A Phase Ib First-In-Patient Study Assessing the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ponsegromab in Participants with Cancer and Cachexia.

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 mAb against GDF-15, in adults with advanced cancer, cachexia, and elevated GDF-15 serum concentration. PATIENTS AND METHODS: Participants (n = 10) received open-label ponsegromab subcutaneous 200 mg every 3 weeks for 12 weeks in addition to standard-of-care anticancer 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 postdose) through week 15. Increases in body weight were observed at all time points during the treatment and follow-up periods. A least-squares mean (SE) increase of 4.63 (1.98) kg was observed at week 12, an increase of approximately 6.6% relative to baseline. Ponsegromab-mediated improvements in actigraphy-based assessments of physical activity 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.

Patient Willingness to Use Digital Health Technologies: A Quantitative and Qualitative Survey in Patients with Cancer Cachexia.

Purpose: The objective of this study was to gain insights into the patients' perspectives on the impact of cancer cachexia on physical activity and their willingness to wear digital health technology (DHT) devices in clinical trials. Patients and Methods: We administered a quantitative 20-minute online survey on aspects of physical activity (on a 0-100 scale) to 50 patients with cancer cachexia recruited through Rare Patient Voice, LLC. A subset of 10 patients took part in qualitative 45-minute web-based interviews with a demonstration of DHT devices. Survey questions related to the impact of weight loss (a key characteristic in Fearon's cachexia definition) on physical activity, patients' expectations regarding desired improvements and their level of meaningful activities, as well as preferences for DHT. Results: Seventy-eight percent of patients reported that their physical activity was impacted by cachexia, and for 77% of them, such impact was consistent over time. Patients perceived most impact of weight loss on walking distance, time and speed, and on level of activity during the day. Sleep, activity level, walking quality and distance were identified as the most meaningful activities to improve. Patients would like to see a moderate improvement of activity levels and consider it meaningful to perform physical activity of moderate intensity (eg, walk at normal pace) on a regular basis. The wrist was the preferred location for wearing a DHT device, followed by arm, ankle, and waist. Conclusion: Most patients reported physical activity limitations since the occurrence of weight loss compatible with cancer-associated cachexia. Walking distance, sleep and quality of walk were the most meaningful activities to moderately improve, and patients consider moderate physical activity as meaningful. Finally, this study population found the proposed wear of DHT devices on the wrist and around the waist acceptable for the duration of clinical studies.

Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation.

Mutations within PCSK9 (proprotein convertase subtilisin/kexin type 9) are associated with dominant forms of familial hyper- and hypocholesterolemia. Although PCSK9 controls low density lipoprotein (LDL) receptor (LDLR) levels post-transcriptionally, several questions concerning its mode of action remain unanswered. We show that purified PCSK9 protein added to the medium of human endothelial kidney 293, HepG2, and Chinese hamster ovary cell lines decreases cellular LDL uptake in a dose-dependent manner. Using this cell-based assay of PCSK9 activity, we found that the relative potencies of several PCSK9 missense mutants (S127R and D374Y, associated with hypercholesterolemia, and R46L, associated with hypocholesterolemia) correlate with LDL cholesterol levels in humans carrying such mutations. Notably, we found that in vitro wild-type PCSK9 binds LDLR with an approximately 150-fold higher affinity at an acidic endosomal pH (K(D) = 4.19 nm) compared with a neutral pH (K(D) = 628 nm). We also demonstrate that wild-type PCSK9 and mutants S127R and R46L are internalized by cells to similar levels, whereas D374Y is more efficiently internalized, consistent with their affinities for LDLR at neutral pH. Finally, we show that LDL diminishes PCSK9 binding to LDLR in vitro and partially inhibits the effects of secreted PCSK9 on LDLR degradation in cell culture. Together, the results of our biochemical and cell-based experiments suggest a model in which secreted PCSK9 binds to LDLR and directs the trafficking of LDLR to the lysosomes for degradation.