HDSA 2026: Oral therapies take center stage in ongoing Huntington’s studies

Several late-stage clinical trials are now recruiting participants to test whether three experimental oral therapies can slow the progression of Huntington’s disease, with active or planned sites in the U.S.

Representatives from three pharmaceutical companies described the development status of those therapies in a clinical trial showcase at the 41st Huntington’s Disease Society of America (HDSA) annual convention, held June 25-27 in Phoenix.

Huntington’s is caused by excessive repeats of a genetic sequence called CAG in the HTT gene. This leads to the production of a mutant form of the huntingtin protein that forms toxic clumps that are thought to drive nerve cell damage. Reducing mutant huntingtin (mHTT) levels could, therefore, help slow Huntington’s progression.

Several oral therapies now in clinical testing are designed to slow Huntington’s progression, but they work in different ways. Votoplam and SKY-0515 are designed to reduce mutant huntingtin levels, while pridopidine targets another pathway involved in nerve cell health.

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Votoplam trial seeks to slow early Huntington’s progression

Novartis’ votoplam (formerly called PTC518) works by targeting the messenger RNA (mRNA) made from the HTT gene. This intermediate molecule carries instructions from DNA that cells use to produce the huntingtin protein.

Votoplam tricks the body into trying to use a section of HTT’s mRNA that doesn’t contain genetic code for huntingtin. Normally, cells exclude this noncoding section, called an intron, during protein production. When cells include the intron, the mRNA is broken down as part of the cell’s quality control process, reducing production of both healthy and mutant huntingtin.

“The goal is that we would lower … the abnormal huntingtin enough to slow progression of disease while still keeping a safe amount of normal huntingtin,” said Jamie Hatcher-Martin, MD, PhD, Novartis’ U.S. clinical program lead for neurodegeneration and a practicing neurologist.

One-year data from the previous Phase 2 PIVOT-HD clinical trial (NCT05358717) showed that the once-daily therapy reduced huntingtin levels and suggested it might slow disease progression in participants with early-stage Huntington’s.

The global Phase 3 INVEST-HD trial (NCT07326709), which started dosing last month, is aiming to test votoplam in a larger group of early-stage Huntington’s patients. It will include up to 770 adults, ages 21 to 70, with a confirmed genetic diagnosis and mild or subtle symptoms of Huntington’s.

“I’m very happy to say we have several spots open in the U.S. already, as well as other countries,” Hatcher-Martin said. “We’re continuing to open more sites now almost on a weekly basis.”

Participants are being randomly assigned to receive either votoplam or a placebo for up to three years. The main goal is to show that votoplam leads to less decline in the Composite Unified Huntington’s Disease Rating Scale (cUHDRS) score, a measure used to track progression in earlier stages of Huntington’s.

SKY-0515 study targets two proteins linked to Huntington’s

Skyhawk Therapeutics is also developing an mRNA-targeting therapy called SKY-0515. In addition to targeting the mRNA made from the HTT gene, SKY-0515 is designed to reduce levels of another protein called PMS1.

Throughout life, PMS1 is involved in promoting increases in the number of CAG repeats in a cell’s copy of the HTT gene, which may contribute to earlier symptoms or faster disease progression.

“The hope is that by reducing PMS1, we can slow that CAG growth that happens later in life and that we can slow down disease progression,” said Marie-Eve Brault, PhD, Skyhawk’s director of discovery biology.

After showing early signs that it might slow Huntington’s progression in a Phase 1/2 trial (ACTRN12623001161617), SKY-0515 is being tested against a placebo in the Phase 2/3 FALCON-HD study.

FALCON-HD includes an Australian and New Zealand portion (NCT06873334) that is fully enrolled and a global portion (NCT07378644) that is still enrolling up to 400 participants.

Eligibility requirements for the global portion include being 25 or older and having early-stage Huntington’s. While Skyhawk hasn’t yet opened trial sites in the U.S., investigators expect to activate the first this month and several others throughout the rest of the year.

The main goal of both FALCON-HD portions is to assess changes in the cUHDRS score after 72 weeks, or nearly 1.5 years.

Pridopidine trial builds on earlier subgroup findings

Pridopidine, Prilenia’s candidate, has a different mechanism of action. It activates the sigma-1 receptor (S1R), a protein that “plays a very important role in monitoring cellular function and cellular health, especially in neurons,” said Nils Confer, PhD, Prilenia’s executive medical director. “We think … [it] is competing with or pushing back against what the mutant huntingtin protein is doing.”

Prilenia is testing whether activating this receptor, whose function is impaired in Huntington’s, may help slow disease progression.

Earlier clinical trials did not meet their main goals, which focused on the therapy’s effects on chorea, the involuntary movements that are a hallmark of Huntington’s. However, their data have given investigators better insight into how pridopidine works, according to Confer.

A Phase 3 trial called PROOF-HD (NCT04556656) found no overall benefit with pridopidine in terms of Huntington’s progression. However, a subgroup of participants who weren’t taking antidopaminergic medications — which are commonly used for psychiatric symptoms and chorea — experienced a significantly slower decline in cUHDRS scores.

Now, the newly launched Phase 3 PRECISE-HD trial (NCT07609108) is expanding on these findings, and is evaluating pridopidine, taken twice daily, versus a placebo for 52 weeks in approximately 400 people with Huntington’s who are not using antidopaminergic medications at the start of the study.

“I’m very much excited to announce to you that this study is underway,” Confer said. “We have already started the study [and] we’re already activating sites in the U.S.” He added that more information will be available in coming weeks.

The study is recruiting participants ages 23 to 65 with adult-onset Huntington’s disease in early or early-intermediate stages. According to the trial listing, participants will complete six in-clinic visits and five telephone visits during the one-year treatment period. The main goal is to assess changes in cUHDRS with pridopidine versus a placebo.

The study also has several secondary goals, including a speech assessment. Prilenia decided to include this metric, which isn’t standard in Huntington’s trials, because of signs in past studies that the medication might help preserve speech.

Across all three trials, participants who complete the placebo-controlled portion may be eligible to enter an open-label extension, in which all participants would receive the experimental therapy for a longer period.

Note: The Huntington’s Disease News team is providing virtual coverage of the Huntington’s Disease Society of America’s annual conference June 25-27. Go here to see the latest stories from the conference.