Since January of 2003, deCODE has been working on behalf of FSMA to create a new drug for treating SMA from hits discovered in our drug screens at Aurora / Vertex. 

The goal of the project is to increase the amount of functional SMN protein produced from a second almost identical gene called SMN2, which remains intact in SMA patients.  Normally the SMN2 gene makes very little functional protein.  However, boosting the amount produced from the intact SMN2 gene is a viable therapeutic strategy for SMA. This strategy is described below.

1. Most people have SMN1 and SMN2 genes. Full-length SMN protein is the main product of the SMN1 gene.  Short SMN protein is the main product of the SMN2 gene.
2. In SMA, the SMN1 gene is missing, which vastly decreases the amount of full-length SMN protein.
3. The goal of drug treatment is to increase the amount of full-length SMN protein produced from the SMN2 gene.

The FSMA-sponsored drug program at deCODE chemistry has focused on optimizing drug-like properties into a promising series of compounds known as 2,4-diaminoquinazolines, which were first discovered in our high-throughput drug screens at Aurora/Vertex.  In order to do this, deCODE made about 1,000 close relatives of the original compound in a process call lead optimization.  This process is used to turn a compound with desired bioactivity in a Petri dish into a practical human drug.

Lead optimization is a reiterative process whereby compounds found to be more effective than the parent compounds are then further modified until the greatest bioactivity is obtained, toxicities and off-target activities are reduced, and drug-like properties are maximized.  deCODE has now generated optimized analogues that have many of the features of required in a SMA drug: the ability to increase SMN levels in the spinal cord of SMA mice and SMA cellular models, the ability to work at low concentrations, metabolic stability, efficient penetration of the blood-brain barrier, and an attractive pharmacokinetic profile.  

In 2007 the project team nominated a clinical candidate. 

Currently, the clinical candidate is undergoing a series of experimental studies directed at filing an Investigational New Drug application with the FDA. This application includes data from an extensive series of preclinical safety studies, which take about 9 to 12 months and $2 to 3 million to complete.  If the FDA accepts the IND application, first-in-human testing can then be initiated with safety studies, typically in healthy volunteers.

A summary of this project  was recently published in the Journal of Medicinal Chemistry.  See the paper abstract here.