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FSMA Drug Discovery Programs The ultimate goal at FSMA is to find an effective treatment and cure for SMA.
In order to achievethis FSMA has invested substantial funds in pre-clinical SMA
drug development since 2000.
Traditionally it has been difficult to attract major pharmaceutical companies to conduct research
for orphan diseases like SMA, which have small patient populations with small potential for profit.
Therefore FSMA has taken the strategy of providing seed funding to encourage biotech and
pharmaceutical partners to engage in SMA drug research. Our objective is to reduce the risk
for industrial partners by simultaneously providing funding, research tools, scientific expertise,
and established clinical networks. This strategy effectively lowers the barriers for embarking
in SMA drug discovery. Quniazoline Program:
Our first venture into drug discovery began in 2000 as collaboration with Aurora Biosciences,
since acquired by Vertex Pharmaceuticals. The initial goal of our collaboration was to develop
screening tools to search for chemical compounds that could increase SMN levels from the
SMN2 gene. Several compounds with the capability of doing this were discovered, and one of these
compound classes called Quinazolines has since been chemically modified at deCODE
Chemistry with full funding by FSMA to optimize and generate drug-like properties.
Tetracycline Program:
One major goal at FSMA is to build a therapeutics pipeline for SMA, which will greatly increase
our chances of successfully developing a SMA therapy. Therefore in March 2006 we began
funding a second drug discovery program at Paratek Pharmaceuticals that focuses on
Tetracycline-like compounds that correct SMN2 splicing. This projects takes a different approach to increasing SMN levels than our Quinazoline program described above. Importantly because these two classes of compounds work in
different and complimentary ways, they have the potential to increase SMN levels to a higher
level in combination use than with either drug alone. Building a Drug Pipeline:
Families of SMA hopes to fund several additional early stage drug programs in the near future
to broaden the SMA therapeutics pipeline further. As the figure below illustrates, drug development is a long-term and high-risk process. Continuing to build our drug pipeline is critical as just 10% of drugs entering clinical trials ever
receive FDA approval -- we must continue to take as many shots on goal as possible to find a
safe and effective treatment and cure for SMA! The Drug Development Process: 1. Molecular targets for drug screening are typically identified through basic research.
2. These targets are used to design drug identification assays for screening large numbers
of chemical compounds.
3. Compounds found in screens are called “hits”.
4. “Hits” undergo further testing to verify they have the desired bioactivity in cell culture models
of disease.
5. Medicinal chemistry programs are used to make chemical relatives of the lead compounds
during a phase of the project called lead optimization. Lead optimization is a reiterative process
whereby compounds that are more effective than the parental compounds are further modified
until the greatest bioactivity is obtained, toxicities and off-target activities are reduced, and
drug-like properties are maximized.
6. When lead optimization is complete, a clinical candidate is selected. Then an extensive
series of preclinical safety studies are completed on the clinical candidate to be included in
an Investigational New Drug Application (IND) to the FDA.
7. If the FDA accepts an IND application, first-in-human (FIH) testing can begin with Phase I
safety studies, typically in healthy volunteers. This begins the clinical development process of
Phase I, II, and III clinical trials.
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