garetosmab (REGN2477) / Regeneron, Sanofi - LARVOL DELTA

Opportunities to Reduce Patient Burden in Clinical Trials for People Living With Obesity in the US (OBESITY WEEK 2025) - "Therapies, including bimagrumab (anti-activin type II), trevogrumab (anti-myostatin) and garetosmab (anti-activin A), aim to improve the quality of weight loss by preserving lean mass and augmenting the amount of weight loss attributable to fat mass. Integrating the perspective of people living with obesity will ensure that clinical trials are reflective of real-world experiences, reducing patient burden, improving recruitment and retention and ultimately generating high quality data."

Clinical • Genetic Disorders • Obesity

Pharmacological intervention: Challenges and promising outcomes for fat loss and preservation of lean body mass in the treatment of overweight and type 2 diabetes. (PubMed, Diabetes Obes Metab) - "Activin II receptor inhibition with bimagrumab demonstrated significant preservation and increases in LBM, along with FM reduction, in both preclinical and phase 2 studies in individuals with overweight and T2D. Similar effects were observed for myostatin and activin A inhibitors (trevogrumab, garetosmab), latent myostatin inhibitors (apitegromab, SRK-439), and Selective Androgen Receptor Modulators (enobosarm)...Pharmacological adjunct therapies show potential for improving body composition and physical function during GLP-1 RA-induced weight loss. Preliminary findings are promising, but larger, controlled trials are necessary to confirm efficacy and safety before clinical implementation can be considered."

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

A Narrative Review of Phase II and III Clinical Trials for the Pharmacological Treatment of Fibrodysplasia Ossificans Progressiva (FOP): Efficacy, Safety, and Challenges in Treatment Strategies. (PubMed, Drug Des Devel Ther) - "Promising pharmacological approaches include retinoic acid receptor γ (RARγ) agonists, such as palovarotene, and monoclonal antibodies targeting activin A, like garetosmab. Nevertheless, safety concerns and the complexities of clinical trial implementation highlight the need for innovative approaches to ensure effective and equitable treatments. Future research should prioritise long-term safety, efficacy, and patient-centred outcomes to improve FOP management."

Journal • P2 data • P3 data • Review • Genetic Disorders • Rare Diseases

Study of Safety and Effects of Garetosmab in Healthy Obese Men and Post-Menopausal Women (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Regeneron Pharmaceuticals | N=48 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Genetic Disorders • Obesity • IGF1

Results from Phase 2 COURAGE Trial Demonstrating Potential to Improve Quality of GLP-1 receptor agonist-induced Weight Loss by Preserving Lean Mass, Presented at EASD (GlobeNewswire) - "Complete 26-week results further demonstrate that combining semaglutide with trevogrumab (anti-GDF8/anti-myostatin) helped prevent about half of semaglutide-induced loss of lean mass, while increasing fat mass loss. Numeric improvements in metabolic and lipid parameters including waist circumference, blood pressure, cholesterol, triglycerides and A1C, were observed across all treatment groups."

P2 data • Obesity

Anti-Myostatin (trevogrumab) with and without anti-Activin a (garetosmab) preserves lean mass and increases loss of fat mass in people with obesity treated with semaglutide (EASD 2025) - P2 | "A weight management strategy combining trevo with or without garet on top of sema is associated with LM preservation and greater FM loss. The full dataset of this study will be presented at EASD."

Late-breaking abstract • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Phase 3, Randomized, Placebo-Controlled Study to Assess the Safety and Efficacy of Garetosmab in Fibrodysplasia Ossificans Progressiva: Baseline Characteristics of Patients in the OPTIMA Study (ASBMR 2025) - P3 | No abstract available

Clinical • P3 data

COURAGE: A Study to Test if Trevogrumab or Trevogrumab With Garetosmab When Taken With Semaglutide is Safe and How Well They Work in Adult Patients With Obesity for Weight Loss, Fat Loss, and Lean Mass Preservation (clinicaltrials.gov) - P2 | N=1005 | Active, not recruiting | Sponsor: Regeneron Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity • APOB

Icovamenib Rescues Human Myotube Atrophy Ex Vivo and Displays Complete Lean Mass Preservation in a Type 2 Diabetes Rat Model (ADA 2025) - "The direct impact of icovamenib on myotube recovery and lean mass preservation was investigated. Ex-vivo derived 3D-engineered healthy human myotubes were cultured with icovamenib or garetosmab for 16 days, beginning one day prior to atrophy induction with Activin A or dexamethasone (dex), and myotube morphology was assessed. Icovamenib enhanced healthy myotube morphology and promoted recovery from drug-induced atrophy ex vivo. In ZDF rats, combination of icovamenib and low dose sem induced greater body weight reduction with protected lean mass. Collectively, these results support combination of icovamenib with GLP-1RA based therapies as a promising strategy to enhance body weight reduction with preservation of muscle homeostasis."

