Research Project
10081315
Peroxynitrite-Destroying Reactive Species Decomposition Accelerants to Treat Migraine Pain Project Summary /Abstract The World Health Organization ranks migraine as the 3rd most prevalent disease worldwide and 8th most disabling. Migraine is the most common neurological disorder, and the first cause of disability under the age of 50. One of the primary reasons for the disabling nature of migraine is the poor efficacy of currently-available therapeutics. Less than 50% of patients taking oral triptans, the most frequently prescribed migraine drug, are pain-free at 2 hrs after onset and medication. Recently-introduced CGRP inhibitors, while serving as useful additional tools for practitioners, are far from perfect: CGRP antagonists produce low improvement in patient response over placebo, while anti-CGRP monoclonal antibodies (monthly injection) offer modest improvement, however are of no use for acute/rescue therapy. Thus, there is a compelling need for new therapeutics to treat migraine pain. The goal of this work is to identify a development candidate worthy of IND-enablement and clinical testing as a highly-effective therapeutic for the treatment of migraine. The expected outcome of this project is identification of a Reactive Species Decomposition Accelerant (RSDAx) compound with very good to excellent pharmacokinetic properties, improved efficacy in preclinical studies compared to existing drugs used to treat episodic migraine, and excellent safety. Further refinement in preclinical tolerability and safety screens will identify a strong development candidate for IND enablement and clinical development, as a novel therapeutic for migraine pain. Innovation: if successful, this work will result in the development of the first orally-administered, non-metal-containing PN-targeting drug to treat episodic migraine. The Target Product Profile (TPP) for a first-in-class peroxynitrite-targeting therapeutic to treat episodic migraine will be differentiated from the major existing therapeutic classes of migraine drugs, namely the triptans and the CGRP antagonists. The work in Phase I of this SBIR/STTR project demonstrated that agents that destroy peroxynitrite, referred to as Reactive Species Decomposition Accelerants (RSDAxs), are indeed effective in preclinical models of migraine pain. In support of the mission of NINDS to reduce the burden of neurological disease, CerSci?s vision is that the therapeutic developed under this project will ultimately have a life-changing impact on the millions of people worldwide suffering from episodic and chronic migraine pain. The key technical objectives (Specific Aims), as described in the Research Strategy, are: Aim 1 - Conduct rat pharmacokinetic (PK) studies in order to identify an orally-bioavailable RSDAx compound that achieves plasma exposures associated with efficacy in non-migraine pain models, Aim 2: Test efficacy of PK-optimized compounds (from Aim 1) in a rat dural inflammatory challenge migraine model measuring mechanical hypersensitivity, Aim 3: Test efficacy of CST compounds (from Aims 1-2) in a nitric oxide induced migraine model measuring mechanical hypersensitivity in mouse, and Aim 4: Select a development candidate for FDA IND-Enablement in support of clinical development as a therapeutic to treat migraine pain.
