Neuro News Roundup: Huntington Disease Awareness Day – Latest Literature


In honor of Huntington Disease Awareness Day, held May 15, 2024, get caught up on some of the latest news in HD, with data updates and expert insights all in one place from the NeurologyLive® team.

The NeurologyLive® team has been hard at work in the year conducting interviews with thought leaders and covering the news on the latest updates in the clinical care of individuals with movement disorders such as Huntington disease (HD), and others.

For Huntington Disease Awareness Day — May 15, 2024 —our team offers an update on those new developments in the literature and insight into the expert opinions about how they’re shaping the ever-changing care paradigm in HD into one place.

Click here for more coverage of the latest neuromuscular news from NeurologyLive®.


FDA Approves Sprinkle Formulation of Neurocrine Biosciences’ Valbenazine for Tardive Dyskinesia or Huntington disease Chorea

Recentlyt, the FDA approved Neurocrine Biosciences’ therapy valbenazine (Ingrezza) oral granules, a new sprinkle formulation of the treatment capsules for oral administration, for patients with tardive dyskinesia (TD) or chorea associated with HD. The oral granules capsules (40 mg, 60 mg and 80 mg) are intended to be opened for sprinkling on soft foods prior to administration.

The new drug application (NDA) filing for the sprinkle formulation included chemistry, manufacturing, and controls information and data demonstrating the bioequivalence and tolerability of the oral granule sprinkle capsules compared with the currently approved valbenazine capsules. Valbenazine is currently available as the only single-capsule, once-daily treatment option with no complex titration for adults with TD and the treatment of chorea associated with HD. It is the only selective vesicular monoamine transporter 2 (VMAT2) inhibitor that offers three effective dosages (40 mg, 60 mg and 80 mg) that can be adjusted by the healthcare provider based on patient response and tolerability.

"We developed Ingrezza Sprinkle to make administration easier for patients who have difficulty swallowing or prefer not to take a capsule," Eiry W. Roberts, MD, the chief medical officer at Neurocrine Biosciences, said in a statement.1 "We are pleased to offer the proven efficacy of Ingrezza in reducing uncontrollable movements in a new formulation."

Pridopidine Maintains Effectiveness in Huntington Disease Without Antidopaminergic Medications

Analyses from the phase 3 PROOF-HD trial (NCT04556656) showed that pridopidine (Prilenia Therapeutics), an orally available small molecule and potent sigma-1 receptor agonist in development for HD, significantly improved or stabilized outcome measures for at least 1 year. In addition, the agent displayed superiority to the placebo up to week 78 on all end points after excluding patients on antidopaminergic medication (ADMs).2 These findings suggest pridopidine still maintains benefit on several clinical measures of disease progression in patients with HD without the help of these therapies.

Excluding participants on ADMs (pridopidine, n = 79; placebo, n = 99), pridopidine-treated patients showed improvement from baseline on the Unified Huntington Disease Rating Scale (cUHDRS) up to week 52 and sustained benefit up to week 78 compared with placebo. Similarly, quantitative motor (Q-Motor) and Stroop Word Reading (SWR) improved from baseline at week 26 and sustained up to week 78 in comparison with the placebo. In addition, investigators observed a trend for improvement in Quality of Life (HD-QoL) also in this group of patients.

Pridopidine is now in preregistration phase in HD, with a first submission planned mid 2024, and is also set to commence a global phase 3 study in ALS later this year. We are making significant strides forward and this is reflected by presentation of the data at one of the most important medical congresses in the field of neurology,” Jina Swarz, MD, PhD, chief medical officer at Prilenia, said in a statement.

Gene Therapy AMT-130 Shows Potential Benefit in Phase 1/2 Clinical Trials for Huntington Disease

Recently announced 30-month interim data from the ongoing U.S. and European multi-center phase 1/2 clinical trials assessing AMT-130 (uniQure), an investigational gene therapy for HD, showed evidence of potential dose-dependent clinical benefit relative to the nonconcurrent criteria-matched natural history. The combined data presented from these trials has a cut-off date of September 30, 2023, and does not include efficacy and biomarker data from the control patients who crossed over to treatment.3

Among 39 patients in the both trials, treatment with AMT-130 resulted in a 0.39-point difference on composite Unified Huntington’s Disease Rating Scale (cUHDRS) at 30 months and a 1.24-point difference at 18 months for the low- and high-dose, respectively (baseline values; low-dose, 14.1; high-dose, 14.9). Notably, the therapy demonstrated a 0.95-points difference on Total Functional Capacity (TFC) at 30 months in the low-dose group and 0.49-points difference at 18 months in the high-dose (baseline values; low-dose, 11.9; high dose, 12.2). Additionally, patients on active therapy showed a 2.80-point difference in Total Motor Score (TMS) at 30 months in the low-dose and 1.70-point difference in the high-dose at 18 months (baseline values; low-dose, 13.3; high-dose, 12.1).

