Ofirnoflast Shows Activity Across High-Risk Mutated MDS Subtypes

In an interview with CancerNetwork® at the 2026 Society of Hematologic Oncology (SOHO) Annual Meeting, David Sallman, MD, discussed subgroup findings from the phase 2a HT-6184-MDS-001 trial (NCT07052006) evaluating ofirnoflast (HT-6184), a first-in-class oral allosteric NEK7 inhibitor designed to block NLRP3 inflammasome activation, in patients with lower-risk MDS who were refractory to, intolerant of, or ineligible for erythropoiesis-stimulating agents (ESAs).¹

The final phase 2 results showed an overall hematologic improvement rate of 66.7% among 30 evaluable patients, with multilineage activity across erythroid, platelet, and neutrophil responses, and red blood cell transfusion independence of at least 8 weeks in 55.6% of transfusion-dependent patients. Sallman noted that these responses occurred across WHO subtypes and mutational backgrounds, including in patients with and without SF3B1 mutations or deletion 5q, and highlighted a patient with a TP53 mutation, first described at an earlier congress, who achieved elimination of their TP53 clone alongside a marked improvement in hemoglobin.²

Sallman is an associate member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

Transcript:

CancerNetwork: Responses occurred across various WHO subtypes and mutational backgrounds, including patients with or without SF3B1 mutations or deletion 5q. Does NEK7 inhibition overcome the negative prognostic impact of high-risk mutations such as TP53, ASXL1, or RUNX1 in lower-risk MDS?

Sallman: When we look at lower-risk therapies across all our agents, almost two-thirds of patients have SF3B1 mutations, which are [associated with a more favorable prognosis], and most of these patients are predominantly anemic. We have relatively little data with any agent across the other molecular subsets. What we know is that once patients have already been through prior therapies—in this case, they were all refractory or intolerant to an ESA, or would not have been expected to respond if they were ESA ineligible—these patients can have higher-risk mutations and be molecularly upstaged. A lot of these patients were intermediate risk by the Revised International Prognostic Scoring System (IPSS-R), and by the molecular IPSS [critieria], some of them were likely even high risk.

What we did see is that regardless of whether a patient had an epigenetic, splicing, or other class of mutation, we didn't see any group respond better or worse. But to your specific question about adverse mutations, there was 1 [patient with a TP53 mutation]—this was presented at an earlier congress—who had elimination of their TP53 clone. This was one of the most striking findings, both pharmacodynamically, in terms of reduction of inflammatory cytokines, and in the magnitude of hemoglobin improvement.

This is one of the holy grails. We know that once a patient becomes multi-hit for TP53, and we've done a lot of work on this, these patients do horribly. One of the big questions, whether in high-risk clonal cytopenia of undetermined significance [CCUS] or low-risk MDS, is whether we can prevent that single-hit-to-multi-hit acquisition. I would love to run a specific cohort in TP53-mutant disease across high-risk CCUS and low-risk MDS because if we can eliminate the clone before it acquires that second hit, we could potentially make one of the most major changes ever in low-risk MDS. Again, an “n” of 1 is an “n” of 1, but at least we're seeing responses in some patients with adverse mutations.

This also opens the door for consideration in higher-risk [disease], not just as monotherapy but in combination with a hypomethylating agent [HMA] or an HMA plus venetoclax [Venclexta], across high-risk MDS and [acute myeloid leukemia]. There's some growing preclinical data suggesting that could make sense, but ultimately the data will speak for itself.

References

1. Sallman D, Bafna V, Nath UK, et al. Ofirnoflast (HT-6184), a first-in-class allosteric NEK7 inhibitor, achieves durable transfusion independence (TI) and hematological improvement-erythroid (HI-E) in ESA-refractory lower-risk myelodysplastic syndrome (LR-MDS): phase 2 final results. Presented at: 2026 SOHO Annual Meeting; September 9-12, 2026; Houston, TX.
2. Halia Therapeutics announces positive phase 2a data for ofirnoflast in lower-risk MDS at ASH 2025. News release. Halia Therapeutics. December 8, 2025. Accessed September 10, 2026. https://haliatx.com/news/halia-therapeutics-announces-positive-phase-2a-data-for-ofirnoflast-in-lower-risk-mds-at-ash-2025