PTC Therapeutics Shares 24-Month Votoplam Data Showing Dose-Linked Huntington’s Slowing Signals

Key Points

• Votoplam showed dose-dependent slowing of Huntington’s progression in Stage 2 at 24 months versus a matched natural-history cohort — about 52% slowing at 10 mg and 28% at 5 mg on the cUHDRS — though differences were not statistically significant (10 mg trended with p<0.10).
• Safety and biomarkers remained favorable after 24 months with no treatment-related NfL spikes (median NfL below baseline for both doses) and no new adverse-event signals, while Stage 3 participants showed emerging functional benefit on the TFC subscale.
• PTC and Novartis have initiated the Phase 3 INVEST‑HD trial (≈770 patients, 3:2 randomization to 10 mg vs placebo, up to 36 months); Phase 3 start triggers a $50M milestone and could support accelerated-approval discussions pending interim analyses.

PTC Therapeutics NASDAQ: PTCT reported top-line results from a 24-month interim analysis of the PIVOT-HD long-term extension (LTE) study evaluating Votoplam in Huntington’s disease, highlighting what the company described as continued favorable safety and signals of dose-dependent slowing of disease progression in earlier-stage participants.

On the conference call, CEO Matthew Klein said the interim LTE findings “give us confidence that Votoplam has the potential to provide long-term meaningful effect in slowing the progression of Huntington’s disease,” while emphasizing that all study participants and investigators remain blinded to treatment assignments.

Study background and use of natural history comparator

Klein reviewed the Phase 2 PIVOT-HD design as a 12-month, placebo-controlled study in individuals with Stage 2 and Stage 3 Huntington’s disease, followed by an LTE in which placebo participants were re-randomized to high or low dose Votoplam. Because there is no placebo group after month 12, the LTE protocol specified use of a matched natural history cohort from the Enroll-HD Disease Registry to contextualize effects at month 24.

Klein said Enroll-HD includes more than 30,000 patient records and contains the key inclusion criteria used in PIVOT-HD. He added that the comparator cohort was matched on variables that influence disease progression and that baseline characteristics were “well-matched…with no relevant differences across the groups.” In response to analyst questions about the integrity of the approach, Klein said FDA expectations favor prespecification of the natural history plan and matching criteria, both of which he said were done in the LTE protocol and analysis plan.

Stage 2: dose-dependent slowing on cUHDRS vs natural history

In Stage 2 participants who had 24 months of Votoplam treatment (those initially randomized to active treatment at the start of the placebo-controlled phase), Klein said Votoplam showed dose-dependent slowing of progression on the composite Unified Huntington’s Disease Rating Scale (cUHDRS) relative to natural history:

• 52% mean slowing versus natural history at 10 mg
• 28% mean slowing versus natural history at 5 mg

He noted that from month 12 to month 24 the curves continued to diverge from natural history, which he said supports an increased treatment effect over time. However, he cautioned the differences did not reach statistical significance, though the 10 mg effect trended with a p-value below 0.10.

Asked about the subscale contributions—particularly whether the Symbol Digit Modalities Test (SDMT) appeared to drive the composite result—Klein said the cUHDRS is valued because it captures multiple domains, including motor, cognitive, and functional capacity, and that the company was “not reading too much in depth to what one individual scale is saying,” emphasizing that contributions were seen across several subscales at 10 mg.

Biomarkers and safety: no NfL spikes, consistent adverse events

Klein said that at 24 months the company continued to see no evidence of treatment-related neurofilament light chain (NfL) spikes. For both 5 mg and 10 mg in Stage 2, NfL levels were below baseline, which he described as a departure from the expected natural history of increasing NfL over time. Responding to a question about the absence of dose-dependence in NfL, Klein said the relationship between specific NfL levels and disease progression in Huntington’s disease is “not that well understood,” but that it is generally appreciated NfL should rise over time. He said the reduction versus baseline in both dose groups was “most encouraging.”

On safety, Klein said the profile “remains favorable after 24 months of treatment,” with no new adverse event signals, and that the overall adverse event profile was consistent across dose levels and disease stages, and consistent with what was observed in the placebo group. He added that in the long-term extension, all Stage 3 and 4 adverse events and serious adverse events were deemed not treatment related.

Stage 3: emerging signals, especially on functional measures

For Stage 3 participants, Klein said the company is “beginning to see signals of potential favorable treatment effect” at 24 months. He highlighted benefit versus natural history on the Total Functional Capacity (TFC) scale at both dose levels, calling TFC a particularly relevant cUHDRS subscale in Stage 3 due to the functional decline that defines that stage.

He said the overall cUHDRS showed a trend of benefit for 5 mg at month 24 and “what may be an early signal of slowing of progression from month 12 to 24” for 10 mg. Klein also said there were no treatment-related NfL spikes in Stage 3, with median levels below baseline for both doses at month 24.

When asked about the apparent “flattening” of curves at later time points and whether dropouts could affect interpretation, Klein said the 24-month data presented were “as observed” with no modeling, and that there have been “very few dropouts,” with high compliance in the trial.

Phase 3 INVEST-HD enrolling; milestone and regulatory discussions to come

Klein said the Phase 2 LTE results increase confidence in the design of the Phase 3 INVEST-HD global trial, which he said Novartis “shared earlier today is now enrolling.” He described INVEST-HD as enrolling earlier symptomatic individuals with a normal TFC score of 13, including Stage 2 and “very early Stage 3,” with participants randomized 3:2 to receive 10 mg Votoplam or placebo. Target enrollment is approximately 770 patients, and the primary endpoint is change from baseline up to 36 months on cUHDRS. The study will include interim analyses for efficacy and futility, and Klein said the interim efficacy analysis could “potentially…accelerate a timeline for approval,” though details on timing were not disclosed.

On regulatory strategy, Klein said “all options remain on the table” including accelerated approval, but that PTC and Novartis plan to further review the interim data and align on appropriate regulatory interactions. In response to a question about financial implications, Klein said Phase 3 initiation triggers a $50 million milestone.

Klein added that MRI analyses, including questions about caudate volume, are still in progress and were not yet available, and that the company expects to share a fuller dataset at a future scientific meeting.

About PTC Therapeutics NASDAQ: PTCT

PTC Therapeutics, Inc is a biopharmaceutical company focused on the discovery, development and commercialization of small molecule and biologic therapies for the treatment of rare genetic disorders. Since its founding in 1998, PTC has dedicated its efforts to addressing high unmet medical needs by targeting underlying genetic causes of disease. The company's research platform emphasizes mechanisms such as nonsense suppression and RNA modulation, enabling the development of novel treatments for conditions with limited therapeutic options.

Among PTC's approved products is Translarna (ataluren), a first-in-class therapy designed to treat nonsense mutation Duchenne muscular dystrophy in select markets.

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