Hoth Therapeutics has announced significant progress in the development of HT-KIT, a precision antisense oligonucleotide (ASO) therapy targeting systemic mastocytosis (SM) and other KIT-driven malignancies, according to a recently published press release.
The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for HT-KIT, a designation intended to support and encourage the development of therapies for rare conditions.
SM is characterized by the abnormal proliferation of mast cells, often driven by the D816V mutation in the KIT gene. KIT is a receptor tyrosine kinase that plays an important role in mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. survival and proliferation.
HT-KIT silences KIT at the mRNA transcript level. This means the mutated gene cannot be translated into an abnormally functioning protein. This approach is designed to overcome mechanisms of resistance such as secondary mutations or compensatory signaling.
Early results from clinical trials of HT-KIT suggest the treatment may have a strong effect, with over 80% suppression of KIT expression and rapid tumor reduction observed in multiple models.
Additionally, early testing showed significant tumor-volume reduction by Day 8 in xenograft models of SM, evidence of apoptotic (programed cellular death) signaling consistent with KIT pathway knockdown. Furthermore, preclinical testing showed no dose-limiting toxicities observed, suggesting a favorable tolerability profile.
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Hoth Therapeutics plans to submit an Investigational New Drug (IND) application and initiate a Phase 1/2 clinical trial, which will evaluate dose escalation and expansion in advanced KIT-driven tumors.
The trial will also measure other variables such as KIT knock-down, serum tryptaseTryptase A protein enzyme that is primarily produced by mast cells and stored in small pockets within the cells, known as granules. High levels of tryptase are a key indicator of SM. (associated with disease activity) and early efficacy signals including objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS).
“HT-KIT’s transcript-level suppression of KIT has now produced consistent anti-tumor performance across models,” said CEO Robb Knie. “We are preparing for a disciplined entry into first-in-human evaluation.”
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