Huntington’s Update: Two Oral Treatments Advance as Researchers Push to Intervene Earlier

Two experimental pills are advancing through large Huntington’s disease trials, even as researchers turn their attention to a genetic process that may be quietly damaging brain cells years before symptoms ever appear. Neither development amounts to a breakthrough, and no new treatment has been approved. But together they illustrate where the field is headed: lowering the harmful huntingtin protein, slowing the genetic changes that worsen the disease over time, and treating patients earlier, before too many brain cells are lost.

Novartis reports sustained huntingtin lowering with Votoplam

The most concrete update came from Novartis, which shared additional long-term data on votoplam, an experimental once-daily pill formerly known as PTC518. In its second-quarter financial report, released July 21, the company said a 10-milligram dose of votoplam had continued to lower mutant huntingtin after 24 months of treatment in people with early-stage Huntington’s disease, and described the drug’s safety profile as favorable. Mutant huntingtin is the abnormal protein produced by the altered HTT gene, and researchers believe reducing it could ease the damage it inflicts on brain cells. The data came from an extension of the Phase 2 PIVOT-HD study, in which everyone received the active drug rather than a placebo. Without a comparison group, it’s hard to know from these results alone whether votoplam is actually slowing the disease or simply moving a biological marker in the right direction.

That larger question now falls to the Phase 3 INVEST-HD trial, which is enrolling roughly 770 adults with early symptomatic Huntington’s disease and randomly assigning them to receive votoplam or a placebo. The study will track changes on the Composite Unified Huntington’s Disease Rating Scale, or cUHDRS, a combined measure of movement, cognition, and functional independence. That distinction matters. Lowering mutant huntingtin suggests a drug is hitting its target, but it still has to be shown that the change actually helps patients hold onto their abilities or slows their decline.

Skyhawk expands its SKY-0515 trial

A second oral treatment, SKY-0515, is also moving through a large international program. Skyhawk Therapeutics announced July 14 that its Phase 2/3 FALCON-HD trial had cleared the way to expand into the United States, Canada, and the United Kingdom, bringing the total enrollment across more than 10 countries past 175 participants. The Australia and New Zealand arm of the study has already finished enrolling, with 144 participants, while the global portion aims to add as many as 400 more people with Stage 2 or early Stage 3 Huntington’s disease. What sets SKY-0515 apart from most huntingtin-lowering drugs is that it targets two proteins at once. Along with mutant huntingtin, it reduces PMS1, a DNA-repair protein tied to a process called somatic expansion.

In its earlier Phase 1/2 program, Skyhawk reported reductions of up to 69% in mutant huntingtin and 26% in PMS1, along with encouraging early changes in cUHDRS scores. Those figures are preliminary, though, drawn from company-reported analyses rather than a completed Phase 3 trial. FALCON-HD is designed to determine whether those biological changes translate into meaningful differences in movement, cognition, and daily function.

Looking beyond the huntingtin protein

The bigger story in Huntington’s research right now is the growing focus on stopping the underlying mutation from becoming more damaging over time. Huntington’s disease stems from an expanded stretch of DNA in the HTT gene, made up of repeated copies of three genetic letters: CAG. The number of repeats a person inherits helps determine whether the disease develops and roughly when symptoms begin. But that repeat doesn’t stay fixed. It can keep growing inside certain brain cells over the course of a person’s life, a process known as somatic expansion. A recent Science News examination of the research described how scientists are increasingly looking upstream, toward the DNA-repair machinery that allows those repeats to expand in the first place. Brain cells appear able to tolerate the growing mutation for years, but once the repeat crosses a critical threshold, normal gene activity can break down and degeneration may accelerate.

That has turned proteins like MSH3 and PMS1 into promising drug targets. Both are normally part of the body’s DNA-repair system, but in Huntington’s disease, they inadvertently help the CAG repeat grow longer. Several companies and research groups are now developing treatments aimed at reducing or blocking those proteins. Latus Bio is pursuing a gene therapy that targets MSH3, while SKY-0515 is already testing whether lowering PMS1 alongside mutant huntingtin can change the disease’s course. So far, no treatment has proven in a controlled human trial that halting somatic expansion actually delays symptoms or slows disability.

What it all means

The news this week is encouraging, but still early. Votoplam and SKY-0515 both raise the possibility of treating Huntington’s disease with a daily pill instead of an invasive procedure, and both have shown they can shift important biological markers. Now each is being tested to see whether those shifts actually matter in patients’ lives.

The broader move toward targeting somatic expansion could reshape how Huntington’s is treated altogether, replacing the wait until damage is already visible with treatment that intervenes years earlier, at the genetic level. The most effective strategy may ultimately combine both approaches: one drug to stop the CAG repeat from expanding further, another to clear out the harmful protein already being produced.

For now, that remains a scientific hypothesis rather than a proven course of treatment. Whether it holds up will depend on what comes out of INVEST-HD, FALCON-HD, and the somatic-expansion trials still to follow.