Clesacostat

Already at the head of the metabolic dysfunction-associated steatohepatitis (MASH) pack, Madrigal Pharmaceuticals is looking to firm up its position with a new deal for a pipeline asset recently cast aside by Pfizer.On Friday, Madrigal said it struck an exclusive global licensing agreement with Pfizer for ervogastat, a Phase II oral DGAT-2 inhibitor that had previously been part of the latter's internal MASH programme and was being developed as a combination with clesacostat, a liver-targeted inhibitor of acetyl-CoA carboxylase (ACC), before being shelved late last year.Madrigal will pay Pfizer $50 million upfront, with additional unspecified milestone payments and royalties tied to future development and sales.Madrigal's Rezdiffra (resmetirom) was the first FDA-approved treatment for non-cirrhotic MASH patients when it was cleared in 2024. The THR-β selective agonist, also approved in Europe, generated $287.3 million in its most recently reported quarter and is tracking toward $1 billion in annual revenues, CEO Bill Sibold has said."With Rezdiffra as the anchor…our broadened portfolio now spans several key pathways that will define the future of MASH treatment," David Soergel, chief medical officer, said in a release Friday. "Along with studies of our oral GLP-1 receptor agonist, we look forward to adding ervogastat to our growing clinical programme."Combo possibilitiesErvogastat targets the final stage of how the liver assembles and stores triglycerides, interrupting the process before toxic fat can accumulate, trigger inflammation and damage liver tissue. Madrigal cited a published Phase II study where 72% of patients treated with a 150-mg dose of ervogastat saw their liver fat drop by at least nearly a third, while 61% achieved reductions of half or more, as measured by MRI-PDFF scans. Patients also showed better liver enzyme levels and reduced liver stiffness on vibration-controlled transient elastography, and all active doses were well tolerated."Because Rezdiffra and ervogastat act on distinct yet complementary pathways that drive liver fat accumulation, this combination has potential to produce additive antisteatotic and antifibrotic efficacy," said Quentin Anstee, lead investigator on the Phase II study.Madrigal plans to conduct a drug-to-drug interaction study with Rezdiffra this year and consult with the FDA on the design of a possible Phase II combination trial.Last July, Madrigal bet up to $2.1 billion for exclusive worldwide rights to a GLP-1 agonist called SYH2086 under an agreement with CSPC Pharmaceutical in a bid to create a best-in-class oral combination therapy for MASH.Despite being first with a marketed treatment for MASH, Madrigal is no longer alone after Novo Nordisk's Wegovy (semaglutide) was granted an accelerated FDA approval — a first for a GLP-1 drug in the disease — last August (see – KOL Views Q&A: Wegovy and Rezdiffra could be friends with mutual benefits in MASH). Eli Lilly has also been trying to capture a piece of the MASH pie with its dual GLP-1/GIP drug tirzepatide.

Pfizer has put the kibosh on two early-stage programs from its $43 billion Seagen buyout. \n Pfizer has axed 11 programs including two pipeline assets from its $43 billion Seagen acquisition, work on a BioNTech-partnered mRNA vaccine and a midstage metabolic dysfunction-associated steatohepatitis (MASH) combo.The most advanced clinical program dropped by Pfizer in its latest pipeline update is a phase 3 asset for sickle cell disease (SCD) that came to the pharma via its $5.4 billion acquisition of Global Blood Therapeutics in 2022.This summer, the P-selectin inhibitor inclacumab failed to reduce a painful complication of sickle cell compared to placebo. That late-stage trial had been one of two studies for inclacumab in SCD, with Pfizer terminating the other last year due to “slow recruitment.”When asked about the discontinuation, a Pfizer spokesperson pointed to this summer’s phase 3 miss and the fact that Pfizer still touts osivelotor, the only remaining clinical asset from the Global Blood Therapeutics buyout. The HbS polymerization inhibitor is currently in late-stage development in SCD.Also on the chopping block in the company\'s third-quarter clear-out is a midstage MASH combo. The investigational treatment consisted of DGAT2i inhibitor ervogastat and an acetyl-CoA carboxylase inhibitor called clesacostat. The latter drug was previously shelved by Pfizer in 2020 after being tested as a monotherapy for patients with liver scarring. A little bit later, the pharma revived the asset via the investigational duo, which secured FDA fast track status in 2022 for MASH.Pfizer still has ervogastat listed in its pipeline as a midstage monotherapy for MASH, though no phase 2 trials are listed for the asset alone in the federal registrar ClinicalTrials.gov.As of publication, the drugmaker has not responded to Fierce’s questions about the axed combo.The Nov. 4 pipeline update also features a string of phase 1 culls, including the discontinuation of bispecific molecule PF-08046049, a product previously coded SGN-BB228 from Pfizer’s $43 billion Seagen buyout. The CD228x4-1BB costimulatory antibody was being studied in melanoma and other solid tumors, with primary findings expected for next month, according to ClinicalTrials.gov. The three-part study enrolled 41 patients and is the only trial listed on Pfizer’s pipeline for the bispecific. The drugmaker also put the kibosh on PF-08046045, a CD30-directed antibody-drug conjugate that also came from Seagen. The investigational ADC was being tested in patients with advanced lymphoma.Then there’s a mRNA vaccine that was being advanced with partner BioNTech. Dubbed PF-07911145, the prophylactic vaccine was being assessed for varicella, the herpesvirus that causes chickenpox and shingles.The partners are known for their collaboration on the COVID-19 vaccine Comirnaty. In its pipeline update, Pfizer said it would end development of the Comirnaty vaccine for children aged 6 months through 4 years.This was largely expected as the FDA previously said it might not renew Pfizer\'s pediatric COVID shot authorization and did indeed rescind the emergency use authorization in August.The company’s spokesperson did highlight an ongoing phase 3 trial of a variant-based Comirnaty that started in 2022 . The trial could potentially allow for “a single uniform dose to be administered across approved age ranges” rather than differing dose levels for children, the spokesperson explained.Next up in the discard pile is PF-07314470, an investigational bispecific antibody that Pfizer was hoping could serve as a subcutaneous injection for atopic dermatitis. However, a phase 1 study evaluating the product was terminated in August after enrolling 23 healthy volunteers, according to ClinicalTrials.gov.The study was axed “for business reasons,” with “no safety concerns” prompting the decision, according to the federal database.The early-stage atopic dermatitis study is the only in-human trial for PF-07314470 listed in Pfizer’s pipeline. Pfizer\'s string of third-quarter discontinuations also featured the company\'s bispecific IgG1 antibody coded PF-07826390. The investigational bispecific was being tested in an open-label phase 1 expected to wrap at the end of October. The study recruited nine patients with varying types of solid tumors.Pfizer isn’t studying the asset in any other publicly disclosed trials, according to ClinicalTrials.gov.Also discarded is PF-07941944, a potential respiratory syncytial virus (RSV) infection treatment that was studied in healthy volunteers. A program for complicated urinary tract infections coded CTB+AVP (PF-07612577) is getting the boot, too.On the approved side, Pfizer has stopped development of bladder cancer treatment Padcev in patients with the BCG-unresponsive non-muscle-invasive form of the disease.The pharma didn’t respond to Fierce’s questions regarding the reasoning behind the discontinuations.In total, that leaves 101 pipeline programs, including 30 phase 3 studies, according to Pfizer’s online pipeline updated today.On the pharma’s third-quarter earnings call held Nov. 4, company leaders touted the $1.25 billion deal inked with 3SBio for ex-China rights to a clinical PD-1xVEGF bispecific. The pact was announced in May and puts Pfizer in the running against BioNTech, Merck & Co. and Summit Therapeutics in a hot immuno-oncology field. Meanwhile, the company is undergoing a massive cost-realignment initiative designed to save $7.7 billion through 2027. Part of the plan is to reallocate $500 million in savings toward the pipeline by the end of next year, the pharma said today.And of course, there’s the Metsera deal. CEO Albert Bourla, Ph.D., stood firm on the company’s position that it would be acquiring the next-gen obesity biotech despite a recent surprise offer from Novo Nordisk—an offer Pfizer is suing over.If Pfizer’s efforts are successful, the drugmaker would gain a pipeline led by MET-097i, an injectable GLP-1 receptor agonist that could support monthly dosing. The biotech’s clinical-phase pipeline also features a monthly injectable amylin analog that could be combined with MET-097i, and an oral GLP-1 that is designed to drive more weight loss than small molecules and avoid scalability challenges tied to other oral peptides.