Development of drug product to support a Phase 0/1b dose escalation trial of MT-125 in recurrent high grade gliomas

PROJECT SUMMARY
Glioblastoma (GBM), marked by its aggressive, fast-growing nature and high mortality rate, makes up nearly
half of all malignant brain tumors. Survival is limited to an average of three months without treatment. The
current standard treatments – maximal safe tumor resection, radiation, and chemotherapy – only extend
survival to about one year, largely because GBM is highly invasive and prone to recurrence. GBM cells tend
to either invade or proliferate, but not both simultaneously; however, blocking one process tends to activate
the other. This suggests that an effective therapy must target both pathways concurrently. Dual inhibition of
non-muscle myosin II molecular motors (NMIIA and IIB) has been shown to meet this need, though the
development of a clinically viable treatment has been hindered by the lack of a CNS-penetrant small molecule
inhibitor that is both safe and effective. Through targeted medicinal chemistry, MT-125 has emerged as a
promising candidate. This compound is a dual inhibitor of NMIIA and IIB, exhibiting excellent brain penetrance
and a favorable safety profile, essential for GBM therapy. In preclinical studies, MT-125 has demonstrated the
ability to suppress both invasion and proliferation, thereby significantly extending survival. Additionally, MT-
125’s novel mechanism allows it to act synergistically with FDA-approved CNS-permeant kinase inhibitors and
radiotherapy, leading to dramatically increased survival in patient-derived and genetically engineered GBM
mouse models. Notably, MT-125 is effective against GBMs that are IDH wild-type and MGMT unmethylated,
a subset of tumors that are notoriously resistant to current treatments. The FDA has recently granted Orphan
Drug Designation to Myosin for MT-125 in the treatment of malignant gliomas, and the company has received
favorable Pre-IND guidance from the FDA’s Division of Oncology 2. The goal of this SBIR
Commercialization Readiness Pilot (CRP) Program application, which builds on the company’s currently
funded NCI Fast Track STTR with Dr. Rosenfeld (Mayo Clinic), is to perform analytical and process transfer,
and GMP manufacturing of MT-125 drug product in support of a Phase 0/1b clinical trial in glioblastoma.
Activities include analytical method transfer/development and validation, process transfer for the liquid drug
product as well as a <5L lab scale batch preparation followed by an optional engineering batch (8L) as well as
stability. Manufacture of the GMP drug product, packaging and release testing will provide clinic-ready material
per cGMP standards.

Grant Number: 1SB1CA302068-01
NIH Institute/Center: NIH
Principal Investigator: Michael Brownstein