ponsegromab (PF-06946860) / Pfizer - LARVOL DELTA

Efficacy and safety of ponsegromab in patients with colorectal cancer and cachexia: A subgroup analysis of the PROACC-1 phase 2 study. (ASCO-GI 2026) - P2 | "Funded by Pfizer Clinical Trial Registration Number: NCT05546476 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Clinical • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

RIVER-mPDAC: A phase 2b/3 study of ponsegromab for the treatment of cachexia in patients with metastatic pancreatic ductal adenocarcinoma receiving first-line chemotherapy. (ASCO-GI 2026) - P2/3 | "Funded by Pfizer Clinical Trial Registration Number: NCT06989437 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Clinical • Metastases • P2/3 data • P2b data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

The evolving landscape of cancer cachexia prevention: A review of metronomic chemotherapy and drug repurposing strategies. (PubMed, Med Oncol) - "A good number of preclinical and early clinical studies have shown evidence for both approaches, particularly for Ponsegromab, a Growth Differentiation Factor-15 (GDF-15) inhibitor. Due to the multifactorial nature of cachexia, a multimodal, integrated intervention is a good substitute for the maximum tolerated dose, which can be effective against it. Future directions in cancer therapy should emphasize the development of robust clinical trial designs with cachexia-specific endpoints to advance precision prevention strategies."

Journal • Review • Cachexia • Metabolic Disorders • Muscular Atrophy • Oncology • GDF15

Advancements of investigational agents for cancer cachexia: what clinical progress have we seen in the last 5 years? (PubMed, Expert Opin Investig Drugs) - "This review covers key investigational therapies developed over the past five years, with a focus on agents targeting Growth Differentiation Factor 15 (GDF-15), including ponsegromab, AV-380, and NGM120. Additional agents include ghrelin receptor agonists (e.g. anamorelin), anabolic/catabolic modulators (ACM-001), and cannabinoids (ART27.13). The evolving role of low-dose olanzapine is also discussed in the 2023 ASCO guideline update...The lack of standardized endpoints, heterogeneity of the syndrome, and absence of FDA-approved treatments remain major barriers to treatment implementation. Multimodal strategies combining pharmacological treatment with nutritional and rehabilitative support are likely to define future therapeutic success."

Journal • Cachexia • Oncology • GDF15

Nutrition in cachexia: support by pharmacological options? (DGHO 2025) - "According to initial clinical studies there is a group of particularly promising agents, including: the selective androgen enobosarm, S-pindolol, which has a mixed effect on beta receptors, the central appetite stimulant anamorelin, which has been approved in Japan, the cytokine-blocking substances bermekimab (anti-IL1alpha), tocilizumab (anti-IL6) and ruxolitinib (Jak1/2 inhibitor), the atypical neuroleptic olanzapine and newer GDF-15 antibodies such as ponsegromab. For approval, effects on the spectrum of symptoms, performance and body composition will probably be required."

Anorexia • Cachexia • Fatigue • GDF15 • IL1A

Ponsegromab: The new miracle drug for cancer cachexia. (PubMed, Indian J Pharmacol) - No abstract available

Journal • Cachexia • Oncology

GDF-15 levels and clinical correlates in head and neck cancer patients: developing a risk model for cachexia (COSA 2025) - " Adults diagnosed with HNC, scheduled to receive definitive cisplatin-based chemoradiotherapy, were recruited from four tertiary hospitals in Australia and Italy. These pilot data suggest aberrant GDF15 production occurs in HNC patients, identifying a new clinical cohort that may benefit from ponsegromab."

Clinical • Colorectal Cancer • Head and Neck Cancer • Oncology • Pancreatic Cancer • Solid Tumor • GDF15

Efficacy and safety of ponsegromab in patients with cancer-associated cachexia: Results from the open-label extension of a randomized, placebo-controlled, phase II study (ESMO 2025) - P2 | "Table: LBA102 Baseline Wk 12 Wk 24 Wk 52 Wk 64 N Mean (SD) weight, kg N Mean (SD) CFB, kg N Mean (SD) CFB, kg N Mean (SD) CFB, kg N Mean (SD) CFB, kg All Part B Participants 117 56.2 (12.3) 114 +1.26 (3.68) 81 +2.74 (4.89) 43 +4.43 (5.95) 37 +5.18 (5.93) PART A → PART B TREATMENT Placebo → Pons 400 mg 26 53.4 (10.7) 24 -0.30 (2.03) 18 +0.89 (2.49) 6 +1.63 (3.90) 6 +2.28 (3.41) Pons 100 mg → Pons 400 mg 27 52.8 (12.8) 27 +0.84 (3.18) 21 +1.68 (4.51) 11 +4.86 (4.58) 9 +5.57 (4.48) Pons 200 mg → Pons 400 mg 35 58.5 (13.8) 34 +1.36 (3.70) 23 +4.01 (4.70) 14 +4.67 (7.43) 11 +4.01 (6.78) Pons 400 mg → Pons 400 mg 29 58.9 (10.4) 29 +2.83 (4.57) 19 +4.11 (6.47) 12 +5.15 (6.22) 11 +7.61 (6.72) Abbreviations: CFB- change from baseline; Pons- ponsegromab. Conclusions Improvements in body weight during 12-week Part A were maintained with ponsegromab through 64 weeks in Part B. Participants assigned to placebo in Part A showed stabilization of weight during Part B, but weight..."

