We have discovered a novel Type IIb prodrug of riluzole, trigriluzole (FC-4157, BVH-4157), which has the potential to substantially improve therapy for the treatment of the devastating condition of metastatic melanoma acting via a novel glutamatergic mechanism of action. While riluzole has shown promising efficacy in treating melanoma in patients, trigrilluzole is >20X more potent than riluzole itself in a C8161 mouse xenograft model of melanoma, and >10X more potent in a MASS20 allograft model in combination with anti-PD1. Trigriluzole was designed to overcome the limitations of riluzole that have restricted its broader clinical efficacy. For example, riluzole tablets have 60% bioavailability upon oral administration, attributed to Cyp1A2-mediated first-pass metabolism in the liver, which also causes high patient-to-patient variability of exposure. In addition, riluzole is associated with reduced levels when taken with meals (i.e., a negative food effect), requiring a three hour fast (one hour before and two hours after a meal), with poor patient compliance. Riluzole is dosed twice a day, has dose-dependent effects on liver function tests, exhibits low solubility in water, and intense oral numbness if administered directly to the oral mucosa. Trigriluzole solves these problems because it is not subject to first- pass Cyp1A2 metabolism and may be suitable for once-daily dosing with an extended half life. Trigriluzole is a tripeptide conjugate that is actively taken up from the GI tract by the PepT1 transporter, whereas riluzole is not actively transported, obviating the need for fasting for trigriluzole. Trigriluzole is stable in the GI tract, but cleaves after absorption. High levels of riluzole are observed in the systemic circulation after oral administration of trigriluzole in mice, rats and cynomolgous monkeys. We have achieved the aims of our Phase I and II SBIR grants, as well as conducted many additional studies that were not originally described or anticipated. We have established a co-development partnership with Biohaven Pharmaceuticals, and now seek Bridge Phase II SBIR support to advance trigriluzole through costly Phase II clinical trials in combination with the anti-PD1 antibody nivolumab. Our goal is to develop trigriluzole as an oral anticancer agent used in combination, at least initially, with anti-PD1 antibodies, which could substantially increase the efficacy of anti- PD1 therapy alone. Monotherapy will also be considered in the future, depending on the results of these studies.
In Aim 1, we will conduct additional preclinical biomarker and patient derived xenograft (PDX) activities to support the introduction of trigriluzole into human clinical trials for metastatic melanoma, including obtaining the required IND approval. In the PDX model, we will look for possible biomarkers such as differences in signal transduction in key pathways (MAPK, Pi3K/AKT), changes in expression of VEGF, IL-8, CD34, CCL4, and MCSF, and changes in the quantity and contents of tumor-derived exosomes in the peripheral blood.
In Aim 2, our collaborators at the Cancer Institute of New Jersey at Rutgers University will conduct Phase II human clinical trials for the treatment of metastatic melanoma in combination with nivolumab.

Public Health Relevance

Metastatic melanoma is a life-threatening condition with few treatment options. We have discovered trigriluzole (FC-4157), a Type IIb tripeptide prodrug of riluzole, that is actively transported by the PepT1 transporter from the GI tract, and shows outstanding activity in a mouse xenograft and allograft models of melanoma, acting by a glutamatergic mechanism of action. This program advances trigriluzole through Phase Ib and II clinical trials for the treatment of melanoma, in combination with the anti-PD1 antibodies pembrolizumab (Phase Ib) and nivolumab (Phase Ib and II), seeking to improve clinical outcomes for these two agents with a lower overall toxicity profile.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZCA1)
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Kurtz, Andrew J
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Fox Chase Chemical Diversity Center, Inc
United States
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Pelletier, Jeffrey C; Chen, Suzie; Bian, Haiyan et al. (2018) Dipeptide Prodrugs of the Glutamate Modulator Riluzole. ACS Med Chem Lett 9:752-756
Pelletier, Jeffrey C; Velvadapu, Venkata; McDonnell, Mark E et al. (2014) Intramolecular Rearrangement of ?-Amino Acid Amide Derivatives of 2-Aminobenzothiazoles. Tetrahedron Lett 55:4193-4195
McDonnell, Mark E; Vera, Matthew D; Blass, Benjamin E et al. (2012) Riluzole prodrugs for melanoma and ALS: design, synthesis, and in vitro metabolic profiling. Bioorg Med Chem 20:5642-8