Riluzole Prodrugs for Melanoma and ALS

DESCRIPTION (provided by applicant): We have identified a novel Type IIb prodrug of riluzole, FC-311, which has the potential to revolutionize therapy for the treatment of the devastating condition of metastatic melanoma acting via a novel glutamatergic mechanism of action, and also be useful to treat amyotrophic lateral sclerosis (ALS) and the many other conditions for which riluzole itself is under clinical evaluation. FC-311 is not subject to the limiting Cyp1A2 metabolism and large patient-to-patient variability of exposure that riluzole is, and has a ~3X longer high-life, higher bioavailability upon oral administration, and shows dramatic efficacy in a xenograft model of melanoma, in a dose dependent manner. We identified FC-311 as the optimal prodrug from among ~30 designed candidates using a systematic in vitro and in vivo screening strategy. We have demonstrated conclusively that FC-311 is not metabolized by Cyp1A2, while confirming that riluzole itself is metabolized nearly exclusively by this enzyme, which has variable levels of expression in the general population. We have achieved all of the aims of our Phase I program of study as well as conducted many additional studies that were not originally described or anticipated. We now seek Phase II support to advance FC-311 through various IND-enabling pre-clinical development activities. Our goal is to develop FC-311 as an oral anticancer agent in order to provide uniform, patient to patient delivery of riluzole active substance. In Aim 1, we will conduct drug substance and chemistry related activities normally considered as part of any drug discovery and development program. These include preparing 300 g of non-GMP active pharmaceutical agent, selection of suitable salt form, vehicle and formulation, analytical methods development, drug substance stability testing, evaluation of additional riluzole prodrugs for added patent protection, as back-ups, and for possible consideration for additional indications, continued patent prosecution of the important intellectual property involved, and preparation of 5 kg of cGMP of FCC-311. In Aim 2, we will continue the required IND-enabling development activities which include completion of metabolite ID studies (human, rat and dog), determination of full PK parametersin two additional species, correlated to pharmacodynamics, investigation of Cyp450 inhibition effect in addition to the demonstrated lack of Cyp1A2, completion of in vitro, non-GLP toxicology studies (hERG, Ames, genotoxicity), 28 day safety pharmacologytesting in rats and dogs, and further ancillary pharmacology testing on FC-311. We wish to file an IND with the FDA as soon as possible, and then transition into clinical evaluation in melanoma patients. We have established a Riluzole Prodrug Project Leadership Team consisting of eight clinicians, pharmacologists and experienced pharmaceutical experts to provide real time guidance and support to ensure the success of this program. We will file for orphan drug designation for FC-311 for melanoma, and seek toobtain further funding from venture capital and other sources, or partner with a major pharmaceutical company, to advance FC-311 through the various phases of clinical development. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Metastatic melanoma is a cancer with extremely low survival rates and very limited treatment options based on highly toxic agents. Riluzole is a non-toxic drug approved for amyotrophic lateral sclerosis (ALS). We have recently shown exciting preliminary results for riluzole treatment of metastatic melanoma in mice and human subjects. We have now discovered a promising Type II prodrug of riluzole, FC-311, that is expected to treat melanoma in more patients (less patient to patient variability of exposure), has ~3X longerhalf life, greater bioavailability, and equivalent or better dose dependent activity in a mouse xenograft model of melanoma, when compared with riluzole. We seek to continue the development of FC-311 prior to filing an IND and eventual clinical use in melanoma patients.