Shannon L. Lubaczewski

BACKGROUND: Cachexia is a common complication of cancer and is associated with an increased risk of death. The level of growth differentiation factor 15 (GDF-15), a circulating cytokine, is elevated in cancer cachexia. In a small, open-label, phase 1b study involving patients with cancer cachexia, ponsegromab, a humanized monoclonal antibody inhibiting GDF-15, was associated with improved weight, appetite, and physical activity, along with suppressed serum GDF-15 levels. METHODS: In this phase 2, randomized, double-blind, 12-week trial, we assigned patients with cancer cachexia and an elevated serum GDF-15 level (≥1500 pg per milliliter) in a 1:1:1:1 ratio to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg or to receive placebo, administered subcutaneously every 4 weeks for three doses. The primary end point was the change from baseline in body weight at 12 weeks. Key secondary end points were appetite and cachexia symptoms, digital measures of physical activity, and safety. RESULTS: A total of 187 patients underwent randomization. Of these patients, 40% had non-small-cell lung cancer, 32% had pancreatic cancer, and 29% had colorectal cancer. At 12 weeks, patients in the ponsegromab groups had significantly greater weight gain than those in the placebo group, with a median between-group difference of 1.22 kg (95% credible interval, 0.37 to 2.25) in the 100-mg group, 1.92 (95% credible interval, 0.92 to 2.97) in the 200-mg group, and 2.81 (95% credible interval, 1.55 to 4.08) in the 400-mg group. Improvements were observed across measures of appetite and cachexia symptoms, along with physical activity, in the 400-mg ponsegromab group relative to placebo. Adverse events of any cause were reported in 70% of the patients in the ponsegromab group and in 80% of those in the placebo group. CONCLUSIONS: 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.).

OBJECTIVE: This is the first study to assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) for improving depressive symptoms and functioning exclusively in employed patients with major depressive disorder (MDD). METHODS: Gainfully employed (≥20 h/wk) male and female outpatients with MDD were randomly assigned (2:1 ratio) to 12 weeks of double-blind treatment with desvenlafaxine 50 mg/d or placebo. Analysis of covariance was used to compare differences in week 12 adjusted mean changes from baseline on the 17-item Hamilton Depression Rating Scale (HAM-D₁₇) (primary outcome) and Sheehan Disability Scale (SDS) (key secondary outcome) in the intent-to-treat (ITT) population. A predefined, modified ITT population (ie, those in the ITT population with baseline HAM-D₁₇ ≥20) was also analyzed. Tolerability was assessed by recording adverse events and change on the Arizona Sexual Experience Scale. RESULTS: Baseline HAM-D₁₇ scores for desvenlafaxine (n = 285) and placebo (n = 142) were 22.0 and 21.8, whereas baseline SDS scores were 19.8 and 20.4. Adjusted mean differences between desvenlafaxine and placebo were 2.1 (95% confidence interval [CI], 0.78-3.46; P = 0.002) on the HAM-D₁₇ and 1.3 (95% CI, -0.09 to 2.76; P = 0.067) on the SDS. For the modified ITT sample, desvenlafaxine (n = 208) and placebo (n = 102), baseline HAM-D₁₇ scores were 23.8 and 23.9; the SDS baseline scores were 20.1 and 20.8. Mean differences were 2.6 (95% CI, 0.93-4.22; P = 0.002) on the HAM-D₁₇ and 2.1 (95% CI, 0.36-3.76; P = 0.017) on the SDS. Adverse events and Arizona Sexual Experience Scale scores were comparable between groups. CONCLUSIONS: Desvenlafaxine 50 mg/d was efficacious for treating MDD in gainfully employed adults. Between-group differences on the SDS narrowly missed statistical significance in the ITT population alone, but the totality of data suggests functional improvements with active treatment.

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.

Abstract Background Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF‐15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF‐15‐mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab‐mediated inactivation of circulating GDF‐15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF‐15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors. Methods Approximately 168 adults with non‐small‐cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF‐15 concentrations will be randomized in a double‐blind, placebo‐controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12‐week treatment period. This is followed by optional open‐label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian E max model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient‐reported appetite‐related symptoms assessed by Functional Assessment of Anorexia‐Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer‐Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities. Perspective Cancer‐related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF‐15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life. Trial registration ClinicalTrials.gov ID: NCT05546476.

OBJECTIVE: To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder (MDD). METHODS: Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8 weeks of treatment with placebo, low exposure desvenlafaxine (20, 30, or 35 mg/day based on baseline weight), or higher exposure desvenlafaxine (25, 35, or 50 mg/day based on baseline weight). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy assessments included Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement scales. Safety assessments included adverse events and the Columbia-Suicide Severity Rating Scale. RESULTS: The safety population included 363 patients (children, n = 109; adolescents, n = 254). No statistical separation from placebo was observed for either desvenlafaxine group for CDRS-R total score or for any secondary efficacy endpoint. At week 8, adjusted mean (standard error) changes from baseline in CDRS-R total score for the desvenlafaxine low exposure, desvenlafaxine high exposure, and placebo groups were -23.7 (1.1), -24.4 (1.1), and -22.9 (1.1), respectively. The incidence of adverse events was similar among groups. CONCLUSION: Low and high exposure desvenlafaxine groups did not demonstrate efficacy for the treatment of MDD in children and adolescents in this double-blind, placebo-controlled trial. Desvenlafaxine (20-50 mg/day) was generally safe and well tolerated with no new safety signals identified in pediatric patients with MDD in this study.