Huntington disease is caused by an expansion mutation beyond 36 CAG (cytosine-adenine-guanine) repeats in the IT15 gene, which encodes the huntingtin protein. The CAG score refers to the number of expansions in the codon; the more CAG repeats there are in the gene, the faster clinical symptoms progress. NeuroSearch’s Phase III study showed that the CAG-dependent rate of motor symptoms progression that was seen in the placebo group was not apparent among Huntexil-treated patients.
If NeuroSearch’s finding that Huntexil can delay disease progression in patients with elevated CAGn scores holds up, the financial community and regulatory agencies will be a lot more willing to cut the firm a break despite its statistical blunder.
To date treatment for HD has been supportive only, aimed at suppressing the uncontrolled body movements and progressive cognitive decline characteristic of the disease. The only drug approved in the U.S. for treatment of HD symptoms is Regulin. It was formerly an antipsychotic but now is primarily used in the treatment of various movement disorders including tardive dyskinesia. Regulin works by inhibiting vesicular monoamine transporter 2, a transporter in the central nervous system that moves cytoplasmic dopamine into synaptic vesicles for storage and release.
Huntexil acts as a dopaminergic stabilizer to either enhance or inhibit dopamine-dependent functions in the brain depending on the initial level of dopaminergic activity. Thus, according to the company, there are few or no physiological effects when dopamine levels are normal.
Apart from dopamine blockers and stabilizers like Regulin and Huntexil, treatments in development for HD range from nutritional supplements to antiapoptosis compounds. Even sirtuins are in the HD game, with Siena Biotech reporting in January that its orally active, selective SIRT1 inhibitor SEN0014196 had obtained orphan drug status from the FDA as well as the EMEA. At the time, the company also initiated a Phase I trial in 96 volunteers.
Siena’s drug candidate inhibits the acetylase activity of SIRT1, which appears to modify acetylation of the huntingtin protein. This enhances clearance of the mutated protein but not the normal version of the protein. Siena said that it has performed a series of unpublished studies in which it found the inhibitor to be neuroprotective in cell and animal models. In a mouse model, symptoms were ameliorated and survival times were increased.