Novel Agents on the Horizon for Huntington Disease


Several novel therapies in early stage development are beginning to show promise for patients with Huntington disease.

Dr Claudia Testa

Claudia Testa, MD, PhD, Virginia Commonwealth University

Claudia Testa, MD, PhD

There are several novel therapies in early stage development for patients with Huntington disease that are beginning to show promise, especially those geared at lowering mutant huntingtin (mHTT) protein production, according to a presentation by Claudia Testa, MD, PhD, at the 2018 ANA Annual Meeting.1

"In Huntington disease there is a ton of amazing science and new therapeutic development," Testa, from the Virginia Commonwealth University, told NeurologyLive. "The trials are really pushing into early symptomatic, or those without symptoms, looking at both progression of disease but also biomarkers to see if therapeutics are working or not. The thing everyone is talking the most about are the huntingtin lowering strategies."

The non-allele specific antisense oligonucleotide IONIS-HTTRx, also known as RG6042 (developed by Ionis and Roche), showed a 40% to 60% reduction in mean mHTT as measured in the cerebral spinal fluid. These reductions could correspond to an estimated 55% to 85% reduction in mHTT in the cortex and a 20% to 50% reduction in the caudate regions of the brain, based on prior preclinical work.2

In exploratory analyses,2 the lowering of mHTT was connected with improvements in clinical measures, such as total motor score (TMS; P = .007), symbol digit modalities test (P = .044), Stroop word reading test (P = .60), and total functional capacity (P = .066). There was a significant correlation between degree of mHTT lowering and the composite Unified Huntington's Disease Rating Scale (cUHDRS) score at day 85 (P = .004). Adding to this, the treatment was not associated with any serious adverse events and no patients discontinued the study.

In addition to IONIS-HTTRx, another mHTT lowering therapy, WVE-120101 (developed by Wave) is also currently in development as a potential therapy for Huntington disease. This antisense oligonucleotide, which is allele specific, does not have clinical data currently available. A phase 1/2 study is currently enrolling participants (NCT03225833).

"The Wave compound is allele specific, it only takes down mutant huntingtin and doesn't touch the wild type. The Roche compound, and other stuff in development, takes down both," Testa said. "We don't know how much is safe for lowering normal huntingtin. You seem to be able to take away some of it."

The wave of potential therapies is generating excitement, as the search for a successful treatments for patients with Huntington disease has been met by several setbacks over the past decade. Most recently, in July 2018, laquinimod did not improve UHDRS-TMS for patients enrolled in the phase 2 LEGATO-HD trial. "Ten years ago, there was little to nothing going on. There were some really well-designed trials that taught us a lot but now there is a whole slew of novel things that are changing the landscape," Testa said.

While no treatments have been approved to alter the course of Huntington disease progression, there have been moderate advancement in controlling some of the symptoms of the disease. In 2017, deutetrabenazine (Austedo) joined tetrabenazine (Xenazine) for the treatment of chorea associated with Huntington disease. Adding to these approvals, several promising approaches are currently in clinical trials, said Testa.

Other agents currently in the pipeline are showing promise for the management of symptoms associated with Huntington disease. The first agent, SRX246, is being developed as a treatment for irritability in a phase 1/2 trial. This trial has fully enrolled and results are expected in the next few months (NCT02507284). Additionally, the anti-smoking agent varenicline could potentially improve motor and cognitive symptoms.

"Symptomatic therapeutics are still an active space, and are very important," Testa said. "There's an ongoing trial and compound targeting irritability, which is really an underappreciated and underrated really corrosive symptom in Huntington disease."

In addition to symptom management, other studies are exploring agents geared toward neuroprotection, most of which come from natural sources. The stilbenoid resveratrol is being explored in a phase 3 study that plans to randomize 102 patients to receive resveratrol or placebo. The primary endpoint is focused on caudate atrophy. The estimated primary completion date is January 2019 (NCT02336633). Additionally, triheptanoin oil, an anapldrotic therapy, is being examined in a phase 2 study to improve brain energy restoration (NCT02453061).

Other studies are looking at disease-modifying strategies to treat Huntington disease. The anti-SEMA4D monoclonal antibody pepinemab (VX15/2503) is being explored in a phase 2 for late prodromal and early manifest Huntington disease. The study is comparing safety and efficacy between pepinemab and placebo (NCT02481674).

"This is a neuroinflammation or an immunomodulatory compound. SEMA4D is in the pathway to activate microglia and astrocytes. If you decrease that activation, you bring down neuroinflammation and provide a neuroprotective or disease-modifying effect," said Testa, who is involved in the study. "This could be a great partner for a huntingtin lowering strategy."

Although still in preclinical development, mRNA-targeted gene therapies are also generating excitement, given the benefits seen with this class of therapies in other disorders. A number of adeno-associated virus—based therapies are currently in the works, including AMT-130 and VY-HTT01. Clinical trials testing these therapies hope to begin enrolling in 2019.


  1. Testa C. Advances in Huntington’s Disease. Presented at: 143rd American Neurological Association Annual Meeting; Atlanta, Georgia; October 21 to 23, 2018.
  2. Tabrizi S, Leavitt B, Kordasiewicz H, et al. Effects of IONIS-HTTRx in Patients with Early Huntington’s Disease, Results of the First HTT-Lowering Drug Trial. Presented at: 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA, April 21-27, 2018. Abstract CT.002.
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