Phase II year
2022
(last award dollars: 2023)
Phase II Amount
$1,187,190
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.
Public Health Relevance Statement: PROJECT NARRATIVE The work in this proposal focuses on further preclinical development of TT002 to protect from cisplatin-induced hearing loss. If successful, this proposal will allow Ting Therapeutics to initiate conversations with pharmaceutical companies for the manufacturing and commercialization of TT002 and for IND-approval by the FDA for its use as a standard otoprotective component of cisplatin-based therapies.
Project Terms: Adult; 21+ years old; Adult Human; adulthood; Aftercare; After Care; After-Treatment; post treatment; Animals; Anthelmintics; Antihelminthic Agent; Antihelminthic Drugs; Vermifuges; antihelminthic; Antineoplastic Agents; Anti-Cancer Agents; Antineoplastic Drugs; Antineoplastics; Cancer Drug; Neoplastic Disease Chemotherapeutic Agents; Tumor-Specific Treatment Agents; anti-cancer drug; anticancer agent; anticancer drug; Antioxidants; anti-oxidant; Blood; Blood Reticuloendothelial System; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cestoda; Cestodes; Tapeworms; Liquid Chromatography; Cisplatin; CDDP; Cis-diammine-dichloroplatinum; Cis-diamminedichloridoplatinum; Cis-diamminedichloro Platinum (II); Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatina; Cisplatinum; Cysplatyna; Dichlorodiammineplatinum; Peyrone's Chloride; Peyrone's Salt; Platinum Diamminodichloride; cis dichlorodiammineplatinum; cis platinum compound; cis-Diaminedichloroplatinum; cis-Diamminedichloroplatinum; cis-Diamminedichloroplatinum(II); cis-Dichlorodiammineplatinum(II); cis-Platinum; Clinical Trials; Cochlea; Cochlear Organ; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Freedom; Liberty; Future; Germany; Goals; Hair Cells; Corti Cell; ear hair cell; Human; Modern Man; Immunohistochemistry; Immunohistochemistry Cell/Tissue; Immunohistochemistry Staining Method; In Vitro; Investments; Labyrinth; Internal Ear; inner ear; Mus; Mice; Mice Mammals; Murine; Patents; Legal patent; Patients; Perilymph; Pharmacokinetics; Drug Kinetics; Pharmacology; Publishing; QOL; Quality of life; Rights; Safety; Ships; salt; Sodium Chloride; Testing; Time; Toxicology; United States Food and Drug Administration; Food and Drug Administration; USFDA; Work; Zebrafish; Brachydanio rerio; Danio rerio; Zebra Danio; Zebra Fish; sodium thiosulfate; Sodium Hyposulfate; sodium hyposulfite; Measures; Auditory Brainstem Responses; Cavia; Guinea Pigs; Guinea Pigs Mammals; Malignant neoplasm of testis; Malignant Testicular Neoplasm; Malignant Testicular Tumor; Malignant Tumor of the Testis; Testicular Cancer; Testis Cancer; otoacoustic emission; New Drug Approvals; base; Procedures; Clinical; Phase; Chemicals; drug induced hearing impairment; drug induced hearing loss; ototoxic; ototoxicity; Treaty; drug use; Drug usage; Therapeutic; Attenuated; Morphology; Contracting Opportunities; Contracts; Knowledge; Auditory; Oral; intraperitoneal; Protocol; Protocols documentation; Best Practice Analysis; Benchmarking; Tumor Cell; neoplastic cell; Performance; vitamin metabolism; authority; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; Therapeutic Index; technological innovation; Drug Interactions; Pharmacodynamics; Glutathione Metabolism; Glutathione Metabolism Pathway; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; preventing; prevent; Hearing Loss; Hypoacuses; Hypoacusis; dysfunctional hearing; hearing defect; hearing deficit; hearing difficulty; hearing disability; hearing dysfunction; hearing impairment; Dose; Data; Detection; International; Research Contracts; in vivo; Cancer Patient; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Clinical Treatment; trial regimen; trial treatment; FVB Mouse; Observational Study; Observation research; Observation study; Observational research; Rodent Model; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Xenograft Model; xenograft transplant model; xenotransplant model; preclinical study; pre-clinical study; virtual; design; designing; tumor xenograft; Outcome; Cancer cell line; anticancer activity; anti-cancer activity; drug testing; drug detection; chemotherapy; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; healthy volunteer; mouse model; murine model; commercial application; commercialization; tumor; FDA approved; in vitro activity; preclinical evaluation; pre-clinical evaluation; good laboratory practice; phase 1 study; Phase I Study; Regimen; Food and Drug Administration Drug Approval; FDA Drug Approval; webinar; preclinical trial; pre-clinical trial; safety and feasibility; experimental study; experiment; experimental research; efficacy study; preclinical development; pre-clinical development; Drug Screening; hearing preservation; preserve hearing; cisplatin induced hearing loss; cisplatin associated hearing loss; cisplatin induced hearing deficit; cisplatin induced hearing impairment; prevent hearing loss; hearing loss prevention; otoprotectant; otoprotective; pharmacokinetics and pharmacodynamics; PK/PD; in silico; Hearing Protection; protect hearing; guinea pig model
