GW-TT2, a New Drug Product for Tinnitus.

Every soldier, Marine, airman, and sailor will be exposed to hazardous noise at some point in his or her career. One major consequence of noise exposure is tinnitus. Tinnitus can impede communication, reduce environmental and social awareness, and degrade combat performance and mission effectiveness. Tinnitus can also harm a service member’s quality of life and future employability with severe forms of the disease resulting in depression, anxiety, and suicidal ideation. Despite extensive studies, no drugs have been approved by the U.S. Food and Drug Administration (FDA) for use in the amelioration of tinnitus. Exact pathological mechanisms for noise-induced tinnitus are unknown. The current view is that tinnitus can be induced by neural hyperactivity in the central auditory nervous system after peripheral deafferentation associated with acoustic trauma. This abnormal electrical activity may be the direct result of an increase in calcium channel activity. Recent data from our SBIR direct Phase II grant (R44DC018759) showed that L-type, but not T-type calcium channel blockers are effective in the treatment of tinnitus after acoustic trauma. One such blocker of L-type calcium channels is nimodipine (NMDP), an FDA-approved drug with an extensive record of safety and pharmacokinetic data. In the U.S., an NMDP oral formulation is used to reduce ischemic deficits after subarachnoid hemorrhage, and in Europe, an intravenous formulation is approved for the same indication to increase its delivery to the brain. Using an established animal model for tinnitus induced by noise exposure, we developed a new nasal formulation for NMDP (GW-TT2) to reduce its systemic side effects, increase its brain delivery, and improve patients’ experience with the use of this drug. Our hypothesis is that NMDP, when delivered nasally, can be a safe and effective therapy for noise-induced tinnitus. Most importantly, we have recently received positive FDA comments for our Type B Pre-Investigational New Drug (IND) application, which provided a detailed map for our next steps in developing GW-TT2 including guidance on the Chemistry, Manufacturing and Controls (CMC) for the final drug product. Here the objective is to manufacture GW-TT2 for clinical phase I/Ib trials. By working closely with our contract research organizations (CROs), we will: (1) test the feasibility and procedures to make GW-TT2 using non-cGMP (current good manufacturing practices) standards; (2) use the product for toxicity testing on animals; and finally, (3) make cGMP-grade GW-TT2 drug for stability testing and clinical studies. These studies will result in a final drug product suitable for GMP Tox studies and Phase I/Ib clinical studies. If successful, these studies will enable us to open an IND and initiate clinical trials with the goal of providing the first-ever FDA approved drug for tinnitus and address an urgent unmet need for military personnel with tinnitus.