Preliminary Safety and Biomarker Results of the NLRP3 Inflammasome Inhibitor DFV890 in Adult Patients with Myeloid Diseases: A Phase 1b Study

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.

Garcia-Manero:Genentech: Other: Personal fees; Genentech: Research Funding; Helsinn: Research Funding; Astex: Research Funding; Forty Seven: Research Funding; Aprea: Research Funding; Helsinn: Other: Personal fees; H3 Biomedicine: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Astex: Other: Personal fees; Amphivena: Research Funding; Janssen: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; AbbVie: Research Funding; Merck: Research Funding; Curis: Research Funding. Abaza:Kite/Gilead: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Astellas: Consultancy; Rigel: Consultancy; BMS/Celgene: Consultancy; Geron: Consultancy; ALX Oncology: Research Funding; Biosight: Research Funding; Curis: Research Funding; Novartis: Research Funding; Biomea Fusion: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Consultancy; Servier: Consultancy. Velázquez Kennedy:Abbvie Spain S.L.U: Honoraria. Della Porta:Bristol Myers Squibb: Consultancy. Ooi:Abbvie: Other: Sponsorship for conference; GSK: Honoraria; Antegene: Honoraria; Amgen: Honoraria, Other: Sponsorship for conference; Johnson and Johnson: Honoraria; BMS: Honoraria; Pfizer: Other: Sponsorship for conference. Stahl:Kymera: Membership on an entity's Board of Directors or advisory committees; Sierra Oncolgy: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees. Mangaonkar:BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Desai:Rigel: Consultancy; Servier: Consultancy; BMS: Consultancy, Other: Research Support; Kura Oncology: Consultancy, Other: Research Support; Janssen: Other: Research Support. DeZern:Bristol Myers Squibbs: Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; servier: Membership on an entity's Board of Directors or advisory committees; geron: Other: dsmb; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Appellis: Membership on an entity's Board of Directors or advisory committees. Meunier:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Alexion: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Speakers Bureau. Pelizzari:Grifols International S.A.: Other: Travel & Lodging; Bristol Myers Squibb S.r.l. Italy: Other: Travel & Lodging. Platzbecker:Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Sockel:SOBI: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAzz: Honoraria, Research Funding; GSK: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Kishtagari:Sevier Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndex: Current equity holder in publicly-traded company; Geron Coporation: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees. Lu:Novartis: Current Employment, Current equity holder in publicly-traded company. Manganelli:Novartis: Current Employment, Current equity holder in publicly-traded company. Ji:Novartis: Current Employment, Current equity holder in publicly-traded company. Gatlik:Novartis: Current Employment, Current equity holder in private company. Singh:Biomedical Research, Novartis Pharmaceuticals: Current Employment. Beaulieu:Novartis Institutes for BioMedical Research: Current Employment. Pelletier:Novartis: Current Employment, Current equity holder in private company. Rauch:Novartis: Current Employment, Current equity holder in publicly-traded company. Gill:Celgene: Research Funding; PharmaEssentia Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference Support, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference Support, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference Support; Lecture fees, Research Funding; MSD: Consultancy, Honoraria, Other: Conference Support; Lecture fees, Research Funding; Jacobson Pharma Corporation: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference Support; Lecture fees, Research Funding; Astellas: Consultancy, Honoraria, Other: Lecture fees, Research Funding; Imago Biosciences: Research Funding; Otsuka: Consultancy, Other: Conference Support; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees.