Preclinical evaluation of an otoprotectant TT002

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Project Summary Ting Therapeutics LLC is a pharmaceutical company developing drugs to prevent and treat hearing loss. Cisplatin is one of the most widely used drugs to treat cancers. However, cisplatin therapy causes hearing loss in 40-60% of the patients. To date, no drugs have been approved by the Food and Drug Administration for protection from cisplatin-induced hearing loss (CIHL). Most candidate compounds currently in pre-clinical and clinical trials are related to antioxidants, vitamins, and glutathione metabolism, many of which, such as sodium thiosulfate, interfere with cisplatin’s ability to kill the tumor cells. We have performed unbiased in silico virtual screens for otoprotectants against CIHL and identified 20 FDA-approved drugs including TT002, known as niclosamide, an anthelmintic (gut worm) drug used in humans world-wide for nearly four decades. In vitro: TT002 showed a comparable level of protection against cisplatin damage in a cochlear cell line to kenpaullone, with an IC50 of 0.17 μM, substantially (>10X) lower and better than four other benchmark otoprotectants. Moreover, TT002 did not interfere with cisplatin anti-cancer activity in vitro. In vivo: TT002 attenuates hearing loss in adult mice treated with cisplatin (30 mg/kg once) when delivered intraperitoneally (IP) at 10 mg/kg/day for 4 consecutive days. Interestingly, TT002 also protects against NIHL (100 dB SPL 8-16 kHz for 2 hrs) in adult FVB mice when delivered IP at 10 mg/kg/day for 4 consecutive days. In this SBIR Phase II, we will perform Investigational New Drug-enabling experiments to test TT002’s effect on cisplatin’s tumor killing efficacy in vivo and to conduct efficacy studies to define an optimal dosing regimen and therapeutic index. The long-term goal is for TT002 to become a standard otoprotective drug of cisplatin-based therapies. For this purpose, we will demonstrate TT002’s efficacy in a mouse model of cisplatin ototoxicity that mimics the administration protocol in cancer patients (Aim 1). We will determine pharmacokinetics and pharmacodynamics profiles in blood and perilymph, as well as efficacy, in a guinea pig model for cisplatin-induced hearing loss (Aim 2). This Aim will be performed under contract with an independent and reputable Contract Research Organization, Turner Scientific LLC. Finally, we will test drug-drug interactions in vitro and we will verify, in vivo, that TT002 does not interfere with cisplatin’s anti-cancer activity in mouse model xenografts (Aim 3). By successfully completing these studies, Ting Therapeutics will obtain critical data necessary for the initiation of Investigational New Drug enabling complaint preclinical studies and subsequent clinical trials. Ting Therapeutics has filed a Patent Cooperation Treaty (PCT) for both the US and international rights. The completion of this proposal will allow Ting Therapeutics to initiate conversations with pharmaceutical companies and venture investments for the commercialization of TT002.