Halia Therapeutics has dosed the first patient in a Phase 2a clinical trial evaluating HT-6184, a first-in-class NLRP3/NEK7 inflammasome inhibitor, for the treatment of lower-risk myelodysplastic syndromes (LR-MDS). The clinical-stage biopharmaceutical company announced this milestone on December 13, 2023, marking a significant advancement in targeting inflammatory pathways for hematologic malignancies.
Novel Mechanism of Action
HT-6184 represents an innovative therapeutic approach as the first drug candidate to target the protein NEK7 through an allosteric mechanism. NEK7 is an essential component of the NLRP3 inflammasome and is critical for its assembly and the maintenance of NLRP3 activity. In preclinical models, Halia has demonstrated that inhibiting the ability of NEK7 to bind to NLRP3 leads to a disruption in the formation of the NLRP3 inflammasome complex, thereby inhibiting the signaling from the inflammasome and reducing the inflammatory response.
The compound's dual mechanism includes both preventing the formation of the NLRP3 inflammasome and promoting its disassembly once formed, thereby inhibiting the production and release of pro-inflammatory cytokines IL-1β and IL-18.
Trial Design and Endpoints
The Phase 2a trial will evaluate the safety and activity of HT-6184 in up to 40 patients with LR-MDS and will be conducted at multiple sites across India. The study will measure the rate of hematological improvement, including transfusion dependency and changes in hemoglobin levels as primary endpoints. Secondary endpoints will further assess the effect of HT-6184 on biomarkers of inflammasome activation in MDS and the changes in clone size of somatic gene mutations. The trial is expected to be completed by Q4 2025.
Clinical Rationale for MDS Treatment
Myelodysplastic syndromes are a group of cancers in which the bone marrow produces underdeveloped (immature) cells that are abnormal in size, shape, or appearance, which are called "dysplastic." This leads to a reduced number of healthy blood cells, which can result in multiple complications, including anemia, recurrent infections, and progression to cancer.
In recent years, NLRP3 has been discovered and is gaining significance as one of the key biological drivers of ineffective hematopoiesis and inflammation in MDS. The NLRP3 inflammasome, an innate immune sensor, is activated in response to various pathogenic and sterile stimuli, triggering the release of pro-inflammatory cytokines and inducing a lytic cell death process called pyroptosis, leading to systemic chronic inflammation.
Positive Phase I Results
Halia recently announced Phase I trial results evaluating HT-6184, which was shown to be safe, well tolerated and to significantly reduce NLRP3-inflammatory cytokines in healthy volunteers. The Phase 1 study (NCT05447546) evaluated the safety and tolerability of HT-6184 when administered as single or multiple oral doses at escalating dose levels in healthy volunteer subjects.
"The dosing of the first patient in our Phase 2 trial of HT-6184 marks a significant milestone for Halia in further evaluating the potential of targeting the NLRP3 inflammasome to treat a wide spectrum of immunological and inflammatory diseases," said Margit M. Janát-Amsbury, MD, Ph.D., Chief Medical Officer of Halia Therapeutics. "The recent positive results of our Phase I trial investigating HT-6184 are extremely encouraging and highlight the functional activity of HT-6184 in being able to reduce inflammatory cytokines."
Broader Therapeutic Potential
Beyond MDS, persistent activation of the NLRP3 inflammasome is thought to drive the onset and progression of many conditions, including fibrotic, dermatological, and auto-inflammatory diseases. Significant neurodegenerative and neuroinflammatory disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis are also driven by NLRP3 activation.
Halia Therapeutics is discovering and developing a pipeline of novel therapeutics to improve patients' lives with chronic inflammatory disorders and neurodegenerative diseases, with its initial programs targeting NEK7 and LRRK2. The company is headquartered in Lehi, Utah.
