerns, forcing the company to shutter its operations. Business Beyond COVID-19 For the first quarter of 2023, Pfizer posted nearly $18.3 billion in revenue, down 29% from the same period during the prior year. Much of this downtrend could be attributed to the drop in coronavirus-related sales, said Pfizer CEO Anthony Bourla during an investor call Tuesday. Revenues in non-COVID-19 products grew 5%, driven mainly by its anticoagulant Eliquis (apixaban), migraine drug Nurtec ODT (rimegepant) and sickle-cell disease therapy Oxbryta (voxelotor). Pfizer still expects to hit its target of 7% to 9% operational growth for its non-COVID-19 revenues in 2023, which will be due mostly to product launches in the second half of the year. Among these is Zavzpret (zavegepant), a nasal spray for acute migraine in adults that Pfizer won from its $11.6 billion buyout of Biohaven. Two Phase III trials showed that compared with placebo, Zavzpret led to significantly better pain freedom and freedom from the most bothersome migraine symptom within two hours of dosing. The FDA gave Zavzpret its approval in March 2023. Pfizer is also pinning its 2023 hopes on its respiratory syncytial virus (RSV) vaccine candidate, which won the backing of the FDA’s Vaccines and Related Biological Products Advisory Committee in March 2023 for its favorable risk-benefit pro older adults. A final verdict is expected this month. Similarly, the company is anticipating expanded approval for its prostate cancer drug Xtandi (enzalutamide), allowing its use in non-metastatic castration-sensitive prostate cancer. Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Phase 2Drug ApprovalPhase 3VaccineClinical Result

100 Deals associated with Temanogrel

External Link

KEGG	Wiki	ATC	Drug Bank
D09976	-	-	DB05227

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
CREST Syndrome	Phase 2	United States	Pfizer Inc.	03 Nov 2021
CREST Syndrome	Phase 2	United Kingdom	Pfizer Inc.	03 Nov 2021
Microvascular occlusion	Phase 2	United States	Pfizer Inc.	20 May 2021
Microvascular occlusion	Phase 2	Australia	Pfizer Inc.	20 May 2021
Microvascular occlusion	Phase 2	Netherlands	Pfizer Inc.	20 May 2021
Microvascular occlusion	Phase 2	Sweden	Pfizer Inc.	20 May 2021
Microvascular occlusion	Phase 2	United Kingdom	Pfizer Inc.	20 May 2021
Acute Coronary Syndrome	Phase 1	-	Ildong Pharmaceutical Co., Ltd.	01 Feb 2014
Arterial thrombosis	Phase 1	United States	Arena Pharmaceuticals, Inc.	-
Thrombosis	Phase 1	-	Arena Pharmaceuticals, Inc.	-

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04915950 (CTgov)	Phase 2	CREST Syndrome \| Raynaud Disease \| Scleroderma, Systemic	13	Temanogrel (Temanogrel 120 mg)	aginwqnrhj(acpmaehpkg) = zpzuecshzp eawrvxtvvc (ztktwirkee, 4399.5) View more	-	22 Dec 2023
				Temanogrel (Temanogrel 60 mg)	aginwqnrhj(acpmaehpkg) = hahcrhpzqi eawrvxtvvc (ztktwirkee, 5308.2) View more
NCT04848220 (CTgov)	Phase 2	Microvascular occlusion	29	Temanogrel (Temanogrel 20 mg)	dzocbuohsv(mjtzbqptpk) = bkjjxmnobo xgzvxipaop (oewitsirym, 15.35531) View more	-	12 Dec 2023
				Temanogrel (Temanogrel 40 mg)	dzocbuohsv(mjtzbqptpk) = lfvinqyguu xgzvxipaop (oewitsirym, 13.27702) View more

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