Abstract CT108: First-in-patient study of the GDF-15 inhibitor ponsegromab in patients with cancer and cachexia: Safety, tolerability, and exploratory measures of efficacy
Authors: Crawford Jeffrey , Calle Roberto A. , Collins Susie M. , Weng Yan , Lubaczewski Shannon L. , Buckeridge Clare , Wang Ellen Q. , Harrington Magdalena A. , Tarachandani Anil , Rossulek Michelle I. , Revkin James H. 
Published: April 2023

Abstract
Background: Cachexia is common in patients with advanced cancer and has been associated with elevated serum growth/differentiation factor 15 (GDF-15) concentrations. This first-in-patient, phase 1b, study assessed the use of ponsegromab, a monoclonal antibody against GDF-15, in participants with advanced cancer and cachexia.
Methods: Adult participants (n = 10) with cachexia, advanced cancer (non-small cell lung, colorectal, or pancreatic), and elevated serum concentrations of GDF-15 received open-label subcutaneous ponsegromab every three weeks (Q3W) for 12 weeks in addition to standard of care anti-cancer treatment. Study endpoints included assessment of ponsegromab safety, tolerability, and pharmacokinetics. Serum GDF-15 concentrations and exploratory measures of efficacy were also assessed.
Results: No treatment-related adverse events or injection site reactions were reported. No adverse trends in clinical laboratory tests, vital signs, or electrocardiogram parameters attributable to ponsegromab dosing were evident. Ninety-two adverse events deemed unrelated to treatment were reported; most were mild (Grade 1 = 58.7%) or moderate (Grade 2 = 28.3%) in severity. All participants were negative for anti-drug antibodies at baseline (n = 10) and after receiving 5 doses (Q3W) of ponsegromab (n = 9). Mean unbound ponsegromab Ctrough ranged from 4.041-4383 ng/mL between Days 22-106. An elevated GDF-15 concentration was required for inclusion in the study. Following initiation of study treatment, median unbound GDF-15 concentration was reduced to below the lower limit of quantification (0.0424 ng/mL) on day 1 and remained suppressed until week 15 (3 weeks after final dose). Increases in body weight were observed at all time points during the treatment (weeks 3, 6, 9, and 12) and follow-up (weeks 15, 18, and 24) periods. The mean (SD) body weight at baseline was 70.49 (16.97) kg. An LS mean (SE) increase of 4.63 kg (1.98) was observed at week 12 (end of treatment); representing an increase of approximately 6.5% relative to baseline. Improvements in actigraphy-based assessments of physical activity and in quality of life, including appetite, as assessed by Functional Assessment of Anorexia-Cachexia Therapy (FAACT) total and subscale scores, were also observed during the course of ponsegromab treatment.
Conclusions: In participants with advanced cancer, cachexia, and elevated baseline GDF-15, ponsegromab was well tolerated and suppressed serum GDF-15 concentrations to below the median concentration seen in healthy subjects. Preliminary evidence of efficacy, including a mean observed weight gain of approximately 6.5% at 12 weeks, supports continued development of ponsegromab for the treatment of cancer cachexia. Funded by Pfizer. ClinicalTrials.gov: NCT04299048
Citation Format: Jeffrey Crawford, Roberto A. Calle, Susie M. Collins, Yan Weng, Shannon L. Lubaczewski, Clare Buckeridge, Ellen Q. Wang, Magdalena A. Harrington, Anil Tarachandani, Michelle I. Rossulek, James H. Revkin. First-in-patient study of the GDF-15 inhibitor ponsegromab in patients with cancer and cachexia: Safety, tolerability, and exploratory measures of efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT108.