MET-097 / Amneal, Pfizer - LARVOL DELTA

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

MET-233 Is an Ultra-Long-Acting Amylin Receptor Agonist (ADA 2025) - "The pharmacokinetics of MET-233 and cagrilintide were compared after single administration in pigs... The long half-life of MET-233 observed in pigs suggests that infrequent administration in humans may be achievable. Results from chronic administration to rats indicate that MET-233 is highly effective, and additive impact on body weight was observed when coadministered with MET-097. The potency, durability, and combinability of MET-233 and MET-097 highlight the potential of MET-233 as a differentiated treatment option."

Metabolic Disorders • Obesity

Based on positive topline data, Metsera is rapidly advancing MET-233i as a monotherapy and in combination with MET-097i: - "An ongoing monotherapy trial evaluates 12 weekly doses of MET-233i with dose titration, followed by an exposure-matched monthly dose at week 13. Topline data from this trial are expected in late 2025; Metsera has extended an ongoing co-administration trial of MET-233i and MET-097i to twelve weeks, with topline data expected by year-end 2025 or early 2026; The Company also expects to report topline clinical data from its ultra-long acting GIP receptor agonist, MET-034i, in combination with MET-097i, in late 2025. We anticipate that MET-034i will be the third peptide engineered with Metsera’s HALO™ platform to enter clinical testing."

New trial • P1 data • P2b data • Pipeline update • Obesity

Metsera Announces Positive Phase 1 Data of First-in-Class Once-Monthly Amylin Candidate MET-233i (Metsera Press Release) - P1 | N=132 | NCT06924320 | Sponsor: Metsera | "Metsera, Inc...announced positive topline data from the Phase 1 clinical trial of MET-233i, an ultra-long acting amylin analog engineered for class-leading durability, potency, and combinability with Metsera’s fully-biased monthly GLP-1 receptor agonist candidate, MET-097i. In the study, MET-233i demonstrated up to 8.4% mean placebo-subtracted weight loss at Day 36, a 19-day observed half-life supporting once-monthly dosing, and a favorable tolerability profile with no safety signals...MET-233i’s exposure profile after multiple doses matched that of MET-097i, supporting combinability as a potential first-in-category once-monthly multi-NuSH combination...There were no severe or serious adverse events observed in the SAD or MAD portion of the trial to date."

P1 data • Obesity

Metsera to Present New Research Highlighting the Breadth and Momentum of its Next-Generation Obesity Portfolio at the 85th Scientific Sessions of the American Diabetes Association (GlobeNewswire) - "Four presentations on MET-097i, a fully biased, monthly, ultra-long acting GLP-1 receptor agonist, including two clinical data presentations; Additional preclinical presentations on other differentiated portfolio assets, including MET-233i, a monthly, ultra-long acting amylin analog."

Clinical data • Preclinical • Obesity

MET-097i: Phase 2b program on track, with Phase 3 initiation planned in late 2025 (GlobeNewswire) - "We plan to release additional results from this trial at the American Diabetes Association’s (ADA) 85th Scientific Sessions, in addition to several other presentations focused on MET-097i...VESPER-1 is designed to assess weight loss of different weekly doses of MET-097i over 28 weeks in participants with obesity or overweight without type 2 diabetes. The trial was fully enrolled as of end-2024, and preliminary results are expected in mid-2025; VESPER-2 is designed to assess weight loss and tolerability of different weekly doses of MET-097i over 28 weeks in participants with type 2 diabetes and obesity or overweight. Preliminary results are expected in early 2026; VESPER-3 is designed to assess weight loss and tolerability of multiple monthly doses of MET-097i after 12 initial weekly doses in individuals with obesity or overweight without type 2 diabetes. Preliminary results are expected by year-end 2025 or in early 2026..."

Clinical data • New P3 trial • Obesity

VESPER-3: A Phase 2b Study to Evaluate the Efficacy and Safety of Once-Monthly MET097 in Adults With Obesity or Overweight (clinicaltrials.gov) - P2 | N=250 | Active, not recruiting | Sponsor: Metsera | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity

Oral peptide platform: MET-097o oral program accelerated and alternate oral candidate MET-224o on track; four-week data for selected lead expected in late 2025 (GlobeNewswire) - "We plan to initiate Phase 1 trials of MET-097o and MET-224o in mid-2025, and to select and advance the best-performing oral candidate based on the Phase 1 clinical data. Preliminary four-week weight loss, tolerability, and pharmacokinetic data for the selected lead candidate are expected in late 2025."

P1 data • Preclinical • Obesity