Huntington's disease - Emerging treatments

Other vesicular monoamine transporter 2 (VMAT2) inhibitors

While tetrabenazine is available for the management of chorea in patients with Huntington’s disease in most countries, other VMAT2 inhibitors are not as widely available as yet. Deutetrabenazine has been approved by the US Food and Drug Administration (FDA) for the treatment of chorea in Huntington’s disease, but is not approved in Europe as yet. The US approval follows positive results from the FIRST-HD and ARC-HD studies.[104][105] Deutetrabenazine has a similar mode of action to tetrabenazine, but is longer-acting and has less metabolic variability. One head-to-head study with tetrabenazine has not yet been completed, but it is possible that deutetrabenazine may have fewer adverse effects compared with tetrabenazine. Valbenazine has also been approved in the US for the treatment of chorea in Huntington’s disease, but has not been approved in Europe as yet. The drug was tested in one phase 3, randomised, double-blind clinical trial (KINECT-HD).[106]

AMT-130

AMT-130 gene therapy using RNA interference (RNAi) to lower levels of mutant huntingtin (mHTT) protein is undergoing two 12-month blinded phase 1/2 clinical trials with a 4-year open-label extension in patients with early manifest Huntington’s disease.[109][110] It is injected directly into the brain striatum using stereotactic surgery, with a single dose expected to last for the patient’s lifetime. Based on information from press releases, initial topline results from the European phase 1/2 study announced in September 2025 indicate that the therapy has the potential to slow disease progression. The study met its primary endpoint, with a statistically significant 75% slowing of disease progression with high-dose AMT-130 compared with control at 36 months, as measured using the composite Unified Huntington’s Disease Rating Scale (a mean change from baseline of -0.38 in treated patients compared with -1.52 in control patients). A secondary endpoint was also met, with high-dose AMT-130 showing a statistically significant 60% slowing of disease progression as measured by Total Functional Capacity (a mean change from baseline of -0.36 in treated patients compared with -0.88 in control patients). Favourable trends were also found across additional clinical measures of motor and cognitive function, mean cerebrospinal fluid neurofilament light protein (NfL) levels reduced below baseline at 36 months, and the therapy was well tolerated with a manageable safety profile. The FDA has previously granted AMT-130 breakthrough therapy designation and regenerative medicine advanced therapy designation. It is anticipated that a biologics license application will be submitted to the FDA in 2026 requesting accelerated approval of the drug. AMT-130 currently also has orphan drug designation in Europe.[107][108]

Other 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, demonstrating the feasibility of running large-scale phase 3 trials in Huntington’s disease cohorts. Perhaps the most promising approaches with regard to disease modification are the emerging therapies aimed at lowering levels of mHTT protein by targeting either the DNA or the RNA of the mHTT gene. Aside from RNAi therapeutics (such as AMT-130 above), RNA targeting can also be achieved by using antisense oligonucleotides (ASOs) 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.[111] However, no clinical improvement was seen in a phase 3 study (GENERATION-HD1).[112] One phase 2 trial targeting younger patients with lower disease burden is ongoing (GENERATION-HD2).[113] An interim review of a phase 2 clinical trial of the oral small molecule splicing modifier PTC518 found a beneficial effect on central nervous system biomarkers and clinical outcomes.[114]

Mercaptamine

Used in the treatment of cystinosis, mercaptamine increases brain-derived neurotrophic factor, a growth factor depleted in the brains of Huntington's disease patients. The effect of mercaptamine on motor progression in Huntington's disease has been evaluated in a phase 2/3 trial. While mercaptamine was safe and well tolerated, its effect on motor progression did not reach statistical significance.[115]

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.[116]

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.[117] PDE10A inhibitors have been shown to restore basal ganglia circuitry in Huntington's disease animal models.[118] The PDE10A inhibitor PF-02545920 was tested in a phase 2 trial and failed to show significant improvement in motor, cognitive, or behavioural measures.[119]