Two Years In: New Long-Term Extension Data from PIVOT-HD for Votoplam

On April 28th 2026, PTC Therapeutics shared new data from the long-term extension of PIVOT-HD, the Phase 2 clinical trial of votoplam, the daily pill designed to lower huntingtin (HTT) protein in people with Huntington’s disease (HD). This is the first look at how participants are doing at the two-year mark, and it adds an important new chapter to the votoplam story.

A quick recap: what is votoplam and where does it stand?

Votoplam (formerly PTC-518) is a small molecule drug that works by altering how the HTT gene’s RNA message is processed. The drug causes the RNA to be sent to the cell’s trash can before it can be used to make HTT protein, reducing levels of both the regular and HD version of the protein throughout the body. Unlike some other HTT-lowering approaches in development, votoplam is taken as a daily pill, which means no injections or surgery required.

The original PIVOT-HD trial was a 12-month placebo-controlled study testing votoplam at 5 mg and 10 mg doses against a sugar pill in people with HD-ISS Stage 2 and Stage 3 disease. It met its primary endpoint, lowering HTT protein levels in the blood. It also showed early encouraging signals on some clinical measures, particularly in Stage 2 participants. 

In December 2024, Novartis partnered with PTC to take votoplam forward, and has since launched the global Phase 3 trial, INVEST-HD. Following the end of PIVOT-HD’s placebo-controlled period, all participants were offered the chance to continue taking votoplam in a long-term extension study. Those who had been on placebo were randomized to either the 5 mg or 10 mg dose. Everyone, participants and investigators, remains blinded to what they took originally.

What’s new: the 24-month data

Control group

The new results come from that long-term extension, at the two-year mark. This is an important distinction from the original trial because there is no longer a placebo group. Everyone in this analysis has been taking votoplam for 24 months. 

To understand whether the drug is having an effect on disease progression, PTC compared participants’ outcomes to those of a carefully matched group of people from ENROLL-HD, a large international natural history registry that has been tracking HD progression in tens of thousands of people over many years. This kind of comparison, called a natural history control, is a reasonable approach for long-term studies, though it comes with limitations compared to a randomized controlled trial.

Disease progression

The main takeaway from this recent data release is that participants who were HD-ISS Stage 2 at the start of the trial taking the 10 mg dose showed 52% slowing of disease progression on the cUHDRS compared to the natural history cohort. Those on the 5 mg dose showed 28% slowing. This dose-dependent pattern (more drug, more effect) is exactly what researchers hope to see and adds confidence that the signal they see is coming from the drug – good news!

Brain cell damage

On top of that, a biomarker called neurofilament light chain (NfL), which measures ongoing nerve cell damage, remained below baseline at 24 months for participants on both doses. In natural history data, NfL typically rises over time in people with HD as their brains continue to get more sick. Keeping it flat or reduced is an encouraging sign that votoplam may be preserving brain cell health.

Safety

Safety data at 24 months continued to look reassuring. No new safety signals emerged with longer exposure (the clinical jargon for participants taking the drug for a longer period of time), and importantly, no participants in the extension study discontinued treatment due to adverse events. The serious adverse events that did occur were not considered treatment-related. For a drug that participants have now been taking for up to two years, that continued tolerability is an important finding in its own right.

What about people at Stage 3?

For participants who were HD-ISS Stage 3 at the start of the trial, the picture is less clear. PTC described “potential signals of slowing of progression” at 24 months, which sounds encouraging, but uses notably more cautious language than the Stage 2 results. 

Adding to the uncertainty, PTC hasn’t yet shared how Stage 3 participants performed on each of the individual tests that make up the cUHDRS. The cUHDRS combines measures of movement, thinking, and daily function into a single score, and knowing which components are moving, and which aren’t, is essential for understanding what votoplam is may be doing in this group. Until that data is available, the Stage 3 picture remains incomplete.

A note on SDMT: HD affects everyone differently

One of the more interesting details in the new data concerns which measures appear to be driving the benefit for folks in Stage 2. The cUHDRS is a composite score made up of four subscales: 

• TFC (Total Functional Capacity) – a measure of one’s ability to carry out day-to-day tasks, like work, manage finances, and various life tasks
• TMS (Total Motor Score) – measures HD-related motor symptoms, like chorea and dystonia
• SDMT (Symbol Digit Modalities Test) – measures thinking and processing speed to assess cognitive function
• SWRT (Stroop Word Reading Test) – measures attention and processing to assess cognitive capacity

In the Stage 2 group, favorable trends were seen across all four subscales for the 10 mg dose, but the changes to SDMT scores are particularly notable, suggesting it may be the primary driver of the improvement in the cUHDRS we see in this group.

