NINDS Releases Update on the SMA Project.

December 20, 2012.

Update Synopsis:
In pursuit of its mission to reduce the burden of neurological disease, the National Institute of Neurological Disorders and Stroke (NINDS) established the Spinal Muscular Atrophy (SMA) Project, a networked contracts program to accelerate the development of therapeutic candidates for SMA. SMA is a neurodegenerative disease with variable severity ranging from limited motor neuron loss and normal life expectancy (Type III) to progressive infantile paralysis and death (Type I).

Early on, the SMA Project decided to focus on small molecule drugs, rather than gene therapy, stem cells or biologics. Indoprofen was chosen as the starting point for a medicinal chemistry program after a systematic review of FDA approved drugs that had demonstrated activity in SMA-relevant assays and models.

The Project adopted a multi-tiered system for compound synthesis and testing, which is referred to as a drug development "testing funnel" because the number of compounds decreases as the testing for desired drug properties advances. The goals of the medicinal chemistry optimization effort for indoprofen included increasing the potency and brain penetrance of the drug and eliminating its inhibitory activity on cyclooxygenase, which had previously been found to be a liability for clinical use.

Over a 5-year-period, the SMA Project synthesized and screened more than 1,400 analogs of indoprofen. Of the compounds screened in tier 1 assays, over 150 were selected for further characterization and advanced to the next tier of the testing funnel. This included several assays to measure increases in SMN protein levels in patient fibroblasts, and assessments of compound bioavailability, genotoxicity and safety profiles.

Starting in July 2012, the NINDS initiated discussions with several pharmaceutical and biotechnology companies to determine whether ALB-111 meets their technical requirements as a late-stage lead compound, and if so, to identify a partner to conduct the next steps of preclinical drug development.

Click here to for the entire update from NINDS on the SMA Project, including extensive background information and key accomplishments and findings.