Abstract
Purpose: Cachexia is common in patients with advanced cancer and is associated with elevated serum growth differentiation factor 15 (GDF-15) concentrations. This first-in-patient (phase Ib), 24-week study assessed use of ponsegromab, a monoclonal antibody against GDF-15, in adults with advanced cancer, cachexia, and elevated GDF-15 serum concentration. Experimental Design: Participants (n = 10 received open-label ponsegromab subcutaneous 200 mg every 3 weeks for 12 weeks in addition to standard-of-care anti-cancer treatment Ponsegromab safety, tolerability, and pharmacokinetics were assessed in addition to serum GDF-15 concentrations and exploratory measures of efficacy. Results: No treatment-related treatment-emergent adverse events, injection site reactions, or adverse trends in clinical laboratory tests, vital signs, or electrocardiogram parameters attributable to ponsegromab were identified Median serum unbound GDF-15 concentration at baseline was 2.269 ng/mL Following initiation of study treatment, median unbound GDF-15 concentrations were below the lower limit of quantification (0.0424 ng/mL) from day 1 (3 hours post-dose) through week 15 Increases in body weight were observed at all time points during the treatment and follow-up. A least-squares mean (standard error) increase of 4.63 kg (1.98) was observed at week 12, an increase of approximately 6.6% relative to baseline Ponsegromab-mediated improvements in actigraphy-based assessments of physical activit and in quality of life, including appetite as assessed by Functional Assessment of Anorexia-Cachexia Therapy total and subscale scores, were also observed. Conclusions: Ponsegromab was well tolerated, suppressed serum GDF-15 concentrations, and demonstrated preliminary evidence of efficacy These findings support the continued development of ponsegromab for the treatment of cachexia. ClinicalTrials.gov: NCT04299048
