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 | "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

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

STING-GDF15-STAT3 signaling contributes to neuroinflammation after intracerebral hemorrhage. (PubMed, Exp Neurol) - "These findings suggest that the STING-GDF15-STAT3 signaling axis contributes to neuroinflammatory responses and secondary brain injury after ICH, and may represent a potential therapeutic target for haemorrhagic stroke."

Journal • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Inflammation • Vascular Neurology • GDF15 • STING

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

A Study to Learn About the Study Medicine Called Ponsegromab in Adults With Lung Cancer-Associated Significant Body Weight Loss (clinicaltrials.gov) - P1 | N=80 | Not yet recruiting | Sponsor: Pfizer | Trial completion date: Mar 2029 ➔ Jul 2029 | Initiation date: Jul 2026 ➔ Oct 2026 | Trial primary completion date: Feb 2028 ➔ May 2028

Trial completion date • Trial initiation date • Trial primary completion date • Cachexia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

Efficacy and Safety of Ponsegromab in Non-Small Cell Lung Cancer and Cachexia: A Subgroup Analysis of PROACC-1 Phase 2 Study (IASLC-WCLC 2026) - P2 | "Conclusions : Among patients with NSCLC, cachexia, and elevated GDF-15 levels, GDF-15 inhibition with ponsegromab 400 mg through 12 weeks resulted in body weight and skeletal muscle gains and was generally well tolerated. $$graphic_3BAA7305-B383-4E06-B694-C856D510D327$$"

Clinical • P2 data • Cachexia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GDF15

Novel Antibodies for Managing Cachexia. (PubMed, Annu Rev Med) - "Ponsegromab, a monoclonal antibody that is a highly selective and potent inhibitor of GDF-15, has resulted in improved body weight and other cachexia-related symptoms in patients with cancer...Through the development of these treatments, many unexpected potential therapeutic applications have been identified, highlighting the broad, systemic impacts of cachexia. As research continues, it is imperative to focus on clear trial design and endpoints."

Journal • Review • Anorexia • Cachexia • Oncology • 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

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

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

A Study to Learn About the Study Medicine Called Ponsegromab in Adults With Lung Cancer-Associated Significant Weight Loss (clinicaltrials.gov) - P1 | N=80 | Not yet recruiting | Sponsor: Pfizer

New P1 trial • Cachexia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

Growth Differentiation Factor 15 (GDF-15): Associations with Anorexia, Markers of Sarcopenia, Progression and Mortality in Chronic Kidney Disease (ERA 2026) - "Growth Differentiation Factor 15 (GDF-15) is an established mediator of anorexia and cachexia, and a recent phase 2b trial of the GDF-15–neutralising antibody, ponsegromab, improved weight and appetite in cancer...GDF-15 was also independently associated with CKD progression and all- cause mortality, supporting its utility as a prognostic biomarker in CKD. Image"

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

Targeting Cancer Cachexia: A Mechanistic Evaluation of Anti-GDF-15 Antibody-Based Combination Therapies. (PubMed, J Cachexia Sarcopenia Muscle) - P3 | "These data provide proof-of-principle that mechanistically distinct approaches targeting muscle anabolism and appetite may act additively with GDF-15 neutralization, particularly in cancer cachexia settings with lower GDF-15 dependence."

Journal • Cachexia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GDF15

De novo and scaffold-based design of GDF15 binders for cancer cachexia diagnostics and therapeutics. (PubMed, Exp Mol Med) - "Second, the highest-affinity binder was engineered as an Fc-fusion decoy receptor, thereby effectively neutralizing GDF15 signaling in cell-based assays (IC50 = 7.2 nM), demonstrating comparable in vitro potency to ponsegromab, a monoclonal antibody currently undergoing phase II clinical trials. Together, this work establishes a versatile artificial intelligence-driven binder design pipeline with broad potential for next-generation diagnostics and therapeutics in cancer cachexia and other GDF15-mediated diseases."

Journal • Cachexia • Oncology • Rare Diseases • GDF15

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

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

Pathogenesis, Diagnostic Pathways, and New Therapeutic and Nutritional Strategies for Pancreatic Cancer-Associated Cachexia. (PubMed, Cancers (Basel)) - "This review highlights that, despite the absence of pharmacological agents specifically approved for CAC in the United States and Europe, current guidelines recommend multimodal supportive care, including low-dose olanzapine, nutritional support, and exercise-based interventions. Furthermore, we identify recent phase 2 trials targeting the GDF-15 pathway, such as the GDF-15 inhibitor ponsegromab, which have demonstrated significant improvements in body weight and physical activity, suggesting a potential breakthrough in targeted therapies for CAC...It manifests as a lethal systemic pathology that demands early identification and targeted personalized pharmacological and nutritional interventions. Early diagnosis and targeted intervention represent promising strategies for improving survival and quality of life in this high-risk patient population."

Journal • Review • Anorexia • Cachexia • Immunology • Metabolic Disorders • Muscular Atrophy • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcopenia • Solid Tumor • Systemic Inflammatory Response Syndrome • 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

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

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

LBL-049: A novel neutralizing antibody against GDF15 for the treatment of cachexia (AACR 2024) - "In HT1080 tumor-induced or cisplatin-induced mouse cachexia model, LBL-049 prevented weight loss by neutralizing circulating GDF-15 in a dose dependent manner, at low dose of 1 mpk in HT1080 cachexia model, LBL-049 was more efficacious than ponsegromab to restore the body weight loss. LBL-049, a novel GDF15 neutralizing antibody with high affinity and specificity, showed great potency to inhibit GDF15/GFRAL/RET signaling in vitro and prevent weight loss in various mouse cachexia models, which are encouraging for future development for the treatment of cachexia."

Oncology • GDF15 • TGFB1

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

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