NeuroVoices: Danny Bega, MD, on Huntington Agent Votoplam, Ongoing Phase 3 Study, and Broader HD Therapeutic Landscape

Huntington disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric features. It most commonly presents in adulthood, with a mean age of onset of approximately 40 to 50 years, although juvenile and late-onset cases also occur. Early clinical manifestations may include subtle oculomotor abnormalities, impaired coordination, mild involuntary movements, deficits in executive function, and mood changes such as depression or irritability.¹

Recent research efforts to modify disease progression in HD have led to the advancement of investigational therapies into later-stage development. For example, Novartis has initiated the global phase 3 INVEST-HD trial (NCT07326709), a randomized, double-blind, placebo-controlled study evaluating its oral therapy votoplam in participants with early-stage HD. Advancement into this phase 3 study was supported by interim findings recently reported from the long-term extension phase (NCT06254482) of the phase 2 PIVOT-HD study (NCT05358717) of votoplam.²

In a new iteration of NeuroVoices, Danny Bega, MD, movement disorders neurologist and director of the Huntington's Disease Center at Northwestern Medicine, discussed the ongoing development of votoplam in the phase 3 INVEST-HD trial. He noted that the phase 3 study aims to confirm target engagement and evaluate clinical efficacy in slowing disease progression in patients with Huntington disease, focusing on early symptomatic individuals with preserved independence to optimize detection of clinical change. He also discussed the broader HD therapeutic landscape, including gene therapies, antisense oligonucleotides, and other investigational agents.

NeurologyLive: Could you provide an overview of the study design of the phase 3 INVEST-HD trial?

Danny Bega, MD: Right now, there is a lot in the space of HD research in terms of slowing down disease progression. Novartis is currently working on a drug that’s an oral medication. The company had some initial success with a phase 2 study, and now we’re moving into a phase 3 study. Actually, a couple of sites have just started recruiting for it, and more sites are going to be starting to recruit for the study in the coming weeks and months.

The large phase 3 INVEST-HD trial is looking at a drug called votoplam and comparing it to placebo. It’s an oral medication that’s called a splicing modulator. This is a really interesting medication, where what it does is introduce a premature stop codon in the RNA, where the code for the abnormal huntingtin protein is normally made. By introducing a stop codon as the mRNA is being read for translation, it reads a stop codon and then doesn’t produce the mutant huntingtin protein.

In the phase 2 study, it showed that it did reduce the mutant huntingtin protein production in a dose-dependent way. There were 3 arms: a placebo arm, a low-dose votoplam arm, and a higher-dose votoplam arm. There was no reduction observed in the mutant huntingtin protein in the placebo group, and in the double-blind phase. There was about a 20% reduction in the lower-dose group and closer to a 40% reduction in the higher-dose group. It was a dose-dependent reduction over a period of a year in their phase 2 trial, and it showed good safety outcomes as well.

There was target engagement, which we’re excited about, and seeing reduced huntingtin protein production. There were some signals of slowing down progression on some clinical outcome measures, although that wasn’t the primary objective of the phase 2 study. Now, the phase 3 study will aim at first confirming that it’s reducing the mutant huntingtin protein in a larger population, focusing just on the higher dose and comparing that to placebo, but also, importantly, looking at the clinical outcome measures and seeing if it actually does translate to slowing down disease progression on these measures.

What are the key inclusion and exclusion requirements for enrolled participants in the trial?

The most important criteria is a confirmed genetic diagnosis of HD—meaning we have someone with 40 CAG repeats or more that’s confirmed on a gene test, and that they are showing some symptoms or signs of the disease that are observable on our exam. Typically, what we’re referring to is some objective motor manifestations of the disease, but not impairing their function in terms of their level of independence.

We’re defining what we call early symptomatic people, where there are some objective symptoms, but they’re still able to carry out their day-to-day activities independently. This would even include people who could potentially still be working, still handling all their basic needs. They don’t necessarily have to be working, but they have to be capable of being independent in all their activities.

The reason for this is that, while this is a bit specific in terms of the group that we’re looking for, this group has been described as probably being the best one for being able to follow disease progression and detect whether you’re slowing down progression more successfully on clinical measures. If you take a group of people who don’t yet have symptoms, it’s going to be harder to demonstrate that you’re slowing down disease progression. Whereas if people have symptoms, it’ll be easier to track the change and see that you’re slowing down those changes compared with a group that’s not receiving the medication or to a group getting a placebo.

