A safety signal has derailed Theseus Pharmaceuticals’ quest to develop a gastrointestinal stromal tumor (GIST) treatment. The dose-limiting toxicity drove the biotech to stop enrollment and end development, sending its stock down 65% and leaving its hopes of navigating the R&D maze resting on other assets.
Massachusetts-based Theseus saw one dose-limiting toxicity across the first six cohorts of the study—a heart attack death that may have been linked to THE-630—but it was able to keep escalating up to 27 mg. The safety profile took a turn for the worse at that dose. The third patient enrolled at the dose level suffered a grade 3 hand-foot skin reaction (HFSR), a side effect associated with multikinase inhibitors.
In response, the biotech expanded the cohort to include six patients. One of the patients enrolled in the expansion cohort had a grade 2 HFSR. Both reactions required dosing of the pan-variant inhibitor of the receptor tyrosine kinase KIT to stop for at least seven days and were classed as dose-limiting toxicities.
The toxicities in two of the six patients happened at the dose level below the cohort Theseus identified as its projected target exposure. With one-third of people having HSFRs at 27 mg, the biotech said the dose exceeds the maximum tolerated dose. And with Theseus calculating that lower doses “would provide exposure well below the target level,” it sees no future for the molecule in GIST.
No significant skin toxicity was seen in preclinical toxicology studies, but lower clinical doses suggested it may be a problem. Theseus saw three HFSRs in the lower-dose cohorts, but the only grade 3 case was at 27 mg. The failure of THE-630 sets back efforts to address a major unmet need in GIST.
First-line treatment with Gleevec improves outcomes in most patients, achieving a response rate of 51% and median progression-free survival of 18.9 months, but there is a need for better treatments of people who relapse after taking the tyrosine kinase inhibitor. Used as second, third and fourth-line treatments, Pfizer’s Sutent, Bayer’s Stivarga and Deciphera Pharmaceuticals' Qinlock have sub-10% response rates.
Theseus continued to work on KIT after nominating THE-630 as a development candidate, leading to the discovery of a series of chemically distinct, pan-variant inhibitors of the target for treatment of early-line GIST. The biotech plans to nominate a development candidate in the first half of next year, and, with its cash runway now stretching into 2026, has the money to recover from the setback.
The KIT candidate will slot into a pipeline now led by the EGFR inhibitor THE-349. Theseus expects to file to study THE-349 in humans in the fourth quarter. The biotech is part of a clutch of companies trying to expand the portfolio of approved EGFR inhibitors and looks set to follow the likes of Blueprint Medicines, Black Diamond Therapeutics and Bridge Biotherapeutics into the clinic.