PF-08653944 / Amneal, Pfizer - LARVOL DELTA

VESPER-1: A Phase 2b Study to Examine the Safety and Efficacy of Once-Weekly MET097 in Adults With Obesity or Overweight (clinicaltrials.gov) - P2 | N=225 | Active, not recruiting | Sponsor: Metsera | Trial primary completion date: Dec 2025 ➔ Jul 2025

Trial primary completion date • Genetic Disorders • Obesity

A Study of MET233 in Combination With MET097 in Individuals With Obesity or Overweight With or Without Diabetes (clinicaltrials.gov) - P1/2 | N=132 | Recruiting | Sponsor: Metsera | Phase classification: P1 ➔ P1/2 | Trial completion date: Jan 2026 ➔ Mar 2027 | Trial primary completion date: Oct 2025 ➔ Jan 2027

Phase classification • Trial completion date • Trial primary completion date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Pfizer is planning an expansive obesity development program across its robust pipeline, with plans to advance 20+ trials in 2026. (Pfizer Press Release) - "This includes 10 Phase 3 trials of PF’3944, including the recently initiated Phase 3 VESPER-4 pivotal study investigating once-weekly PF’3944 in people with obesity or overweight and without type 2 diabetes; the planned Phase 3 VESPER-5 study investigating once-weekly PF’3944 in people with obesity or overweight with type 2 diabetes; the planned Phase 3 VESPER-6 study with once-monthly PF’3944 in obesity or overweight; and at least seven additional planned Phase 3 studies of PF’3944 designed to target comorbidities and increase patient optionality and access."

New P3 trial • Trial status • Obesity • Type 2 Diabetes Mellitus

This Study Will Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of MET097 in Adult Participants With Overweight or Obesity (clinicaltrials.gov) - P1/2 | N=120 | Completed | Sponsor: Metsera | Active, not recruiting ➔ Completed | N=262 ➔ 120

Enrollment change • Trial completion • Genetic Disorders • Obesity

Pfizer’s Ultra-Long-Acting Injectable GLP-1 RA Shows Robust and Continued Weight Loss with Monthly Dosing in Phase 2b Trial (Pfizer Press Release) - "The study demonstrated statistically significant weight reduction with up to 12.3% mean placebo-adjusted weight loss at week 28 (efficacy estimand). The study included up to two titration steps and weekly dosing with PF’3944 until week 12, followed by monthly dosing to week 28. The primary endpoint of weight reduction from randomization to week 28 was superior to placebo in all four dose regimens tested (P < 0.001). The detailed results from VESPER-3 will be presented on June 6, 2026, at the 86th Scientific Sessions of the American Diabetes Association...PF’3944 also maintained a well-tolerated and favorable safety profile through week 28 that is consistent with the GLP-1 RA class."

P2b data • Obesity

VESPER-4: Efficacy and Safety of MET097 Once-Weekly in People With Overweight or Obesity (clinicaltrials.gov) - P3 | N=3500 | Recruiting | Sponsor: Metsera

New P3 trial • Genetic Disorders • Obesity

VESPER-2: A Study to Evaluate the Efficacy and Safety of Once-Weekly MET097 in Adults With Obesity or Overweight and T2DM (clinicaltrials.gov) - P2 | N=133 | Active, not recruiting | Sponsor: Metsera | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2026 ➔ Mar 2026 | Trial primary completion date: Apr 2026 ➔ Dec 2025

Enrollment closed • Trial completion date • Trial primary completion date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Pfizer wins $10 billion bidding war for Metsera as Novo Nordisk exits (Reuters) - "Metsera accepted a sweetened offer from Pfizer late on Friday, citing U.S. antitrust risks in Novo's bid that it had previously called superior...Pfizer has agreed to pay $86.25 per share in cash, a premium of 3.69% to Metsera's Friday close, Metsera said in a statement. The offer includes $65.60 per share in cash and a contingent value right entitling holders to additional payments of up to $20.65 per share in cash...In a statement, Pfizer said it was pleased to have reached a revised agreement with Metsera, and expects to close the merger soon after Metsera's November 13 shareholder meeting....Metsera's experimental obesity drugs, MET-097i, a GLP-1 injectable, and MET-233i, which mimics the pancreatic hormone amylin, are projected to reach $5 billion in combined peak sales, according to Leerink Partners analyst David Risinger."

