Promising data from Phase 2 study in myelodysplastic syndrome has potential implications for wider application in age-related diseases.
US biotech Halia Therapeutics has announced promising topline findings from its ongoing Phase 2 clinical trial of its oral treatment for lower-risk myelodysplastic syndromes. The drug, HT-6184, targets the NEK7 protein, which is critical to the activation of the NLRP3 inflammasome, a protein complex that drives inflammatory responses implicated in many age-related conditions.
Myelodysplastic syndromes (MDS) are a group of hematologic cancers characterized by dysfunctional bone marrow, leading to abnormal blood cell production, but Halia’s work in this area also has relevance in the context of aging and longevity. MDS predominantly affects individuals aged 65 and older, and its pathology intersects with clonal hematopoiesis, an age-related condition linked to increased risks of leukemia and cardiovascular diseases.
The heightened activity of the NLRP3 pathway in aging bone marrow contrasts with its dormancy in younger, healthier individuals. By targeting this pathway, Halia hopes to potential to not only treat MDS but also address broader age-associated inflammatory processes.
In an interview with Longevity.Technology earlier this year, Halia CEO David Bearss told us, “With this study, we hope to show we can target inflammation in the bone marrow of individuals that have myelodysplastic syndrome and relieve the inflammatory signalling and restore the normal function of differentiation of these stem cells. If we can do that, then potentially we can break clonal hematopoiesis, and the implications of that could be huge.”
By inhibiting the binding of NEK7 to NLRP3, HT-6184 disrupts inflammasome assembly, curbing inflammatory signaling and promoting its disassembly. This mechanism has demonstrated efficacy in preclinical models and now shows promise in a clinical trial, with the first cohort of 18 MDS patients demonstrating significant hematological improvements after 16 weeks of monotherapy. According to Halia, the response exceeded pre-established benchmarks, enabling progression to the trial’s next phase with an expanded cohort.
The trial’s primary endpoints focus on hematologic improvements such as transfusion independence and hemoglobin level changes. Secondary measures include assessing biomarkers of inflammasome activity and the size of somatic gene mutation clones. Conducted at multiple sites in India, the trial aims to provide comprehensive insights into HT-6184’s therapeutic potential, with final results anticipated by mid-2025.
“The high frequency of erythroid response following treatment with HT-6184 validates the key importance of the NLRP3 inflammasome and myddosome pathways as pathogenetic drivers of ineffective hematopoiesis in MDS, offering the prospect of a safe and effective oral therapeutic for LR-MDS patients,” said Dr Alan List, a member of Halia’s scientific advisory board.
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Main photograph: Dr David Bearss, CEO of Halia Therapeutics.