Late-breaking abstract • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Interim Results from Ongoing Phase 2 COURAGE Trial Confirm Potential to Improve the Quality of Semaglutide (GLP-1 receptor agonist)-induced Weight Loss by Preserving Lean Mass (Regeneron Pharmaceuticals Press Release) - P2 | N=999 | COURAGE (NCT06299098) | Sponsor: Regeneron Pharmaceuticals | "Regeneron...announced interim results from the ongoing Phase 2 COURAGE trial investigating novel combinations of semaglutide (GLP-1 receptor agonist) and trevogrumab (anti-GDF8/anti-myostatin) with or without garetosmab (anti-activin A) for the treatment of obesity. The trial demonstrated that approximately 35% of semaglutide-induced weight loss was due to loss of lean mass, and further demonstrated that combining semaglutide with trevogrumab with or without garetosmab helped preserve lean mass while increasing loss of fat mass. The interim analysis was conducted when 50% of patients reached week 26 in the trial. The combination of semaglutide with trevogrumab was generally well-tolerated; the triplet combination of semaglutide with both antibodies had a substantially higher rate of discontinuations due to tolerability issues and other adverse events..."

P2 data • Obesity

Study of Safety and Effects of Garetosmab in Healthy Obese Men and Post-Menopausal Women (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals

New P1 trial • Genetic Disorders • Obesity • IGF1

COURAGE: A Study to Test if Trevogrumab or Trevogrumab With Garetosmab When Taken With Semaglutide is Safe and How Well They Work in Adult Patients With Obesity for Weight Loss and Fat Loss (clinicaltrials.gov) - P2 | N=999 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Active, not recruiting ➔ Recruiting | Trial completion date: Aug 2026 ➔ Nov 2026 | Trial primary completion date: Feb 2026 ➔ May 2026

Enrollment open • Trial completion date • Trial primary completion date • Genetic Disorders • Obesity • APOB

OPTIMA: A Study to Assess Safety, Tolerability and Efficacy of Garetosmab Versus Placebo Administered Intravenously (IV) in Adult Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P3 | N=63 | Active, not recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: Sep 2026 ➔ Feb 2029

Trial completion date • ACVR1

A Generic Detection Method for the Doping Control Analysis of Fc-Fusion Proteins and Monoclonal Antibodies in Equine Plasma. (PubMed, Drug Test Anal) - "This study is aimed at developing a generic detection method for doping control analysis of nine targeted proteins, each containing the Fc domain of human IgG or IgG from other species in equine plasma, namely, three recombinant Fc-fusion proteins (sotatercept, follistatin-Fc (FST-Fc), and erythropoietin-Fc (EPO-Fc)) and six mAbs (bimagrumab, domagrozumab, garetosmab, landogrozumab, bedinvetmab (Librela), and frunevetmab (Solensia)). The results have demonstrated the method's applicability to equine doping control. This generic method involving affinity purification by Protein A has provided a pragmatic and effective approach to cope with the doping control of novel Fc domain-containing proteins."

Journal • ACVR2A

Select Upcoming 2025 Milestones (GlobeNewswire) - "Report additional data from Phase 1/2 study for DB-OTO (AAV-based gene therapy) in patients with hearing deficit due to variants of the otoferlin gene (mid-2025); Report results from Phase 3 study for pozelimab (C5 antibody) in combination with cemdisiran in myasthenia gravis (second half 2025)....Report results from Phase 2 study for semaglutide in combination with trevogrumab (myostatin antibody) with and without garetosmab (Activin A antibody) in obesity (second half 2025); Report results from Phase 2 study for mibavademab (LEPR agonist antibody) in combination with tirzepatide in obesity (second half 2025); Report results from Phase 3 study for garetosmab (Activin A antibody) in fibrodysplasia ossificans progressiva (FOP) (second half 2025)."

