Huntington's disease - Emerging treatments

Pridopidine

Pridopidine, a highly selective sigma-1 receptor (S1R) agonist, has been granted fast track designation for development as a potential treatment for Huntington’s disease by the US Food and Drug Administration (FDA). Pridopidine has been reported to be generally safe and tolerable in patients with Huntington’s disease for up to 60 months, with some evidence of efficacy in slowing functional decline, especially in patients with early-stage disease.[105][106] A phase 3, randomised, double-blind, placebo-controlled study is under way.[107]

Disease-modifying therapies

A number of clinical trials of potential disease-modifying agents for symptomatic Huntington's disease gene carriers have been carried out and reported, but none has demonstrated clinically significant efficacy. They have, however, demonstrated the feasibility of running large-scale phase 3 trials in Huntington’s disease cohorts. Deutetrabenazine has been approved by the FDA for the treatment of chorea in Huntington’s disease. This follows positive results from the FIRST-HD and ARC-HD studies.[108][109] Deutetrabenazine is a small molecular inhibitor of vesicular monoamine 2 transporter (VMAT2) and has a similar mode of action to tetrabenazine. Laquinimod is an immunomodulatory agent previously trialled in multiple sclerosis. Perhaps the most promising approaches with regard to disease modification are the emerging therapies aimed at lowering levels of mHTT (mutant huntingtin) protein by targeting either the DNA or the RNA of the mHTT gene. RNA targeting can be achieved by using antisense oligonucleotides (ASOs), RNA interference (RNAi), or small molecule splicing inhibitors. Several ASOs have undergone trials. In a first human phase 1b/2a study, dose-dependent reductions of mHTT were observed in participants treated with non-allele-selective ASO (delivered intrathecally), which were also safe and well tolerated.[110] However, no clinical improvement was seen in a phase 3 study (GENERATION-HD1).[111] Further trials with novel allele-selective ASO are planned. Gene therapy using RNAi (AMT-130) is undergoing a 12 month blinded trial with a 4 year open-label extension.[112]

PBT2

PBT2 is a metal protein-attenuating compound that acts by reducing metal-induced aggregation of mHTT protein. A phase 2 trial, the Reach2HD study, showed that PBT2 was safe and well tolerated, and plans are currently under way for a phase 3 trial.[113]

Cysteamine

Used in the treatment of cystinosis, cysteamine increases brain-derived neurotrophic factor, a growth factor depleted in the brains of Huntington's disease patients. The effect of cysteamine on motor progression in Huntington's disease has been evaluated in a 3-year phase 2/3 trial. While cysteamine was safe and well tolerated, its effect on motor progression did not reach statistical significance.[114]

Selisistat

A member of the sirtuin family, selisistat causes reduction of mHTT protein levels. This molecule has been investigated in a phase 2 study, but no effect on the Unified Huntington Disease Rating Scale (UHDRS) was seen.[115]

Phosphodiesterase 10A inhibitors

The enzyme phosphodiesterase 10A (PDE10A) is found in the striatum, and it is reduced in Huntington's disease patients many years before the onset of manifest disease.[116] PDE10A inhibitors have been shown to restore basal ganglia circuitry in Huntington's disease animal models.[117] The PDE10A inhibitor PF-02545920 was tested in a phase 2 trial and failed to show significant improvement in motor, cognitive, or behavioural measures.[118]