ponsegromab (PF-06946860) / Pfizer - LARVOL DELTA

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

New trends in supportive care of head and neck cancers. (PubMed, Curr Opin Oncol) - "In recent years, new knowledge has emerged regarding the underlying causes and predictive models for the supportive care of HNC patients. Unfortunately, this expanding body of knowledge primarily adds to complexity without translating into practical applications or substantial improvements for patients. Future efforts should prioritize the standardization of therapeutic algorithms, and the generation of robust evidence based on existing preclinical models."

Journal • Cachexia • Dermatitis • Dermatology • Gastrointestinal Disorder • Head and Neck Cancer • Immunology • Infectious Disease • Mucositis • Oncology • Pain • Solid Tumor

Ponsegromab for the Treatment of Cancer Cachexia. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Cachexia • Oncology

Ponsegromab for the Treatment of Cancer Cachexia. (PubMed, N Engl J Med) - No abstract available

Journal • Cachexia • Oncology

Ponsegromab for the Treatment of Cancer Cachexia. (PubMed, N Engl J Med) - No abstract available

Journal • Cachexia • Oncology

Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis. (PubMed, J Neuroinflammation) - "The levels of GDF15 were elevated in the brains of septic mice. Targeting GDF15 with an anti-GDF15 antibody was found to improve sepsis-induced cognitive and memory impairment by reducing the microglial inflammatory response and phagocytosis. These results indicate that GDF15 could serve as an important therapeutic target for treating SAE."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Infectious Disease • Inflammation • Septic Shock • GDF15

GARDEN TIMI 74: A Study of Ponsegromab in People With Heart Failure (clinicaltrials.gov) - P2 | N=781 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting

Enrollment closed • HEOR • Cardiovascular • Congestive Heart Failure • Heart Failure • GDF15

Ponsegromab for Cancer Cachexia - A New Dawn for an Old Condition? (PubMed, N Engl J Med) - No abstract available

Journal • Cachexia • Oncology

Thank you @theNCI Blog for highlighting important strides in #cachexia research including recent @Nejm report investigating the anti-GDF15 drug ponsegromab

Will Ponsegromab Be a Game Changer for Cancer Cachexia? (National Institute of Health) - "The group of participants treated with the highest dose, 400 mg, in fact, gained back more than 5% of their body weight, reported one of the study's investigators, Jeffrey Crawford...In addition, ponsegromab didn't appear to interfere with patients' responses to their cancer treatments, Dr. Crawford explained. But because the trial was small and people were only treated for 12 weeks, 'it's hard to say definitively' whether that's the case, he cautioned."

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GARDEN TIMI 74: A Study of Ponsegromab in People With Heart Failure (clinicaltrials.gov) - P2 | N=781 | Recruiting | Sponsor: Pfizer | N=416 ➔ 781 | Trial completion date: Jun 2025 ➔ Mar 2026 | Trial primary completion date: Mar 2025 ➔ Mar 2026

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

New cancer cachexia treatment boosts weight gain and patient activity - "Side effects were minimal, Dunne said, and in fact ponsegromab appeared to be safer than common appetite stimulants used by cachexia patients....'This is super exciting,' said Dunne."

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#ESMO24 Possible breakthrough in cancer #cachexia with #Ponsegromab, anti-GDF 15. Significant weight gain, especially in patients with #colorectalcancer. @CathyEngMD @CCAlliance @FightCRC @OncoAlert