Clinical data • Myasthenia Gravis • Obesity • Rare Diseases

The impact of weight loss on fat-free mass, muscle, bone and hematopoiesis health: Implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation. (PubMed, Metabolism) - "Novel compounds in the pipeline, such as Bimagrumab, Trevogrumab, and Garetosmab-which inhibit activins and myostatin signaling-have demonstrated promise in preventing muscle loss while promoting fat loss...Since this dual therapeutic approach could help address the challenges of muscle and bone loss during weight loss, well-designed studies are needed to optimize these strategies and assess long-term benefits. For the time being, considerations like advanced age and prefrailty may affect the choice of suitable candidates in clinical practice for current and emerging anti-obesity medications due to the associated risk of sarcopenia."

Journal • Review • Cardiovascular • Diabetes • Genetic Disorders • Hematological Disorders • Metabolic Disorders • Obesity • Osteoporosis • Sarcopenia

COURAGE: A Study to Test if Trevogrumab or Trevogrumab With Garetosmab When Taken With Semaglutide is Safe and How Well They Work in Adult Patients With Obesity for Weight Loss and Fat Loss (clinicaltrials.gov) - P2 | N=999 | Active, not recruiting | Sponsor: Regeneron Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity

Combined GDF8 and Activin A Blockade in Healthy Volunteers: Safety, Efficacy, and Pharmacokinetics (OBESITY WEEK 2024) - "In healthy participants, trevogrumab and garetosmab were generally well tolerated. Combination tx led to greater-than-additive increases in muscle mass, with reductions in fat. Results suggest that GDF8 and activin A are key negative regulators of muscle mass in humans and that combination blockade may be a promising therapeutic approach in muscle atrophy and obesity settings."

Clinical • PK/PD data • Genetic Disorders • Muscular Atrophy • Obesity

COURAGE: A Study to Test if Trevogrumab or Trevogrumab With Garetosmab When Taken With Semaglutide is Safe and How Well They Work in Adult Patients With Obesity for Weight Loss and Fat Loss (clinicaltrials.gov) - P2 | N=999 | Recruiting | Sponsor: Regeneron Pharmaceuticals | N=624 ➔ 999 | Trial primary completion date: Jun 2026 ➔ Feb 2026

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

Comparison of PET/CT versus CT only in the assessment of new heterotopic ossification bone lesions in patients with fibrodysplasia ossificans progressiva. (PubMed, Bone) - P2 | "LUMINA-1, a phase 2, randomized, double-blind study (NCT03188666), evaluated the safety and efficacy of garetosmab, an anti-activin A antibody, versus placebo in adult patients with FOP...CT-only imaging showed similar performance to PET/CT in the detection and characterization of new HO lesions. CT-only imaging therefore is a viable option for the assessment of therapies on new HO in patients with FOP."

Clinical • Journal • Rare Diseases

INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling. (PubMed, Acta Pharmacol Sin) - "Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy with garetosmab or atezolizumab. We demonstrate that INHBA and activin A are involved in anti-tumor immunity by inhibiting the IFN-γ signaling pathway, which can be considered as potential targets to improve the responsive rate of PD-1/PD-L1 blockade."

IO biomarker • Journal • Breast Cancer • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRCA • CD4 • CD8 • CXCL10 • CXCL9 • IFNG • INHBA

Characterization of flare-ups and impact of Garetosmab in adults with Fibrodysplasia Ossificans Progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial. (PubMed, J Bone Miner Res) - P2 | "In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 weeks, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups with effects sustained during the entire trial."

Clinical • Journal • Retrospective data • Pain • Rare Diseases

OPTIMA: A Study to Assess Safety, Tolerability and Efficacy of Garetosmab Versus Placebo Administered Intravenously (IV) in Adult Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P3 | N=63 | Active, not recruiting | Sponsor: Regeneron Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2026 ➔ Oct 2026 | Trial primary completion date: Apr 2025 ➔ Jul 2025

Enrollment closed • Trial completion date • Trial primary completion date • ACVR1

COURAGE: A Study to Test if Trevogrumab or Trevogrumab With Garetosmab When Taken With Semaglutide is Safe and How Well They Work in Adult Patients With Obesity for Weight Loss and Fat Loss (clinicaltrials.gov) - P2 | N=624 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Active, not recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

The Effect of Combined Activin A and Myostatin Blockade on Body Composition—A Phase 1 Trial (ADA 2024) - "Combined administration of trevogrumab and garetosmab led to dose-dependent, greater‑than‑additive increases in TMV and lean mass, while decreasing fat mass in healthy participants."

P1 data • Diabetes • Metabolic Disorders