Research Project
8654322
DESCRIPTION: The following proposal is a follow-on Phase 2 b application from our initial proposal (1-R42 DA 030001). U.S. drug overdose deaths, mostly commonly from opioids, now exceed deaths from automobile accidents. There is a significant unmet medical need to provide additional pharmacologic options for treatment of opioid overdose. Emergency medical service personnel would prefer a non- injection based antidote to avoid accidental needle-sticks, and associated risks of hepatitis or HIV, in the revival of opioid overdose victims. Some communities prescribe/provide naloxone (NLX) injection, for injection or nasal administration, to high-risk pai patients or drug abusers. A proven needle-free delivery system would be an advance in all settings. The specific objective is to create a NLX nasal spray (NS) that offers a novel therapeutic option for a rapid-acting, interventional medication intended to acutely reverse the effects of prescription (e.g. Oxycontin(R)) and illicit (e.g. heroin) opioids. The hypothesis of th ongoing Fast Track STTR project was that a NLX NS could be created and will have biopharmaceutics comparable to NLX subcutaneous (SC) and intramuscular (IM) injection, without the use of a needle. Previous published research has demonstrated nasal delivery of NLX is feasible and produces pharmacologically appropriate responses. A NLX nasal spray product has been created and is undergoing commercial-scale manufacturing development ahead of typical drug development schedule. An IND is now active (#106431) and a pilot bioavailability study to compare NLX nasal spray pharmacokinetics to approved injection routes and doses is being conducted in parallel with this grant review. Data from the pilot study will allow us to make adjustments (based upon pharmacokinetic modeling) in nasal spray drug concentration and manufacturing of the final drug product for further clinical testing. Our firm ha had extensive negotiations with the Food and Drug Administration (FDA) regarding the development path for NLX NS (see Appendix). The new aims of this Phase 2 b proposal follow the STTR aims, aligned with the scientific and regulatory agreements made with the FDA and will result in the rapid commercialization of NLX nasal spray. The project hypothesis will be tested by the following Specific Aims: 1. Validate all analytical methods according to FDA/ICH GMP and GLP guidance's 2. Manufacture another clinical study batch of NLX NS under commercial scale conditions and continue long-term stability studies of all batches compliant with FDA/ICH GMP guidance's 3. Conduct a confirmatory pharmacokinetic study of the formulation as compared to approved IM doses, in order to further inform the pivotal comparative bioavailability study statistical model 4. Conduct a human nasal tolerability study of the final formulation