SDMT measures how quickly someone can match symbols to numbers, which serves as a proxy for processing speed and visual attention, both of which are affected in HD. This is a cognitive, not a motor, measure. 

This contribution to the observed benefit is a reminder that HD is an individual disease. While some people experience motor symptoms most prominently, others find that cognitive changes are more central to their daily experience of HD. A drug that meaningfully slows disease progression by slowing cognitive decline could matter enormously to the people for whom that’s the sharpest edge of the disease.

Why Novartis chose the population they did for their Phase 3 trial

This brings us to INVEST-HD, the Phase 3 trial that Novartis is sponsoring. INVEST-HD will enroll approximately 770 people with early HD, specifically people with a TFC score of exactly 13 and early motor signs. This is the same group that showed the clearest benefit in PIVOT-HD.

It’s worth explaining why this population was chosen. If Novartis had enrolled people who were fully pre-symptomatic, before any motor or cognitive signs, it would be difficult to know whether the drug was improving anything, only whether it was holding symptoms at bay. 

By enrolling people who already have early measurable symptoms, INVEST-HD creates the conditions to detect both stabilization and improvement. That’s a stronger test of what the drug can do.

It’s also worth noting that while they selected a population where they feel they’re most likely to see a benefit, this doesn’t mean that if votoplam is successful it won’t work for people in earlier or later stages of HD. If data from folks who are at Stage 2 look good, they’ll very likely expand who might be a good candidate for this drug.

What’s still missing

The recent data release is interim, and several pieces of information have not yet been publicly reported. Novartis has confirmed that the full 24-month long-term extension data will be presented at a scientific meeting later in 2026. So while we’re working with topline results for now, a more complete picture is yet to come.

HTT lowering was the primary endpoint of the original PIVOT-HD trial, and at 12 months, votoplam showed durable, dose-dependent lowering. The 24-month HTT samples haven’t been analyzed yet, so we don’t have confirmation that this lowering is maintained at the two-year mark. We expect it will be, but confirmation matters.

For HD-ISS Stage 3 participants, we are also still missing the full breakdown of how participants performed on each of the individual tests that make up the cUHDRS score. The cUHDRS combines measures of movement, thinking, and daily function into a single score, and knowing which components are moving, and which aren’t, is essential for understanding what votoplam is actually doing in this group. That breakdown is still missing for Stage 3, which means we’re working with an incomplete picture.

Brain MRI data from the extension study were also flagged as forthcoming. MRI can provide information about whether brain volume is being preserved, but it’s critical to note that this measure is difficult to interpret in HD. Brain volume changes can reflect multiple processes, including not just brain cell loss but also neuroinflammation, and it’s not always possible to disentangle the two. We’ll report on MRI data when it becomes available, but it will require careful interpretation.

Finally, it’s worth noting that the comparison to natural history, while carefully constructed using ENROLL-HD data, is not the same as a head-to-head randomized placebo-controlled comparison. INVEST-HD, now underway, is designed to provide exactly that.

Summary

• Votoplam is a daily pill that lowers HTT protein; it met its primary endpoint in the Phase 2 PIVOT-HD trial and is now being developed by Novartis
• New 24-month data come from the long-term extension study, where all participants are on votoplam and progression is compared to a matched natural history cohort from ENROLL-HD – there is no longer a placebo group
• In HD-ISS Stage 2 participants, the 10mg dose showed 52% slowing of disease progression on the cUHDRS; the 5mg dose showed 28% slowing; a dose-dependent pattern that adds confidence to the signal
• NfL, a marker of nerve cell damage, remained below baseline at 24 months for both doses, in contrast to the increases typically seen in natural history
• The Stage 2 benefit appears to be driven across all four cUHDRS subscales, particulalry SDMT, a cognitive measure of processing speed 
• For HD-ISS Stage 3 participants, only “potential signals” of benefit were observed, and key subscale data including SDMT have not yet been reported for this group
• Novartis has launched the Phase 3 INVEST-HD trial, targeting people with a TFC of exactly 13 and early motor signs, a population where PIVOT-HD showed its strongest signal
• Still outstanding: 24-month HTT protein levels, full Stage 3 subscale data, and brain MRI results