Ofirnoflast (HT-6184), a first-in-class oral allosteric NEK7 inhibitor, produced a hematologic improvement (HI) in patients with erythropoiesis-stimulating agent (ESA)–refractory, –intolerant, or –ineligible lower-risk myelodysplastic syndrome (MDS), according to final results from the phase 2a HT-6184-MDS-001 trial (NCT07052006) presented at the
In the modified intention-to-treat (mITT) population (n = 30), 66.7% experienced overall HI. The HI rate was 55.6% among transfusion-dependent patients (n = 18) and 75.0% among non–transfusion-dependent patients (n = 12). When broken down by lineage, erythroid HI (HI-E) occurred in 63.3% of patients overall, platelet HI (HI-P) occurred in 60.0%, and neutrophil HI (HI-N) was observed in 60.0%.
Among transfusion-dependent patients, 55.6% achieved red blood cell (RBC) transfusion independence (TI) for at least 8 weeks per International Working Group (IWG) 2018 criteria, with a median TI duration of 28.0 weeks (range, 11.3-34.9); 70% of 8-week responders (n = 10) maintained TI beyond 16 weeks. A complete response (CR) or marrow CR (mCR) per IWG 2006 criteria was recorded in 33.3% the overall patient population.
“[Responses included] multilineage responses that would be consistent with complete remission” lead study author David Sallman, MD, said in a presentation of the data. “Responses have been quite robust, with an average hemoglobin improvement of 5 g/dL, and [these have been observed] across all subsets with corresponding quality-of-life improvements.”
Sallman is an associate member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.
Ofirnoflast is designed to prevent formation and promote disassembly of the NLRP3 inflammasome, whose chronic activation drives the ineffective, pyroptotic hematopoiesis that characterizes MDS.
In June 2026, the FDA granted ofirnoflast fast track designation for lower-risk MDS.2
The single-arm study used a Simon's two-stage design and enrolled adult patients with MDS or non-proliferative MDS/myeloproliferative neoplasm (white blood cell count <13,000/µL) per WHO 2022 criteria who had very low–, low–, or intermediate-risk disease per Revised International Prognostic Scoring System (IPSS-R) criteria.1 Patients were required to have symptomatic anemia (hemoglobin level <9 g/dL) or RBC transfusion dependence, and they needed to be refractory to, intolerant of, or ineligible for ESAs.
Ofirnoflast was administered orally at 2 mg once per day on a 5-days-on/2-days-off schedule for up to 32 weeks.
The primary end point was HI per IWG 2018 criteria. Secondary and exploratory end points included biomarker and molecular response, safety and tolerability, pharmacokinetics, the rate of HI with ofirnoflast plus an ESA, and quality of life measured with the QOL-E instrument.
The trial enrolled an intention-to-treat (ITT) population of 37 patients, of whom 30 comprised the modified ITT (mITT) efficacy population.
In the mITT population, the median age was 66 years (range, 31-86), 63.3% of patients were male, and all patients were Asian. MDS with low blasts was the most common diagnosis (63.3%), and patients were evenly split between IPSS-R low-risk (50.0%) and intermediate-risk (50.0%) disease. At baseline, the median hemoglobin level was 7.4 g/dL; 53.3% of patients were ESA-refractory, 23.3% were intolerant, and 23.3% were ineligible. Sixty percent of patients were transfusion-dependent.
Among transfusion-dependent patients, RBC-TI lasting at least 16 weeks was achieved by 38.9% of patients, and of the patients who reached 8-week TI, 70% sustained it beyond 16 weeks.
CR by IWG 2006 criteria was reported in 30% of patients in the mITT population, and mCR occurred in 3.3%. Among HI-E responders (n = 19), the median hemoglobin rose from 7.5 g/dL at baseline to a peak of 12.2 g/dL on treatment, corresponding to a median peak increase of 4.6 g/dL (range, 0.8-7.4). Hematologic responses were observed across WHO MDS subtypes and independent of somatic mutation status, including in patients with SF3B1-mutant and del(5q) disease.
Patient-reported outcomes on the QOL-E instrument showed meaningful within-patient improvement in the fatigue domain in 44% of evaluable patients and in the social/family domain in 62%; 64% of transfusion-dependent patients reported improvement in the patient-reported impact of transfusion burden at the end of study.
Exploratory biomarker analyses showed reductions from baseline by week 16 in TNF-α (P = .013) and oxidized mitochondrial DNA (P = .022), and higher baseline levels of IL-1β and oxidized DNA were associated with larger absolute reductions (Spearman rho, –0.73 and –0.90, respectively; P < .001), which investigators characterized as consistent with on-target engagement of the pyroptosis pathway.
In the safety population (n = 37), treatment-emergent adverse effects (TEAEs) of any grade occurred in 51.4% of patients, with 27.0% considered treatment-related. Grade 3 or higher TEAEs were reported in 10.8% of patients, and serious TEAEs occurred in 8.1%; none of the serious TEAEs were treatment-related. One death (2.7%), due to febrile neutropenia, was assessed by the investigator as related to underlying disease rather than treatment.
The most common any-grade TEAEs were asthenia (16.2%), fatigue (8.1%), constipation (8.1%), and cough (8.1%). Grade 3 or higher treatment-related AEs were limited to one case each of hypertension and leukopenia (2.7% each).