Commercial • Sales projection • Obesity

Engineering Multireceptor Nutrient-Stimulated Hormone (NuSH) Analogs for Oral Delivery (OBESITY WEEK 2025) - "Background: Multireceptor agonists may raise the efficacy ceiling relative to mono-agonists. Oral ultra-long acting (ULA) multireceptor agonist peptides have the potential to provide similar body weight loss as injectable multireceptor agonists. In vivo t1/2 for M-0001875 projects to a human t1/2 of ~2 weeks based on preclinical and clinical data for the ULA GLP-1RA MET-097. M-0001875 demonstrated exceptional gastrointestinal stability and achieved therapeutically relevant exposure in dogs following oral administration."

Obesity

The VESPER-1 Trial of MET-097: a Fully Biased and Ultra-Long Acting GLP-1 Receptor Agonist (OBESITY WEEK 2025) - P2 | "The results of these trials will characterize the efficacy and tolerability of the ultra-long acting GLP-1RA MET-097 when dosed weekly. A well-tolerated, efficacious NuSH analog with a simplified-titration or titration-free regimen can reduce barriers to the adoption of these therapies at scale."

Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Pfizer Completes Acquisition of Metsera (Businesswire) - "Through this acquisition Pfizer has added a portfolio of promising therapeutic candidates that are complementary to Pfizer’s Internal Medicine pipeline, including MET-097i, a weekly and monthly injectable GLP-1 receptor agonist (RA) about to begin Phase 3 development; MET-233i, a monthly amylin analog candidate being evaluated as monotherapy and in combination with MET-097i in Phase 1 development..."

M&A • Obesity

Novo Nordisk launches bidding war with Pfizer for obesity drugmaker Metsera (Digital Journal) - "Novo Nordisk’s bid valued the US biotech firm at $6 billion...'Under the terms of the proposal, Novo Nordisk would acquire all outstanding shares of Metsera’s common stock at a price of $56.50 per share in cash.'...In addition to the upfront price, Novo Nordisk also committed to paying up to an additional $21.25 per share depending on the achievement of certain milestones for Metsera’s treatments under development. Pfizer was offering an add-on of $22.5 per share...The American and Danish giants are particularly vying for MET-097i, Metsera’s most advanced treatment, currently in phase 2 clinical trials."

Commercial • Obesity

VESPER-1: A Phase 2b Study to Examine the Safety and Efficacy of Once-Weekly MET097 in Adults With Obesity or Overweight (clinicaltrials.gov) - P2 | N=225 | Active, not recruiting | Sponsor: Metsera | Trial completion date: Oct 2025 ➔ May 2026 | Trial primary completion date: Aug 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Genetic Disorders • Obesity

Metsera Reports Positive Phase 2b Results for First- and Best-in-Class Ultra-long Acting GLP-1 RA Candidate MET-097i, Enabling Rapid Transition into Phase 3 (GlobeNewswire) - "Data support Phase 3 initiation in late 2025...At the highest evaluated dose in VESPER-3, there was minimal diarrhea signal and a risk difference from placebo of 13% nausea and 11% vomiting at 12 weeks after two titration steps....Body weight loss in VESPER-1 was dose-dependent, ranging up to a placebo-subtracted mean of 14.1% at 28 weeks at the 1.2 mg dose level, with individual responses as high as 26.5%. An exploratory analysis at the end of the weekly dosing phase of the study extension of VESPER-1 at 36 weeks demonstrated substantial continued weight loss, highlighting that no plateau had been reached. An exploratory analysis at the end of the weekly dosing phase of the study extension of VESPER-1 at 36 weeks demonstrated substantial continued weight loss, highlighting that no plateau had been reached. As VESPER-3 is ongoing, weight loss is not reported."

