ponsegromab (PF-06946860) / Pfizer - LARVOL DELTA

AWT038: Dual GDF15-IL-6 neutralization for cancer cachexia (AACR 2026) - "GDF15 engages GFRAL in the hindbrain to suppress appetite and drive weight loss, and clinical GDF15 blockade (e.g., ponsegromab) has increased body weight, appetite, activity, and lean mass in randomized trials. This dual blockade supports development as supportive care for patients with advanced cancers and elevated GDF15 and/or IL-6, including those receiving platinum-based chemotherapy where GDF15 rises and weight loss is common. If confirmed in clinical studies, AWT038 could complement or surpass single-axis therapies (e.g., GDF15-only inhibitors) by restoring appetite, attenuating inflammation and fatigue, and preserving muscle mass in a population with major unmet need."

Oncology • GDF15 • IL6 • IL6R

Preclinical models of cancer cachexia: Bridging the gap to clinical applications (AACR 2026) - "In this study, we used Ponsegromab (anti-GDF15 monoclonal antibody) as a positive treatment for CC starting when mice had lost ~7% body weight...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

Potential Risks of Blocking GDF15-Based Brain Energy Sensing. (PubMed, J Am Geriatr Soc) - "GDF15 signals energetic stress to the brain, leading to unpleasant symptoms as the body conserves and reallocates energy. In conditions such as frailty and cancer, suppression of GDF15 signaling is expected to lead to an improvement in symptoms, but potentially at the cost of long-term health and survival."

Journal • Oncology • GDF15

Growth Differentiation Factor 15 (GDF-15): Associations with Anorexia, CKD Progression and Mortality in Chronic Kidney Disease (UKKW 2026) - "A recent phase 2 b trial of ponsegromab, a monoclonal antibody targeting GDF-15, showed improvement in weight and appetite in people with cancer...GDF-15 was also independently associated with CKD progression and all-cause mortality. Our findings suggest that GDF-15 may play a causal role in the anorexia of CKD, and treatments targeting GDF-15 could have therapeutic potential for improving appetite and possibly also progression and survival in CKD."

Anorexia • Cachexia • Chronic Kidney Disease • Nephrology • Renal Disease • CST3 • GDF15

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 | "Among patients with CRC, cachexia, and elevated GDF-15 levels, GDF-15 inhibition with ponsegromab through 12 weeks resulted in body weight gain and was generally well tolerated. N: number of participants at baseline. n: number of participants with change from baseline values at Week 12."

Clinical • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • GDF15

C3651021: 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 (clinicaltrialsregister.eu) - P2/3 | N=289 | Not yet recruiting | Sponsor: Pfizer Inc.

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

Regulation of ferroptosis in colorectal cancer through therapeutic modulation and miRNA targeting. (PubMed, Biochem Biophys Rep) - "Interestingly, we also found that medications such as prasterone, tazemetostat, isoxyl, gemcitabine, ponsegromab, scx-2023, and nicotinamide could potentially be used in combination with the identified miRNAs to target ferroptosis in CRC. To further validate the stability and reliability of the predicted protein-ligand interactions, molecular dynamics (MD) simulations and MM-PBSA analyses were performed on selected top-ranking complexes, which confirmed their stable and favorable binding and supported the robustness of our docking results. These findings suggest that targeting these miRNAs and their associated genes, along with using the identified drugs, could be a promising strategy for CRC treatment, leveraging the potential of ferroptosis-inducing therapies."

Journal • Colorectal Cancer • Oncology • Solid Tumor • MIR15A • MIR16 • MIR423 • MIR93 • PARP1 • RRM2 • SLC7A11

Efficacy and safety of ponsegromab, a first-in-class, monoclonal antibody inhibitor of growth differentiation factor 15, in patients with cancer cachexia: A randomized, placebo-controlled, phase II study (ESMO 2024) - P2 | "Ponsegromab improved weight, symptoms, overall activity, and skeletal muscle mass in patients with cancer cachexia and elevated GDF-15, confirming GDF-15 as a primary driver of cancer cachexia."

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

Ponsegromab for the Treatment of Cancer Cachexia. (PubMed, N Engl J Med) - P2 | "Among patients with cancer cachexia and elevated GDF-15 levels, the inhibition of GDF-15 with ponsegromab resulted in increased weight gain and overall activity level and reduced cachexia symptoms, findings that confirmed the role of GDF-15 as a driver of cachexia. (Funded by Pfizer; ClinicalTrials.gov number, NCT05546476.)."

Clinical • Journal • Cachexia • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • GDF15

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 | "Eligible patients are adults (≥18 years) with measurable mPDAC, cachexia (per Fearon criteria), and ECOG PS ≤1 who are receiving 1L chemotherapy (nab-paclitaxel + gemcitabine, or FOLFIRINOX [modification allowed])...The study also includes an optional open-label extension (≤1 year). BL, baseline; FAACT‑5IASS, Functional Assessment of Anorexia/Cachexia Therapy 5-item Anorexia Symptom Scale."

Clinical • Metastases • P2/3 data • P2b data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • GDF15

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