That’s why that’s a defined group. Then, like most trials—because trials are intensive and are really trying to study things in a way that is less messy—it’s harder to include people with more advanced disease, because there are a lot of other variables at play. So, that’s where most of these trials end up being narrowed to people with early symptomatic disease who are still independent.

What study methods are being used in the study beyond disease progression?

The important clinical measures that they’re using in the methods include a score called the composite UHDRS, the Unified Huntington’s Disease Rating Scale. It’s a composite of the 3 basic elements of HD, which are motor abnormalities, cognitive abnormalities, and psychiatric and behavioral abnormalities. It has elements of all of those that are factored in together, rather than just looking at one domain, which is a well-accepted endpoint.

The other measure they look at is the Total Functional Capacity or the TFC scale, which is how independent someone can be. And as I mentioned, we want people to be at full functional capacity to enter this study. But what we want to see is the natural decline in that functional independence that happens. There’s a scale for that, and we want to see that there’s less worsening on that loss of independence scale.

Other measures are biomarkers, where we can actually measure mutant huntingtin protein levels. It can be measured in the spinal fluid, but in the case of mutant huntingtin protein, it can also be measured in the blood. And in the phase 2 study, the study authors were able to show that they lowered it in the blood, so they’ll be looking at that (in the phase 3 trial). There will also be spinal fluid analysis as part of the biomarker analysis.

Another biomarker that we look for is something called neurofilament light (NfL). It’s one that’s been talked about in a lot of different neurodegenerative diseases. It’s a very hot topic—sort of a nonspecific measure of neurodegeneration, of neuronal integrity—and it’s being looked at as a way that slowing increases in NfL may be a sign of slowing down disease progression. So that’s another biomarker that’s going to be looked at in most of these HD trials.

What are you most looking forward to in the HD research and treatment landscape?

I would say the big picture, putting it into perspective where we are in the field with research—we don’t have all of our eggs in one basket in the HD research space, which is good. There have been a lot of headlines about AMT-130, which is also trying to reduce mutant huntingtin protein, but doing it through brain surgery, delivering it directly into the brain. We’re waiting to see what the next moves are with that—it’s a bit of a waiting game to find out what the final word is going to be with the FDA, or whether there’s going to be a bigger trial coming. That’s one avenue.

There are intrathecal treatments that are also trying to lower mutant huntingtin protein using antisense oligonucleotides. We’re participating in the GENERATION HD2 study, which is expected to read out in the coming month or two, and we’re hoping to hear results from the double-blind phase.

Now we’re talking about moving into an oral space, which we’re excited about, because hopefully these other ones that I mentioned will be successful—but if they are, then we’re going to be dealing with scalability, very expensive medications, and potentially ones that are a little bit more difficult to scale. Now we’re in the space of oral medications, which obviously come with the advantage of scalability and costs being more favorable to a larger community that is at risk.

We’re very hopeful. The Novartis trials of PIVOT-HD and INVEST-HD we’re talking about today, but there are also others. There’s Skyhawk Therapeutics, which is coming into play now after they had some success with a phase 2 study, and they’re going to be starting their phase 3 study as well. All of these are kind of focused on lowering mutant huntingtin protein.

Then we’re also still looking at drugs that do other things besides just focusing on mutant huntingtin protein lowering. That includes a drug called pridopidine by a company called Prilenia, which is entering another phase 3 study actively now, and that is to try to stabilize neurons using a different mechanism.

There’s more coming—there’s a lot happening. A lot of these studies do focus on this very specific group of either late prodromal or early symptomatic populations. For people in that group, we need them to participate because we have a lot of trials. But for those who are not in that group, I would also say it’s not that those people should feel shortchanged—we’re trying to get these drugs to everyone. We’re trying to make sure that we study these drugs appropriately and get them out to the people who need them. I think that once we can prove that a drug is effective, then it will be important to get it to a broader population. But right now, we need to study it in a very defined population.

Transcript edited for clarity. Click here to view more NeuroVoices.

REFERENCES
1. Caldeira Brás I, Dawson J, Kay C, Caron NS, Hayden MR. Huntington Disease. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; October 23, 1998.
2. PTC Therapeutics Reports Positive Topline Results from Month 24 Interim Analysis of PIVOT-HD Extension Study of Votoplam. PTC Therapeutics. April 28, 2026. Accessed May 5, 2026. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-reports-positive-topline-results-month-24