New P3 trial • P2b data • Trial status • Obesity

fizer Inc…and Metsera, Inc…announced the companies have entered into a definitive agreement under which Pfizer will acquire Metsera, a clinical-stage biopharmaceutical company accelerating the next generation of medicines for obesity and cardiometabolic diseases. (Pfizer Press Release) - "Under the terms of the agreement, Pfizer will acquire all outstanding shares of Metsera common stock for $47.50 per share in cash at closing, representing an enterprise value of approximately $4.9 billion. Additionally, the agreement includes a non-transferable contingent value right (CVR) entitling holders to potential additional payments of up to $22.50 per share in cash tied to three specific clinical and regulatory milestones: $5 per share following the Phase 3 clinical trial start of Metsera’s MET-097i+MET-233i combination, $7 per share following U.S. Food and Drug Administration (FDA) approval of Metsera’s monthly MET-097i monotherapy, and $10.50 per share following FDA approval of Metsera’s monthly MET-097i+MET-233i combination, if achieved."

Commercial • Obesity

MET-233 is a differentiated efficacious amylin analogue in preclinical studies, combinable with MET-097, an ultra-long acting GLP-1 receptor agonist (EASD 2025) - "Here, we profile MET-233, comparing it to other clinical-stage amylin analogues, cagrilintide, GUB014295, and petrelintide, and present data supporting the development of MET-233 and MET-097 as a combination therapeutic.Materials and Compounds were characterised in vitro via cAMP accumulation assays at human and rat calcitonin receptors (hCTR/rCTR) and human amylin receptor 3 (hAMYR3). In preclinical models, MET-233 is differentiated by its potency (efficacy at very low doses), PK durability, and combinability with MET-097, a fully-biased ULA GLP-1RA. Taken together, these properties suggest the potential for MET-233 to be combined with MET-097 as a differentiated, ULA treatment option for obesity and related diseases."

Preclinical • Metabolic Disorders • Obesity

Metsera to Present Research Highlighting its Next-Generation Obesity Portfolio at the 61st EASD Annual Meeting (GlobeNewswire) - "'Our late-breaker highlights the initial clinical results for our ultra-long acting amylin analog MET-233i, showcasing a potential best-in-class profile. We also have two preclinical presentations, including one highlighting how MET-233i can be combined with MET-097i, our ultra-long acting GLP-1 receptor agonist, in a first-in-category multi-NuSH combination.'"

Late-breaking abstract • P1 data • Preclinical • Obesity

Therapeutic NuSH cocktails: co-administration of an ultra-long acting PYY analogue engineered for tolerability and an ultra-long acting GLP-1 analogue induces significant weight loss in DIO mice (EASD 2025) - "Combination of multiple NuSH with distinct mechanisms of action—here, analogues of GLP-1 and PYY—can achieve greater body weight loss. The long half-life of M-1793 supports dosing weekly or less frequently in humans, consistent with MET-097. Engineering the PK profile, specifically achieving long Tmax and t1/2, of PYY analogues may promote greater tolerability without sacrificing efficacy."

Preclinical • Metabolic Disorders • Obesity

Pipeline Highlights and Upcoming Milestones (Metsera Press Release) - "We expect to release topline data from VESPER-1 together with interim data from the titration phase of VESPER-3 in September 2025. Combined, these data will inform the weekly dosing regimens we plan to investigate in Phase 3 trials; We expect to release topline 28-week results from the monthly dosing portion of VESPER-3 by year-end 2025 or in early 2026; We are on track to initiate the Phase 3 program of MET-097i in late 2025...We expect to announce topline 12-week data from the MET-233i monotherapy trial in late 2025...We expect to announce topline 12-week data from the MET-233/097 co-administration trial by year-end 2025 or in early 2026....MET-097o program and alternate candidate MET-224o on track; four-week topline data for selected lead expected in late 2025."

