Modulation Therapeutics is developing a first in class cyclic peptide coined MTI-101 for the treatment of multiple myeloma. The company currently has a license for the parent molecule which has been awarded a patent covering the intellectual property for both composition of matter and use in cancer in the US and Europe. Modulation Therapeutics is now poised to further advance this class of compounds by the development of a second generation derivative which is PEGylated. MTI-101 is unique with respect to chemical space and mechanism of action. Treatment of myeloma cells with MTI-101 stimulates a CD44 complex resulting in activation of the necroptotic pathway and a robust and sustained increase in intracellular calcium levels leading to cell death. Importantly, MTI-101 is i) more active in patient specimens derived from patients relapsing on therapy compared to specimens obtained from newly diagnosed patients and ii) demonstrates robust synergy when combined with the proteasome inhibitor bortezomib. The goal of the Phase I grant will be to determine the in vivo efficacy and circulating half-life of the PEGylated analog compared to the parent molecule MTI-101. We predict that PEGylation of the molecule will increase the circulating efficacious dose and increase the terminal half-life leading to increased therapeutic index of the molecule. The PEGylated analog will be tested using a syngeneic myeloma in vivo model system. The goals of the Phase II application will be to perform non-GLP and GLP toxicity in rodent (rat) and non-rodent (dog) species, design the Phase I clinical trial and completion of the IND package to the FDA. Additionally, Modulation Therapeutics will invest early into the discovery of companion diagnostics to guide precision therapy for the anticipated Phase III clinical trial. Discovery of companion diagnostics will be accomplished by ex-vivo testing of primary myeloma (CD138 positive) cells using an organotypic model system coupled to gene expression profiling. Preliminary data has identified determinants of calcium flux (Ero1L) expression and necroptosis (BIRC3, TNFAIP3) as putative predictive biomarkers of response. We anticipate early discovery work focused on primary specimens will allow for further validation in phase I-11 clinical trials leading to a potential precision medicine guided phase III clinical trial.
Public Health Relevance Statement: Narrative: Multiple myeloma is a disease that although treatable is not currently curable. Thus clinical data continue to support the dire need to develop novel drugs which are active after patients relapse on standard of care treatment. A promising feature of this compound is that it is more active in primary specimens obtained from patients relapsing on standard of care therapy compared to newly diagnosed specimens. Moreover, MTI-101 when used in combination with the proteasome inhibitor bortezomib results in synergistic cell death. Together our data indicate that further development of MTI-101 is warranted for the treatment of Multiple Myeloma.
Project Terms: analog; arm; Award; base; Binding; Biological Models; BIRC3 gene; bone; Bone Marrow; Bortezomib; Calcium; candidate marker; Canis familiaris; CD44 gene; Cell Death; cell stroma; Cells; Chemicals; Clinical; Clinical Data; clinical development; Clinical Protocols; Clinical Treatment; Clinical Trials; clinically relevant; Coculture Techniques; Coin; companion diagnostics; comparative; Complex; Coupled; Cyclic Peptides; cytokine; Data; design; Development; Disease; Dose; drug clearance; Drug or chemical Tissue Distribution; Drug resistance; E-Cadherin; Europe; experimental study; Extracellular Matrix; Formulation; Future; Gene Expression Profiling; Generations; Genes; Goals; Grant; Half-Life; Hour; Implant; in vivo; in vivo Model; Intellectual Property; Investigational New Drug Application; Investments; Legal patent; Licensing; Malignant Neoplasms; meetings; Methods; Modeling; Monitor; mouse model; Multiple Myeloma; Mus; Necrosis; Newly Diagnosed; novel; novel therapeutics; Outcome; Parents; Pathway interactions; Patients; personalized medicine; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Population; pre-clinical; precision medicine; Precision therapeutics; predictive marker; Proteasome Inhibitor; Rattus; Refractory; Relapse; relapse patients; release of sequestered calcium ion into cytoplasm; Resistance; responders and non-responders; response; response biomarker; Rodent; Route; Sampling; Small Business Innovation Research Grant; Source; Specimen; standard of care; success; synergism; Testing; Therapeutic; Therapeutic Agents; therapeutic evaluation; Therapeutic Index; TimeLine; Toxic effect; tumor; tumor growth; Validation; Work
