ponsegromab (PF-06946860)

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.

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.

P2/3, N=982, Recruiting, Pfizer | Not yet recruiting --> Recruiting

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.

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.

P2/3, N=982, Not yet recruiting, Pfizer | Trial completion date: Jan 2029 --> Jan 2030 | Trial primary completion date: Jan 2029 --> Feb 2028

P2/3, N=982, Not yet recruiting, Pfizer

P2, N=187, Completed, Pfizer | Active, not recruiting --> Completed

P2, N=457, Terminated, 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

P2, N=781, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

P2, N=781, Recruiting, Pfizer | N=416 --> 781 | Trial completion date: Jun 2025 --> Mar 2026 | Trial primary completion date: Mar 2025 --> Mar 2026

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.).