The novel allosteric NEK7 inhibitor ofirnoflast (HT-6184) demonstrates robust and sustained hematologic response in subjects with IPSS-R very low, low or intermediate risk myelodysplastic syndrome (MDS) and symptomatic anemia Free

Introduction With few exceptions, current MDS therapeutics are not effective across all subsets of the disease and none address the core pathogenetic root cause of MDS. The NLRP3 inflammasome is a key driver of ineffective hematopoiesis and inflammation in MDS that directs caspase-1 and IL-1β maturation, leading to GATA-1 degradation, myeloid skewing and pyroptotic cell death of hematopoietic stem and progenitor cells (HSPC). Ofirnoflast (HT-6184) is an oral allosteric inhibitor of NEK7 (NIMA-related kinase 7), a scaffold protein that is indispensable for NLRP3 inflammasome activation. Ofirnoflast blocks inflammasome complex assembly, promotes ASC speck dissolution and inhibits myddosome activation of NF-kB. Ofirnoflast is being developed to extinguish the pro-inflammatory microenvironment that sustains MDS clones and restore effective hematopoiesis.

Methods HT-6184-MDS-001 is a Phase 2 multi-center, Simon's two-stage trial evaluating erythroid hematologic improvement (HI-E) in subjects with IPSS-R very low, low, or intermediate-risk MDS and symptomatic anemia (NCT07052006). Subjects self-administered a 2mg capsule of ofirnoflast daily for five consecutive days, followed by a two-day drug holiday, for four 28-day cycles (16 weeks). Per International Working Group (IWG) 2018 criteria, hematologic improvement was assessed as ≥16-week transfusion independence in subjects with transfusion dependence (TD) at baseline and ≥16-week maintenance of hemoglobin improvement in subjects who were not transfusion dependent (NTB) at baseline. Subjects with HI-E continued treatment for an additional 16 weeks, for a maximum of 32 weeks of treatment. The primary endpoint was rate of hematological improvement after ≥16 weeks of treatment with ofirnoflast. Stage 1 required 18 subjects evaluable for the primary endpoint; ≥3 hematologic responses (17% response rate) would prompt initiation of Stage 2.

Results Across 6 sites in India, 23 subjects (57% male, 43% female, mean age 63.7 [range31-83]) were enrolled in Stage 1 and were evaluable for safety. 5 subjects were found to be ineligible or did not complete the treatment period; 18 subjects (mean age 64.1, [range 31-83]) were evaluable for assessment of HI-E, including 12 (67%) transfusion-dependent (TD) and 6 (33%) not transfusion-dependent (NTD) at baseline. 11 subjects (61%) were refractory to prior erythropoiesis-stimulating agents (ESA). HI-E was assessed per IWG 2018 for TD and for NTD subjects. 13 subjects had HI-E response of ≥16 weeks duration, including 8 subjects with TD and 5 with NTD, for an overall HI-E response rate of 72%; an additional NTD subject experienced a >1.5 g/dL hemoglobin rise for 12 weeks before reaching maximum study duration and met criteria for response but not HI-E. In 9 of the 13 HI-E responders, HI-E was maintained for 32 weeks (the maximum treatment duration). Among the 11 subjects refractory to ESA, 10 subjects (91%) achieved HI-E, including 8 subjects (73%) with HI-E response for 32 weeks. Morphologic WHO subtypes included MDS-LB (n-13), MDS-SF3B1 (n=2), MDS-IB (n=1) and MDS/MPN (n=2); corresponding HI-E responses by subtype were 9 (69%), 2 (100%), 0, and 2 (100%). 67% of subjects with ≥ 1 somatic mutation had HI-E. Among all responders, the median rise in hemoglobin was 3.5 g/dL over 16 weeks and 3.1 g/dL over 32 weeks. Among 23 subjects evaluable for safety, 6 (26%) experienced 18 treatment-related adverse events (TRAE), none of which was an SAE. TRAEs occurring in at least 2 patients (10%) were constipation (n=2), leukocytosis (n=2) and hyperkalemia (n=2). No myelosuppression of any grade was observed. All TRAEs resolved and no TRAE resulted in dose reduction or study discontinuation. With 13 responses (72% response rate) in Stage 1, enrolllment into Stage 2 is underway.

Conclusions In subjects with low risk MDS and anemia, ofirnoflast administered orally induced clinically meaningful and sustained 16- and 32-week erythroid responses across WHO subtypes, including transfusion-dependent and -independent subjects, and irrespective of somatic mutation type. Importantly, ofirnoflastsupported sustained 32-week HI-E in difficult-to-treat ESA-refractory and ESA-intolerant populations. With a robust HI-E rate, favorable safety profile, absence of myelosuppression, a relevant and targeted mechanism of action, ofirnoflastoffers a novel oral alternative that eases the burden of current treatments in a diverse MDS population.