Clinical • Late-breaking abstract • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • GDF15

A Study to Learn About the Medicine Ponsegromab in Adults With Cancer of the Pancreas Which Has Spread and Caused Significant Body Weight Loss and Fatigue (clinicaltrials.gov) - P2/3 | N=982 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open • Cachexia • Fatigue • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Latest Updates on Sarcopenia and Cachexia: Insights from the 17th Sarcopenia, Cachexia, and Wasting Disorders Conference. (PubMed, J Bone Metab) - "The conference also highlighted promising clinical advancements, including the HIPGEN trial on placental-expanded stromal cells for muscle regeneration in hip fracture patients and the ponsegromab study targeting growth/differentiation factor-15 inhibition to mitigate cancer cachexia-associated muscle wasting. This review highlights the integration of basic science, innovative diagnostics, and clinical applications as a promising framework for addressing the complex challenges posed by muscle-wasting disorders. As the field progresses, these insights offer hope for improving the quality of life and survival of affected patients."

Journal • Cachexia • Developmental Disorders • Metabolic Disorders • Muscular Atrophy • Musculoskeletal Diseases • Oncology • Sarcopenia • GDF15

The Multifaceted Role of Growth Differentiation Factor 15 (GDF15): A Narrative Review from Cancer Cachexia to Target Therapy. (PubMed, Biomedicines) - "Targeting the GDF15-GFRAL axis appears therapeutically promising: the monoclonal antibody ponsegromab improved cachexia-related outcomes in the PROACC-1 trial, while visugromab combined with nivolumab enhanced immune response in ICI-refractory tumors. Further investigation is warranted to delineate the role of GDF15 across malignancies, refine patient selection, and evaluate combinatorial approaches with existing treatments."

IO biomarker • Journal • Review • Cachexia • Genito-urinary Cancer • Head and Neck Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • GDF15

GDF15 modulates aging-associated adaptions in the mechanoresponse of periodontal ligament fibroblasts. (PubMed, J Orofac Orthop) - "Aging altered the mechanobiological response of PdL fibroblasts by promoting a hyperinflammatory microenvironment and shifting bone remodeling towards degenerative processes. Senescence-associated increases in GDF15 contributed to these changes by force-dependent intra- and extracellular signaling pathways. Targeting GDF15 could offer a therapeutic potential to optimize bone remodeling and improve orthodontic care for the elderly."

Journal • Inflammation • GDF15

Future landscape: Emerging therapies, novel drug targets, GDF-15 & ponsegromab (ESMO-GI 2025) - "Sponsored By Pfizer"

Gastrointestinal Cancer • Oncology • GDF15

GDF15 LEVELS AND CLINICAL CORRELATES IN HEAD AND NECK CANCER PATIENTS: DEVELOPING A RISK MODEL FOR CACHEXIA (MASCC-ISOO 2025) - "Methods Adults diagnosed with HNC, scheduled to receive definitive cisplatin-based chemoradiotherapy, were recruited from four tertiary hospitals in Australia and Italy. Serum GDF15 levels were highly elevated following chemoradiotherapy compared to baseline (4.5-fold, P<0.0001), and correlated with reductions in weight (R2=0.2, P=0.0027), UAC (R2=0.1714, P=0.0047) and grip strength (R2=0.3779, P<0.0001). Conclusions These pilot data suggest aberrant GDF15 production occurs in HNC patients, identifying a new clinical cohort that may benefit from ponsegromab."

Clinical • Cachexia • Colorectal Cancer • Head and Neck Cancer • Oncology • Pancreatic Cancer • Solid Tumor • GDF15

A Study to Learn About the Medicine Ponsegromab in Adults With Cancer of the Pancreas Which Has Spread and Caused Significant Body Weight Loss and Fatigue (clinicaltrials.gov) - P2/3 | N=982 | Not yet recruiting | Sponsor: Pfizer | Trial completion date: Jan 2029 ➔ Jan 2030 | Trial primary completion date: Jan 2029 ➔ Feb 2028

Trial completion date • Trial primary completion date • Cachexia • Fatigue • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Sarcopenia in Ageing and Chronic Illness: Trial Endpoints and Regulatory Issues. (PubMed, J Cachexia Sarcopenia Muscle) - "Furthermore, novel therapeutic approaches were explored, including 20-hydroxyecdysone, enobosarm, anamorelin, ponsegromab, and nutritional supplementation, alongside broader strategies targeting myostatin-activin signalling inhibition and Akt pathway activation. Given that the population that may be addressed in aging associated sarcopenia is vast, the safety requirement standards applied for studies may be equivalent to those of studies in type 2 diabetes mellitus. Some argued at the meeting that this would make study programs so large that from an economic standpoint only therapies that significantly impact on morbidity/mortality outcomes have a chance to be considered commercially feasible for development."

