TP53 exon 7 (c.742C>T; p. Arg248Trp) vaf suppression by novel oral allosteric NEK7 inhibitor in a patient with low-risk myelodysplastic syndrome in A phase 2 clinical trial

Abstract TP53 exon 7 (c.742C>T; p. Arg248Trp) VAF Suppression by Novel Oral Allosteric NEK7 Inhibitor in a Patient with Low-Risk Myelodysplastic Syndrome in a Phase 2 Clinical Trial Devan Bursey, Victoria Allgood, Andrea Groen, Alan List, Stephen Anthony, David Bearss Halia Therapeutics, Lehi, Utah Background TP53-mutated myelodysplastic syndromes (MDS) represent a high-risk molecular subset characterized by genomic instability, poor overall survival, and resistance to standard therapies such as hypomethylating agents, often independent of allelic state or variant allele frequency (VAF). Although TP53-mutant clones may generate neoantigens, the concurrent pro-inflammatory microenvironment, driven by inflammasome-mediated pyroptosis, can foster immune suppression and limit immune-mediated clonal clearance. Clearance of TP53 mutations in MDS and acute myeloid leukemia (AML) has been associated with improved clinical outcomes and enhanced treatment response. Ofirnoflast (HT-6184) is an oral, first-in-class allosteric inhibitor of NEK7 currently under evaluation in a Phase 2 trial in patients with low-risk MDS and symptomatic anemia (NCT07052006). NEK7 is a scaffold protein that is critical for NLRP3 inflammasome activation and we hypothesized that through inhibition of inflammasome activation, ofirnoflast would down-regulate inflammasome signaling, thereby mitigating pro-inflammatory feedback loops and promote clearance of TP53-mutated clones. Methods In the ongoing Phase 2 trial, patients self-administered a single 2-mg capsule of ofirnoflast once daily for five consecutive days, followed by a two-day drug holiday, each week for an initial 16-week treatment period. Patients without evidence of disease progression at Week 16 were eligible to continue therapy for an additional 16 weeks (maximum of 32 weeks). Genetic profiling was performed using the Oncomine™ Myeloid 69-gene next-generation sequencing (NGS) panel to quantify somatic mutations associated with myeloid disorders. Whole blood samples were collected at baseline, after 16 weeks of therapy, and at the end of Week 32 for patients who continued treatment. Hematologic improvement–erythroid (HI-E) was assessed according to International Working Group (IWG) 2018 criteria at Week 16 and Week 32. VAF changes from baseline were calculated, and a VAF >2% was considered clinically meaningful. Results A single patient carried a TP53 exon 7 mutation (c.742C>T; p.Arg248Trp) at baseline, with a variant allele frequency (VAF) of 4.75%; no additional co-mutations were observed in this patient. The patient was a 66-year-old Asian female with myelodysplastic syndrome with low blasts (MDS-LB), transfusion-independent anemia (hemoglobin 8.2 g/dL), an IPSS-R score of 4.5, and a baseline endogenous erythropoietin (EPO) level of 141 mIU/mL consistent with a compensatory response to anemia and ineffective erythropoiesis. She had previously failed therapy with erythropoiesis-stimulating agents. Following 16 weeks of treatment with ofirnoflast, the TP53 mutation was undetectable by NGS and remained undetectable at Week 32, the end of the treatment period. Concurrently, EPO levels decreased by approximately 50–75%, reaching 59.2 mIU/mL at Week 32, consistent with improved erythropoietic function. The patient achieved a HI-E response, with hemoglobin rising 3.9 g/dL from baseline at Week 32 without transfusion support (Week 16: 11.6 g/dL; Week 32: 12.1 g/dL). Conclusions Ofirnoflast treatment resulted in the sustained molecular clearance of a TP53-mutant clone in an ESA-refractory patient with low-risk MDS, accompanied by a durable 32 Week erythroid response and normalization of EPO levels. These findings suggest that ofirnoflast may restore endogenous anti-clonal immunity through inhibition of inflammasome signaling. Further evaluation in larger TP53-mutant MDS cohorts is warranted to confirm these preliminary observations and assess the potential of ofirnoflast as a targeted, immune-modulating therapy.