Citations

Abstract The growing prevalence of obesity, a risk factor for disorders such as Alzheimer’s Disease (AD), raises concerns about the effects on cognitive health. AD currently impacts 6.9 million Americans aged 65 and older and is characterized by the presence of amyloid beta (Aβ) plaques, neurofibrillary tau tangles, and neuroinflammation, all of which contribute to cognitive impairment. Insulin resistance, common in both obesity and AD, disrupts brain glucose metabolism and accelerates neurodegeneration. Understanding the factors that link these conditions could lead to new strategies for combating disease. Notably, the B-like vitamin choline is necessary for fat metabolism and has been shown to help reduce obesity incidence. However, ∼90% of Americans are deficient, and decreases in this nutrient have been associated with cognitive decline. Here, we examined circulating choline levels, inflammation, and metabolic dysfunction in human participants with obesity (BMI > 30) compared to normal BMIs (18.5–24.9), as well as in 3xTg-AD mice, an AD model, fed a choline-deficient diet throughout adulthood. Our results revealed that obese participants exhibited significantly lower circulating choline levels compared to those with a healthy BMI. Lower choline levels correlated with higher %Body fat and increased markers of insulin resistance. Elevated inflammatory cytokines in obese participants were also seen in 3xTg-AD mice on a choline-deficient diet, which exhibited significant weight gain and metabolic dysfunction. AD-like pathology was also exacerbated in choline deficient 3xTg-AD mice. These findings underscore the relationship between low choline levels, obesity, insulin resistance, and cognitive decline risk. Adequate choline intake may mitigate the risk of obesity, potentially preventing cognitive decline and associated diseases. Highlights Obesity is linked to increased insulin resistance (IR) and systemic inflammation, both of which are recognized risk factors for Alzheimer’s disease (AD). Women exhibit lower circulating choline levels compared to men, and obese individuals display significantly lower choline levels than those with a healthy BMI. Lower circulating choline levels are linked to a higher body fat percentage, increased markers of IR and liver dysfunction, as well as heightened systemic inflammation. 3xTg-AD mice on a choline-deficient diet experience considerable weight gain, metabolic dysfunction, heightened systemic inflammation, and AD-like pathology, resembling the conditions observed in obese human participants.

Introduction Patients with lower-risk (LR) myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) experience shortened survival and significant unmet medical need due to limited disease-modifying treatments. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms, contributing to ineffective hematopoiesis and clonal progression. DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death. Thus, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to patients by restoring normal hematopoiesis and suppressing clonal myeloproliferation. Methods This open-label, phase 1b, multicenter study evaluates DFV890 in patients with very low, low, or intermediate risk MDS per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). The study comprises 2 parts: dose optimization and dose expansion. Eligible patients ≥18 years, with ECOG performance status ≤2, carrying a diagnosis of (a) IPSS-R-defined LR-MDS or (b) CPSS-defined LR-CMML, and have failed to respond to or not tolerated established first-line therapies as defined in the protocol. Key exclusion criteria include previous treatment with agents targeting the NLRP3 inflammasome and IL-1 pathway. DFV890 is administered orally twice daily (BID) for a minimum of 24 weeks (6 cycles of treatment) until treatment discontinuation. In the dose-optimization part, patients are randomized to receive either low- or high-dose, stratified by indication. Primary objectives are to assess safety and tolerability and determine the optimal for DFV890. Secondary objectives include assessment of pharmacokinetics, and evaluation of preliminary efficacy of DFV890 based on hematologic improvement (Garcia-Manero, Blood 2023). Exploratory objectives include assessment of peripheral cytokines and genetic alterations in blood and bone marrow, and patient-reported symptoms. Results As of April 15, 2024, 39 patients (median age, 74 years) with a median of 2 prior lines of therapy (range: 1-5) were treated with DFV890 in the dose-optimization part. Based on an 8-week screening period, 8 patients (20.5%) were RBC transfusion independent at baseline. Eighteen patients received low dose (17 with LR-MDS; 1 with LR-CMML), and 21 patients received high dose (18 with LR-MDS; 3 with LR-CMML). At data cutoff, 10 (25.6%) patients had discontinued treatment. Median duration of exposure was 10.7 weeks (range, 0.6-42.0 weeks). Adverse events (AEs) leading to study drug discontinuation were only reported in the high dose arm (2 patients, grade ≥3 neutropenia, n=1 and blood bilirubin increased, n=1). Treatment-related AEs (TRAEs) were reported in 10 patients (25.6%), with 4 (10.3%) experiencing grade ≥3 TRAEs (anemia [n=2], neutropenia, and rash [n=1 each]). No serious AEs related to DFV890 were reported. Peripheral cytokines were assessed as a marker of preliminary activity. Decrease in plasma IL-18 and IL-1RA levels observed in most patients, with a higher frequency in the low dose arm (IL-18 decreased in 8/8 patients in low dose arm vs. 4/7 in high dose arm; IL-1RA in 7/8 vs. 5/7), potentially due to less frequent dose interruptions. Changes in serum IL-6 levels were more heterogeneous; notably, among the patients with complete mutation and biomarker data, both patients with mutations in TET2 showed dramatic decreases in serum IL-6; IL-18 and IL-1RA also decreased in those patients. In addition, out of 8 patients who were transfusion-independent at baseline, 6 reported an increase in hemoglobin with treatment, 4 of whom with an increment >10% from baseline. Updated data including hematologic response assessment according to IWG will be presented at the meeting. Conclusions Preliminary findings from this ongoing study show a favorable safety profile in patients with LR-MDS and LR-CMML, in line with prior human studies with DFV890. Analysis of peripheral cytokines and hematologic parameters showed early indications of activity in a subset of patients, particularly those with mutations in TET2 and those transfusion independent at baseline. These findings will require confirmation with longer follow-up and in the dose expansion phase of the study.