Third Harmonic Bio, Inc. (Nasdaq:THRD) is on the brink of bringing forward a revolutionary medicine to treat inflammatory diseases. In an exciting turn of events, the biopharmaceutical company has announced its next-generation product candidate, THB335, an oral small molecule KIT inhibitor of remarkable potency and selectivity.
On top of this, the product profile of THB335 is significantly different than that of the company’s prior product candidate, THB001. With the goal of providing clinically meaningful treatments, Third Harmonic is ready to begin the approval process of its novel candidate with a planned filing of a U.S. IND in the first half of 2024.
The results of a Phase 1b clinical trial for THB001, a treatment for chronic inducible urticaria, were recently revealed. Despite the trial’s premature termination due to observed liver transaminitis in two of the five enrolled patients, evidence of clinical benefit was detected in four of them. Partial or complete responses were successfully achieved.
The company revealed initial findings from detailed analyses of THB001 that unexpectedly caused liver toxicity. These thorough investigations evidenced a metabolic route which produced a reactive metabolite contributing to the liver injury. Structural modifications to THB335 are anticipated to diminish this risk, and current studies appear to validate this between the two compounds.
At Third Harmonic Bio, we are thrilled to announce the selection of THB335 – a next-generation compound that incorporates structural modifications to maintain the potency and selective KIT inhibitory activity of our first generation product candidate THB001, while improving its safety profile.
Encouraged by the clinical efficacy results seen in the discontinued Phase 1b study of THB001, where four out of five patients experienced clinical responses in the lowest planned dose cohort, we believe that THB335 has the potential to provide an optimal therapeutic profile against KIT for the treatment of mast cell-mediated inflammatory disorders. We are now working towards getting back in the clinic in the first half of the coming year.
THB001 Clinical Results
The Phase 1b clinical trial of THB001 in chronic inducible urticaria set out to analyze the efficacy, tolerance, safety, and pharmacokinetics of three different dose levels of the drug over a 12-week period. Initially, five people enrolled in the lowest dose cohort of 200mg BID, but unfortunately, the study was swiftly discontinued.
Of those five, the first participant made it through the entire course of treatment, however the two following participants had to discontinue the medication after eight weeks due to liver transaminitis. The remaining two individuals discontinued the study even earlier, at weeks three and four, while the trial’s safety protocol was still supervised.
Patients experienced transaminitis AEs, which were deemed moderate but resolved within the timespan of 17 and 25 weeks. Other AEs were observed as well but were determined to be mild and reversed in time.
Surprisingly, some of the lighter AEs included hematologic and hair color changes, which can be attributed to the inhibition of KIT. Ultimately, the AE profile was determined to be on par with the predicted effects of KIT inhibition.
With astonishing results, the trial observed an 83.1% reduction in serm tryptase levels – a biomarker associated with mast cell activation – from baseline within the first week. Furthermore, four out of five patients demonstrated a partial (two) or complete (two) Critical Temperature Threshold response, even with early termination of dosing. These results signify an encouraging potential for this treatment’s potential to end the suffering of those who experience urticaria.
The company is eagerly anticipating the opportunity to share the outcomes of their study with the scientific community later this year, presenting the full results at an upcoming conference.
THB335, the company’s latest oral small molecule wild-type KIT inhibitor, is set to revolutionize the field, promising significant improvements over THB001. Structurally modified to reduce hepatoxicity risk, THB335 could also have a differentiated metabolic, distribution and physiochemical profile – allowing it to potentially outperform its predecessor.
THB335 is set to make a major advancement in the medical world. With plans to file a U.S. IND and begin clinical trials in the first half of 2024, this groundbreaking drug will soon be on its way to helping those living with chronic spontaneous urticaria and other mast-cell mediated inflammatory disorders.
Phase 2 of THB335’s development will open the door to significant medical breakthroughs, providing an opportunity to dramatically improve the quality of life for countless individuals.
As of March 31, 2023, Third Harmonic Bio had a healthy cash reserve of $282.2 million, ensuring the company’s financial stability for the foreseeable future.
About Third Harmonic Bio, Inc.
Third Harmonic Bio is pioneering the next frontier of medicine, working to develop novel, highly selective, oral small-molecule inhibitors of KIT – a cell surface receptor that acts as the master regulator of mast cell function and survival.
Preliminary clinical studies have shown that KIT inhibition may revolutionize the treatment of mast cell-mediated inflammatory diseases, and that a titratable, oral, intracellular small molecule inhibitor may have the ideal therapeutic profile.
Commercialization of Third Harmonic’s lead drug candidate THB335 is projected for the opening half of 2024, paving the way for a new era of treatment for inflammation.