FDA grants fast track status to MT-125, a first-in-class NMII inhibitor, aiming to bring a novel treatment option to patients with aggressive glioblastoma.
The FDA has granted fast track designation to MT-125, a first-in-class dual inhibitor of NMIIA/IIB, for use as a potential therapeutic option in patients with glioblastoma, according to an announcement from Myosin Therapeutics, Inc.1
The safety and activity of the agent will be evaluated in the ongoing phase 1/2 STAR-GBM trial (NCT07185880).2 Although not yet recruiting, the trial will enroll patients with newly diagnosed histologically or molecularly confirmed IDH wild-type and MGMT unmethylated glioblastoma who are at least 18 years of age and have an ECOG performance status ranging from 0 to 2.
“Receiving fast track designation validates our conviction that MT-125 has the potential to offer an entirely novel treatment approach to patients with even the most aggressive forms of glioblastoma,” Courtney Miller, PhD, chief executive officer of Myosin Therapeutics, stated in a news release.1 “We are energized by the open communication with the FDA that the fast track offers because it will ensure we advance MT-125 as quickly as possible with our patient-centered approach.”
Previously, the regulatory agency granted an orphan drug designation to MT-125 for use in malignant gliomas, including glioblastoma.
NMIIs are motor protein ATPases that interact with actin to regulate cellular functions like movement, division, signaling, and mitochondrial homeostasis. MT-125 simultaneously targets NMIIA and NMIIB, disrupting tumor cell proliferation, invasion, and metastasis and elicits reactive oxygen species through impaired mitochondrial quality control. This mechanism contributes to the survival benefit observed in preclinical models when MT-125 is paired with radiation therapy. Of note, NMIIA is overexpressed in several cancers like glioblastoma, highlighting its key role in tumor biology and the heightened vulnerability of these cells to NMII inhibition.
Those with glioblastoma are known to have a poor prognosis, with no therapeutic options greenlit by the FDA since 2008. The current standard of care for those with newly diagnosed disease is maximal safe surgical resection and concurrent radiation therapy plus temozolomide. Those with unmethylated MGMT are not responsive to temozolomide; effective systemic options are needed for this population.
In animal models, single-agent MT-125 has been shown to extend survival and to have synergy when used with radiation therapy and other oncogenic kinase inhibitors. In an article published in Cell Biomaterials, authors commented on early data with MT-125.3 “MT-125, a blebbistatin derivative, displayed similar potency against both NMIIA and IIB, with no cytotoxicity and limited off-target inhibitory activity against cardiac myosin II. Predictably, its in vitro specificity for NMIIA/IIB translated into superb tolerability for the drug in vivo,” the authors wrote. “The evaluation of MT-125 revealed a comparably short in vivo lifetime, similar metabolite profiles in non-clinical species as that in humans, and satisfactory selectivity for NMIIA/IIB, with minimal cardiac toxicity—further exemplified in the low levels of inhibition in ion channel activity assays. The drug was well tolerated for all three routes of administration (intravenous, oral, and subcutaneous) with no adverse clinical symptoms.”
The first-in-human, phase 1, open-label, single-arm study will examine MT-125 at 25 mg, 50 mg, 83.5 mg, 100 mg, and at the maximum tolerated dose (MTD) and one dose level lower than the MTD for 5 consecutive days, then off 2 days for a total of 6 weeks plus outpatient radiation therapy. Each dose-escalation cohort will include no more than 6 participants.2
The primary outcome measures are dose-limiting toxicities (DLTs) and incidence and severity of adverse effects. The observation period for DLTs will occur in the 6 weeks after the agent is first given. Secondary outcome measures comprise MTD, pharmacokinetic measures, and identification of the recommended phase 2 dose. For the phase 2 portion, investigators will evaluate the overall response rate in those with measurable disease, as well as progression-free survival and overall survival in all patients.
The early-phase trial has been cleared to proceed, according to Myosin Therapeutics, Inc.,1 and is estimated to start in November 2025.2 The estimated primary completion is August 2026.
