On September 14, 2024 Pfizer Inc. reported its Phase 2 study of ponsegromab, a monoclonal antibody directed against growth differentiation factor-15 (GDF-15), met its primary endpoint of change from baseline in body weight compared to placebo in people with cancer cachexia and elevated levels of GDF-15 (Press release, Pfizer, SEP 14, 2024, View Source [SID1234646586]). Cachexia is a common, life-threatening wasting condition that can significantly impact quality of life in affected patients with cancer.ii,iii Results will be presented today as a late-breaking Proffered Paper Presentation (LBA82) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2024 Congress and have simultaneously been published in The New England Journal of Medicine (NEJM).

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"Cachexia is a common condition in cancer patients, associated with weight loss, functional decline, and ultimately poor outcomes. Despite the number of people suffering from cachexia, there are no available options for us to help treat patients," said Jeffrey Crawford, M.D., George Barth Geller Professor for Research at Duke Cancer Institute, and principal investigator. "This study showed us those who received ponsegromab had improvement in body weight, muscle mass, quality of life, and physical function. These findings offer hope that a breakthrough targeted treatment is potentially on the horizon for our patients."

The Phase 2 study included 187 participants with non-small cell lung cancer, pancreatic cancer, or colorectal cancer. Ponsegromab demonstrated significant and robust increases in body weight after 12 weeks across all doses: 2.02% (95% confidence interval (CI), -0.97 to 5.01%) in the 100 mg treatment group, 3.48% (95% CI, 0.54 to 6.42%) in the 200 mg group, and 5.61% (95% CI, 2.56 to 8.67%) in the 400 mg group, compared to placebo. Improvements across multiple domains of the cachexia phenotype were observed in the 400 mg group including in measures of appetite and cachexia symptoms, physical activity and skeletal muscle index. No clinically significant adverse trends were noted with ponsegromab administration. Treatment related adverse events occurred in 8.9% of patients taking placebo and 7.7% of patients taking ponsegromab.i

"Discovered and developed in-house at Pfizer, ponsegromab represents our ability to translate deep scientific expertise into patient benefit," said Charlotte Allerton, Head of Discovery and Early Development, Pfizer. "These results provide strong evidence that we have unlocked a mechanism to interrupt a critical driver of cachexia, GDF-15, which has the potential to impact patients with cancer cachexia and other life-threatening conditions. We look forward to advancing this program as part of our broader cardiometabolic portfolio to address weight management across the spectrum of patient need."

Based on these positive results, Pfizer is discussing late-stage development plans with regulators with the goal of starting registration-enabling studies in 2025. Ponsegromab is also being investigated in a Phase 2 study in patients with heart failure (HF) and elevated serum GDF-15 concentrations (NCT05492500).

About the Phase 2 Trial in Cancer Cachexia
The primary objective of the Phase 2 study (NCT05546476) is to assess the effect of ponsegromab on body weight in patients with cancer (non-small cell lung cancer, pancreatic cancer or colorectal cancer), cachexia and elevated serum GDF-15 concentrations (>1500 pg/mL). Secondary and exploratory endpoints objectives included measures such as: Change from baseline in appetite and cachexia symptoms, digital measures of physical activity, and changes in lumbar skeletal muscle index (LSMI). Patients (n=187) received either ponsegromab (100 mg, 200 mg or 400 mg) or placebo once every four weeks subcutaneously for 12 weeks.

About Cachexia
Cachexia is a complex, disabling, and life-threatening metabolic condition that is estimated to affect about 9 million people worldwide.ii Symptoms such as weight and muscle loss can reduce patients’ ability to tolerate treatment for their underlying chronic diseases, such as cancer and heart failure, and can severely impact quality of life.ii,iii In cancer, cachexia can diminish the efficacy of cancer treatments and is thought to contribute to decreased survival rates and may cause up to 30% of cancer-related deaths.iv Despite its severity, there are no FDA-approved treatments for cachexia.iii

About Ponsegromab
Ponsegromab is an investigational monoclonal antibody designed to treat cachexia by targeting GDF-15. Prior Phase 1b data in participants with cancer cachexia demonstrated proof-of-mechanism for ponsegromab with robust suppression of unbound circulating GDF15 levels observed. The results showed encouraging signals of efficacy that included increases in body weight and encouraging improvements in patient reported outcomes.