Association between growth differentiation factor-15 and adverse outcomes among patients with heart failure: A systematic literature review.

Growth differentiation factor-15 (GDF-15) is an emerging biomarker in several conditions. This SLR, conducted following PRISMA guidelines, examined the association between GDF-15 concentration and range of adverse outcomes in patients with heart failure (HF). Publications were identified from Embase® and Medline® bibliographic databases between January 1, 2014, and August 23, 2022 (congress abstracts: January 1, 2020, to August 23, 2022). Sixty-three publications met the eligibility criteria (55 manuscripts and 8 abstracts; 45 observational studies and 18 post hoc analyses of randomized controlled trials [RCTs]). Of the 19 outcomes identified, the most frequently reported longitudinal outcomes were mortality (n = 32 studies; all-cause [n = 27] or cardiovascular-related [n = 6]), composite outcomes (n = 28; most commonly mortality ± hospitalization/rehospitalization [n = 19]), and hospitalization/re-hospitalization (n = 11). The most common cross-sectional outcome was renal function (n = 22). Among longitudinal studies assessing independent relationships with outcomes using multivariate analyses (MVA), a significant increase in risk associated with higher baseline GDF-15 concentration was found in 22/24 (92 %) studies assessing all-cause mortality, 4/5 (80 %) assessing cardiovascular-related mortality, 13/19 (68 %) assessing composite outcomes, and 4/8 (50 %) assessing hospitalization/rehospitalization. All (7/7; 100 %) of the cross-sectional studies assessing the relationship with renal function by MVA, and 3/4 (75 %) assessing exercise capacity, found poorer outcomes associated with higher baseline GDF-15 concentrations. This SLR suggests GDF-15 is an independent predictor of mortality and other adverse but nonfatal outcomes in patients with HF. A better understanding of the prognostic role of GDF-15 in HF could improve clinical risk prediction models and potentially help optimize treatment regimens.

The mortality burden of cachexia or weight loss in patients with colorectal or pancreatic cancer: A systematic literature review.

Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase® and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (n = 23) or univariate (n = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.

Mortality burden of pre-treatment weight loss in patients with non-small-cell lung cancer: A systematic literature review and meta-analysis.

Cachexia, with weight loss (WL) as a major component, is highly prevalent in patients with cancer and indicates a poor prognosis. The primary objective of this study was to conduct a meta-analysis to estimate the risk of mortality associated with cachexia (using established WL criteria prior to treatment initiation) in patients with non-small-cell lung cancer (NSCLC) in studies identified through a systematic literature review. The review was conducted according to PRISMA guidelines. Embase® and PubMed were searched to identify articles on survival outcomes in adult patients with NSCLC (any stage) and cachexia published in English between 1 January 2016 and 10 October 2021. Two independent reviewers screened titles, abstracts and full texts of identified records against predefined inclusion/exclusion criteria. Following a feasibility assessment, a meta-analysis evaluating the impact of cachexia, defined per the international consensus criteria (ICC), or of pre-treatment WL ≥ 5% without a specified time interval, on overall survival in patients with NSCLC was conducted using a random-effects model that included the identified studies as the base case. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. The standard measures of statistical heterogeneity were calculated. Of the 40 NSCLC publications identified in the review, 20 studies that used the ICC for cachexia or reported WL ≥ 5% and that performed multivariate analyses with hazard ratios (HRs) or Kaplan-Meier curves were included in the feasibility assessment. Of these, 16 studies (80%; n = 6225 patients; published 2016-2021) met the criteria for inclusion in the meta-analysis: 11 studies (69%) used the ICC and 5 studies (31%) used WL ≥ 5%. Combined criteria (ICC plus WL ≥ 5%) were associated with an 82% higher mortality risk versus no cachexia or WL < 5% (pooled HR [95% confidence interval, CI]: 1.82 [1.47, 2.25]). Although statistical heterogeneity was high (I2 = 88%), individual study HRs were directionally aligned with the pooled estimate, and there was considerable overlap in CIs across included studies. A subgroup analysis of studies using the ICC (HR [95% CI]: 2.26 [1.80, 2.83]) or WL ≥ 5% (HR [95% CI]: 1.28 [1.12, 1.46]) showed consistent findings. Assessments of methodological, clinical and statistical heterogeneity indicated that the meta-analysis was robust. Overall, this analysis found that ICC-defined cachexia or WL ≥ 5% was associated with inferior survival in patients with NSCLC. Routine assessment of both weight and weight changes in the oncology clinic may help identify patients with NSCLC at risk for worse survival, better inform clinical decision-making and assess eligibility for cachexia clinical trials.

Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.

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 Emax 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.

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.

Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.

Novel CCR1 antagonists with improved metabolic stability.

The synthesis, biological activity, and pharmacokinetic profile of novel CCR1 antagonists are described.