Journal • Cachexia • Diabetes • Metabolic Disorders • Sarcopenia • Type 2 Diabetes Mellitus

Baseline circulating growth differentiation factor-15 and the cancer phenotype in the PROACC-1 phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia. (ASCO 2025) - P2 | "Among patients with cancer cachexia, GDF-15 elevation was more pronounced in those with more advanced cancer, sarcopenia, and worse performance status. In addition, GDF-15 levels were negatively correlated with markers of nutritional status."

Clinical • P2 data • Cachexia • Colorectal Cancer • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcopenia • Solid Tumor • GDF15

Psychometric Validation and Meaningful Within-Patient Change of the FAACT-5IASS in Patients With Cancer Cachexia (ISPOR 2025) - P2 | " We evaluated the measurement properties of the FAACT-5IASS using data from the ponsegromab randomized, double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov number=NCT05546476) in adult patients with NSCLC, colorectal, or pancreatic cancer and diagnosis of cachexia based on Fearon criteria... The FAACT-5IASS demonstrated robust psychometric properties and a MWPC of 2.86-3.58, supporting the use of the scale in research focused on evaluating appetite and anorexia symptoms in cancer cachexia patients."

Clinical • Anorexia • Cachexia • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

A Study to Learn About the Medicine Ponsegromab in Adults With Cancer of the Pancreas Which Has Spread and Caused Significant Body Weight Loss and Fatigue (clinicaltrials.gov) - P2/3 | N=982 | Not yet recruiting | Sponsor: Pfizer

New P2/3 trial • Cachexia • Fatigue • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

PROACC-1: Study of the Efficacy and Safety of Ponsegromab in Patients With Cancer, Cachexia and Elevated GDF-15 (clinicaltrials.gov) - P2 | N=187 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Anorexia • Cachexia • Colorectal Cancer • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • GDF15

Humanized GDF15 model for simulating weight loss induced by GDF15 secretion in tumors (AACR 2025) - "After 7 days of inoculation, the mice were grouped based on body weight and tumor size, and the treatment group received 10 mg/kg of a ponsegromab analog on the same day. We observed significant weight gain in the treated group compared to the control group, indicating that B-hGDF15 mice and B-hGDF15 MC38 provide an excellent preclinical in vivo model for testing GDF15-targeted drugs."

Oncology • GDF15

Preclinical models of cancer cachexia: Bridging the gap to clinical applications (AACR 2025) - "Motor function assessed via rotarod performance, and grip strength showed coordination and strength impairments in tumor-bearing mice, while Ponsegromab significantly improved grip strength and physical performance in comparison to the hIgG1-treated control group.In conclusion, our validated preclinical cachexia models closely align with clinical CC manifestations, providing a robust platform for the evaluation of novel therapeutic strategies. These models enable detailed exploration of CC mechanisms and support the development of effective interventions to mitigate cachexia and improve patient outcomes."

Preclinical • Oncology • GDF15

FL-501 is a potential best in class GDF-15 inhibitor with extended half-life and potent anti-cachexia activity in preclinical models (AACR 2025) - "In this therapeutic model, mice were treated with cisplatin (5 mg/kg) alone or in combination with either FL-501 or ponsegromab...Further, the targeted inhibition of GDF-15 with FL-501 was able to effectively reverse characteristics of cancer cachexia in multiple pre-clinical models. Taken together, these findings support the continued evaluation of FL501 and its progression into the clinic."

Preclinical • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GDF15

GARDEN TIMI 74: A Study of Ponsegromab in People With Heart Failure (clinicaltrials.gov) - P2 | N=457 | Terminated | Sponsor: Pfizer | N=781 ➔ 457 | Trial completion date: May 2026 ➔ Mar 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2026 ➔ Mar 2025; Following a prespecified interim analysis, and in consultation with the independent Data Monitoring Committee, the Sponsor terminated the study

Enrollment change • HEOR • Trial completion date • Trial primary completion date • Trial termination • Cardiovascular • Congestive Heart Failure • Heart Failure • GDF15

Oncology: What You May Have Missed in 2024. (PubMed, Ann Intern Med) - "Targeted therapies and antibody-drug conjugates, including trastuzumab deruxtecan and enfortumab vedotin, are enhancing precision treatment options in metastatic cancer. Meanwhile, advances in supportive care, such as magnetic resonance imaging-guided prostate cancer screening, ponsegromab for cachexia, and celiac plexus radiosurgery for pain, show enhanced symptom management and quality of life for patients. These innovations highlight the critical role of multidisciplinary approaches, where internal medicine physicians contribute to co-management and toxicity monitoring, ultimately optimizing patient care. By staying current with these developments, internal medicine physicians are positioned to navigate complex oncologic care, ensuring that the benefits of novel therapies are maximized while mitigating their challenges."

Journal • Cachexia • Genito-urinary Cancer • Oncology • Pain • Prostate Cancer • Solid Tumor