"The results from these phase 1/2 trials continue to be very encouraging as they show positive-trending, potentially dose-dependent signals across multiple key clinical and functional measures, in conjunction with further declines in NfL," Edward Wild, PhD, FRCP, professor of neurology at University College London Queen Square Institute of Neurology, consultant neurologist at National Hospital for Neurology & Neurosurgery, and associate director of UCL Huntington’s Disease Center, said in a statement.

Laquinimod Significantly Reduces Caudate Volume in Phase 2 LEGATO-HD Study

Recently published data from the double-blind, placebo-controlled LEGATO-HD study (NCT02215616) showed that treatment with laquinimod did not impact motor symptoms in patients with HD; however, it did significantly reduce caudate volume loss compared with placebo over a 52-week period. These findings represent the first clinical observations supporting a possible role of neuroinflammation in the pathology of HD that could be modulated by therapeutic intervention.4

Published in The Lancet Neurology, the phase 2 trial randomly assigned patients with HD to either laquinimod 0.5 mg (n = 107), 1.0 mg (n = 107), and 1.5 mg (n = 30) or placebo (n = 108), for 52 weeks. Key inclusion criteria included having a CAG repeat length of 36-49, and motor symptoms of HD, as assessed by a Unified Huntington’s Disease Rating Scale (UHDRS)-Total Motor Score (TMS) of more than 5, and a UHDRS-Total Functional Capacity (TFC) score of 8 or higher. Of note, the 1.5 mg group was ultimately discontinued before recruitment was finished because of cardiovascular safety concerns addressed in previous studies of multiple sclerosis.

Despite not meeting the primary end point, those on laquinimod 1.0 mg demonstrated a change in caudate volume (LSM, 3.10 [SE, 0.38]) that differed significantly from placebo (LSM, 4.86 [SE, 0.38]); P = .0002). The exploratory MRI volumetric measures of caudate volume loss for the laquinimod 0.5 mg group, and whole brain volume loss, white matter volume loss, and ventricular volume for the laquinimod 0.5 mg and 1.0 mg groups all consistently showed improvements compared with placebo.

Greater Insights on Skyhawk’s RNA Splicing Agent SKY-0515 for Huntington Disease

More recently, in October, the Australian Human Research Ethic Committee (HREC) approved a phase 1 program to assess Skyhawk’s small molecule HD candidate SKY-0515. SKY-0515, designed for brain penetration and distribution in peripheral tissue, is built to modify the RNA expression of huntingtin (HTT), thus reducing the production of the mutated protein that leads to disease progression in HD.

The phase 1 trial is a first-in-human, multi-part, randomized, double-blind, single- and multiple-ascending dose study assessing SKY-0515 in healthy volunteers and, subsequently, patients with HD. To learn more about SKY-0515 and the upcoming trial, NeurologyLive® sat down with Maura McCarthy, head of corporate development at Skyhawk. She provided context on the benefits behind RNA-splicing treatment approaches, the ways HD trials have changed over the years, and how SKY-0515 has remnants of risdiplam (Evrysdi; Genentech), a previously approved RNA-splicing agent used for spinal muscular atrophy.

1. Neurocrine Biosciences Announces U.S. FDA Approval of INGREZZA® SPRINKLE (valbenazine) Capsules. News release. Neurocrine. April 30, 2024. Accessed May 14, 2024.
2. Geva M, Reilmann R, Feigin A, et al. Analyses of the Phase 3 Trial of Pridopidine’s Outcome on Function in Huntington Disease (PROOF-HD) Demonstrates Efficacy in Participants Without Antidopaminergic Medications. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO.
3. uniQure Announces Update on Phase I/II Clinical Trials of AMT-130 Gene Therapy for the Treatment of Huntington’s Disease. News Release. Published December 19, 2023. Accessed May 14, 2024.
4. Reilmann R, Anderson KE, Feigin A, et al. Safety and efficacy of laquinimod for Huntington’s disease (LEGATO-HD): a multicenter, randomized, double-blind, placebo-controlled, phase 2 study. Lancet Neurol. Published online January 24, 2024. doi:10.1016/S1474-4422(23)00454-4
5. Skyhawk Therapeutics receives HREC approval for a phase 1 study of its SKY-0515 RNA-targeting small molecule for Huntington's disease. News release. Skyhawk Therapeutics. October 23, 2023. Accessed May 14, 2024.
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