Clinical data • Preclinical • Obesity

Additional key pipeline programs: Combination and prodrug candidates continue to advance, with multiple clinical milestones expected in late 2025 and early 2026 (Metsera Press Release) - "Preliminary data from co-administration of MET-034, an ultra-long acting GIP RA (Metsera’s third HALO-engineered peptide in clinical testing), with MET-097i are expected in late 2025; IND-enabling studies progressing for MET-815, a prodrug of MET-097i with potential for quarterly maintenance dosing; clinical trial initiation planned for year-end 2025 or early 2026."

New trial • Preclinical • Obesity

Cellular Characterisation of Signalling and Receptor Trafficking Induced by MET-097, a G Protein-Biased GLP-1R Agonist (ADA 2025) - "We aimed to further elucidate the signalling and trafficking profile of MET-097. In vitro BRET-based biosensors were used to compare clinically relevant GLP-1R agonists. Compared to reference agonists (GLP-1/exendin-4/semaglutide), MET-097 acted as a partial agonist for Gαs and Gαq recruitment at both the plasma membrane (36% and 22% of exendin-4) and endosomal compartments (34% and 37% of exendin-4), yet still showed full cAMP response (115% of exendin-4). We speculate the pharmacological attributes of MET-097 may contribute to a unique pharmacodynamic profile. Of particular interest will be to align these attributes with the efficacy and tolerability observed in clinical trials."

Metabolic Disorders • Obesity • ARRB1

MET-097: Preclinical Characterization of a Potent and Ultra-Long-Acting GLP-1 Receptor Agonist (ADA 2025) - "Preclinical characterization of MET-097 suggests best-in-class efficacy and an ultra-long t1/2 for MET-097. The long t1/2 of MET-097 may unlock versatile dosing options and scalability advantages due to superior weight loss per mg of peptide."

Preclinical • Metabolic Disorders • Obesity

A Twelve-Week Trial of MET097—A Potent and Ultra-Long-Acting GLP-1 Receptor Agonist (ADA 2025) - "This 12-week trial demonstrated substantial weight loss with titration-free weekly dosing. Additionally, the two-step escalation arm was exceptionally well tolerated."

Metabolic Disorders • Obesity

Therapeutic NuSH Cocktails—Coadministration of Ultra-Long-Acting GLP-1, GIP, Glucagon, and Amylin Peptide Analogs Induce Profound Weight Loss in DIO Mice (ADA 2025) - "We sought preclinical proof of concept of their mixability and concerted efficacy. ULA analogs of human GLP-1, GIP, glucagon, and amylin afforded MET-097, MET-034, MET-067, and MET-233, respectively—a peptide combo we call M4...The M4 (25 nmol/kg total peptide) effects on body weight and food intake were compared to retatrutide (26 nmol/kg). In minipigs, M4 peptides had similar half-lives (range: 87-114 h)... M4 peptides may allow for infrequent coadministration in humans. Results from chronic M4 administration to rats confirm that engaging multiple mechanisms can achieve more weight loss. Further, a polymolecular approach allows adjusting of individual agent dose levels to enhance M4's efficacy to tolerability window, even in a semipersonalized way."

Preclinical • Metabolic Disorders

Safety, Tolerability, PK, and Efficacy of MET097—A Next-Generation Nutrient-Stimulated Hormone Peptide Analog for Chronic Weight Management (ADA 2025) - "MET097, an ultra-long acting GLP-1RA, results in significant weight loss sustained 8 wks post-treatment. Ongoing Ph2 studies will evaluate weekly and monthly dosing regimens with and without titration."

Clinical • Metabolic Disorders • Obesity