PF-08653945 / Pfizer - LARVOL DELTA

SOLIS-1: A Study of PF-08653945 and PF-08653944 in Adults With Overweight or Obesity (clinicaltrials.gov) - P2 | N=940 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Metabolic Disorders • Obesity

Co-formulation of ASC36 and ASC35, once-monthly amylin receptor agonist and GLP-1R/GIPR agonist, demonstrated superior weight loss to eloralintide/tirzepatide combo in DIO rats (EASD 2026) - "Animals were randomly divided into 4 groups (N=7 in each group) including vehicle control group, eloralintide_tirzepatide FDC group, MET-233i_tirzepatide FDC group and ASC36_35 FDC group. Based on these encouraging preclinical data, we believe ASC36_35 FDC has the potential to lead to greater weight loss reduction in people with obesity. The clinical studies of ASC36_35 FDC are warranted."

Preclinical • Metabolic Disorders • Obesity

A Study to Learn How the Study Medicine Called PF-08653945 is Taken up Into the Blood in Adults With Overweight or Obesity (clinicaltrials.gov) - P1 | N=57 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

Lecanemab in symptomatic PSEN1 p.Met233Val early-onset Alzheimer's disease: Neuroimaging safety, regional amyloid-PET dynamics, and longitudinal plasma biomarkers. (PubMed, Alzheimers Dement (Amst)) - "Lecanemab demonstrated neuroimaging safety and evidence of biological target engagement in this symptomatic PSEN1 p.Met233Val ADAD carrier. These longitudinal neuroimaging and plasma biomarker findings may help inform interpretation of treatment responses in genetically defined ADAD."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Dystonia • Movement Disorders • APOE • GFAP • NEFL • p-tau181

A Study to Learn How the Study Medicine Called PF-08653945 is Taken up Into the Blood in Adults With Overweight or Obesity (clinicaltrials.gov) - P1 | N=57 | Not yet recruiting | Sponsor: Pfizer

New P1 trial • Genetic Disorders • Obesity

Amylin Analogs: The Next Major Class of Weight Loss Therapy: A Review of Experimental Data and Early-Phase Clinical Trials. (PubMed, Diabetes Obes Metab) - "Amylin-based therapies represent a promising addition to the evolving treatment landscape of obesity. Their emerging efficacy as both standalone and combination therapies supports a multi pathway approach to addressing the biological complexity and heterogeneity of the disease."

Journal • Genetic Disorders • Obesity

A Study of PF-08653945 and PF-08653944 in Adults With Overweight or Obesity (SOLIS-1) (clinicaltrials.gov) - P2 | N=872 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Metabolic 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=381 | Recruiting | Sponsor: Pfizer | N=132 ➔ 381 | Trial completion date: Mar 2027 ➔ Sep 2026 | Trial primary completion date: Jan 2027 ➔ Sep 2026

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

A Study of MET233 in Individuals With Obesity or Overweight (clinicaltrials.gov) - P1 | N=144 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed | Phase classification: P1/2 ➔ P1

Phase classification • Trial completion • Genetic Disorders • Obesity

A Study of PF-08653945 and PF-08653944 in Adults With Overweight or Obesity (SOLIS-1) (clinicaltrials.gov) - P2 | N=872 | Not yet recruiting | Sponsor: Pfizer

New P2 trial • Genetic Disorders • Metabolic Disorders • Obesity

Long-acting amylin-related peptides as therapies for obesity and type 2 diabetes. (PubMed, Peptides) - "The first therapeutically useful amylin receptor (AMYR) agonist, pramlintide was based upon the structure of non-aggregating rat amylin and found limited application as an adjunct to insulin therapy...Amongst these agents is the dual AMYR/ calcitonin-receptor (CTR) agonist, cagrilintide that has also been co-formulated into a once weekly subcutaneous injection with the long-acting glucagon-like peptide-1receptor (GLP-1R) agonist, semaglutide (CagriSema)...Several recently developed long-acting amylin analogues have shown strong efficacy as monotherapy in clinical trials: these include eloralintide, petrelintide, Met-233 and AZD6234...Gastrointestinal side effects, especially nausea, similar to those reported for GLP-1R agonists are commonplace during initiation and up-titration of amylin analogues but mostly resolve during continued use. Evidence is emerging that long-acting AMYR agonists may show potential therapeutic benefits in treatment of patients with fatty liver..."

Journal • Review • Cardiovascular • Diabetes • Genetic Disorders • Hepatology • Hypertension • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

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

A Study of MET233 in Individuals With Obesity or Overweight (clinicaltrials.gov) - P1/2 | N=120 | Active, not recruiting | Sponsor: Metsera | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2026 ➔ Apr 2026 | Trial primary completion date: Oct 2025 ➔ Feb 2026

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

Efficacy of lecanemab in early-onset Alzheimer's disease with a novel PSEN1 (p.Met233Thr) mutation: a case report. (PubMed, Neurol Sci) - No abstract available

Journal • Alzheimer's Disease • CNS Disorders

Association Study of OATP1B3 Polymorphisms on Hepatic Uptake and Drug-Drug Interaction In Vitro. (PubMed, ACS Omega) - "The SNPs rs4149117 and rs7311358, corresponding to Ser112Ala and Met233Ile substitutions, were confirmed as the most frequent alleles...However, because effects are substrate-specific and other hepatic transporters may compensate, final clinical interpretation should be substrate- and evidence-based. Targeted pharmacokinetics and pharmacogenetic studies remain necessary for drugs where OATP1B3 is a major disposition determinant."

Journal • Preclinical

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

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

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

Pharmacokinetics, weight loss, and tolerability of the ultra-long acting amylin analogue MET-233 (EASD 2025) - P1/2 | "In this clinical trial, MET-233 demonstrated a pharmacokinetic profile consistent with monthly dosing, robust body weight loss, and placebo-like tolerability at anticipated starting doses."

Late-breaking abstract • PK/PD data • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

[EASD] Metsera monthly amylin analogue 'MET-233' phase 1 study showed up to 8.4% weight loss. [Google translation] (BioNews) - "In a single-dose (SAD) study, subjects were assigned to five dose groups, ranging from 0.15 mg to 2.4 mg, or a placebo. Analysis on day 8 revealed that a single dose of MET-233 alone resulted in up to 5.3% weight loss compared to the placebo, demonstrating a significant weight loss effect even in the short term....In the multiple-dose regimen (MAD), patients received weekly doses of 0.15–1.2 mg for 5 weeks. At day 36, the MET-233 group demonstrated up to 8.4% weight loss compared to placebo, with the effect being more pronounced in doses of 0.6 mg or higher....There were no safety concerns."

P1 data • 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

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

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