PTC518 PIVOT-HD Study Achieves Primary Endpoint

Rhea-AI Summary

PTC Therapeutics (NASDAQ: PTCT) announced positive results from their Phase 2 PIVOT-HD study of PTC518 (votoplam) in Huntington's disease patients. The study successfully met its primary endpoint, demonstrating significant dose-dependent reduction in blood Huntingtin protein levels at Week 12 (p<0.0001).

Key findings include:

• Blood HTT reduction of 23% at 5mg dose and 36-39% at 10mg dose across Stage 2 and 3 patients
• Dose-dependent clinical benefits in Stage 2 patients at 12 months
• 24-month data showed favorable trends in clinical scales compared to natural history
• Dose-dependent plasma NfL reduction of 8.9% (5mg) and 14% (10mg) at 24 months
• Favorable safety profile with no treatment-related serious adverse events

Positive

• Met primary endpoint with significant HTT protein reduction (p<0.0001)
• Strong dose-dependent efficacy with up to 39% HTT reduction at 10mg
• Favorable safety profile with no treatment-related serious adverse events
• Promising 24-month data showing clinical benefits vs natural history
• Potential for accelerated approval pathway

Negative

• Treatment effect may be limited in Stage 3 patients compared to Stage 2
• 10mg dose group showed no benefit in Stage 3 patients

Insights

Biotechnology Research Expert

PTC518 achieved primary endpoint with dose-dependent HTT protein reduction and shows promising safety profile in Huntington's disease patients.

The Phase 2 PIVOT-HD study demonstrates strong target engagement with 23% reduction in blood Huntingtin (HTT) protein at 5mg and 36-39% at 10mg dose levels (p<0.0001), achieving the primary endpoint with high statistical significance. This HTT protein lowering is crucial as it addresses the fundamental disease mechanism in Huntington's disease.

The data reveals an important distinction between disease stages: Stage 2 patients showed dose-dependent trends across clinical scales, while Stage 3 patients benefited at 5mg but not 10mg, suggesting treatment timing may be critical. This stage-specific response pattern provides valuable insights for patient selection in future trials.

The 24-month data adds substantial weight to efficacy signals, showing dose-dependent trends on key functional measures (cUHDRS, TFC, SDMT) compared to matched historical controls. Particularly significant is the dose-dependent reduction in plasma neurofilament light chain (NfL) - a biomarker of neuronal damage - with a 14% reduction at 10mg (nominal p=0.03), providing objective evidence of potential neuroprotection.

Perhaps most noteworthy is the clean safety profile with no treatment-related serious adverse events or NfL spikes. This safety record differentiates PTC518 from previous Huntington's candidates that were discontinued despite showing target engagement due to safety concerns. The absence of NfL spikes, which indicate neuronal damage, is particularly reassuring for a CNS-targeting therapy.

Financial Analyst

PTC's Huntington's disease therapy achieves primary endpoint with favorable safety profile, potentially opening pathway to first disease-modifying treatment.

The PIVOT-HD Phase 2 results represent a significant clinical milestone for PTC Therapeutics. The study conclusively met its primary endpoint of HTT protein reduction (p<0.0001) while demonstrating favorable dose-dependent trends across clinical measures - a combination that strengthens the drug's scientific and regulatory position.

The company's explicit mention of pursuing discussions for accelerated approval is particularly noteworthy. This regulatory pathway could substantially compress the timeline to potential market authorization, representing a critical value-creation catalyst. The designation as a possible "first disease-modifying therapy" for Huntington's disease positions PTC518 in an uncrowded market with significant unmet medical need.

The 24-month data provides important durability indicators with signals of clinical benefit versus matched historical controls, strengthening the case for both regulatory discussions and eventual market adoption. The compound's clean safety profile - with no treatment-related serious adverse events or concerning NfL spikes - removes a key risk factor that has derailed other Huntington's disease programs.

The dose-dependent efficacy signal in Stage 2 patients, alongside the nuanced response in Stage 3 patients (benefit at 5mg but not 10mg), suggests the company has identified both effective dosing ranges and potential target patient populations. This clarity on dose selection and patient stratification could streamline the path to pivotal trials, potentially reducing development time and costs.

- Study met primary endpoint with dose-dependent blood HTT protein lowering at Week 12 -

- Favorable dose-dependent trends across clinical scales in Stage 2 patients at Month 12 -

- Signals of dose-dependent clinical benefit relative to matched natural history cohort as well as dose-dependent lowering of NfL in Stage 2 patients at Month 24 -

- Continued favorable safety and tolerability profile with no treatment-related NfL spikes -

- PTC will host a conference call on May 5, 2025, at 8:00 am ET-

WARREN, N.J., May 5, 2025 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) today announced results from the Phase 2 PIVOT-HD study of PTC518 (votoplam) in Stage 2 and Stage 3 Huntington's disease (HD) patients. The study met its primary endpoint of reduction in blood Huntingtin (HTT) protein levels (p<0.0001) at Week 12 and favorable safety and tolerability. In addition, the 12-month data from the Stage 2 patients are consistent with the previously reported dose-dependent lowering of HTT protein and dose-dependent trends across clinical scales.

"These PIVOT-HD results confirm that PTC518 lowers Huntingtin protein and shows early signals of clinical benefit with a favorable safety profile," said Matthew B. Klein, M.D., Chief Executive Officer, PTC Therapeutics. "In addition, at 24 months, we observed favorable dose-dependent trends on the cUHDRS and the TFC and SDMT subscales relative to natural history as well as dose-dependent lowering of neurofilament light chain protein. We look forward to discussions on the next development and regulatory steps including the potential for accelerated approval as we work to potentially bring the first disease-modifying therapy to those affected by Huntington's disease."

Results from the full 12-month cohort demonstrate dose-dependent lowering in blood HTT levels, with 23% at the 5mg dose level for both Stage 2 and 3 patients and 39% and 36% at the 10mg dose level for Stage 2 and 3 patients, respectively. For Stage 2 patients, there were dose-dependent trends of benefit on clinical scales including the Composite Unified Huntington's Disease Rating Scale (cUHDRS) and Total Motor Score (TMS) subscale. For Stage 3 patients, there were trends favoring the 5mg dose group relative to placebo, but not the 10mg dose group, suggesting that treatment effect may differ in Stage 3 patients relative to Stage 2 patients.

For all dose levels and disease stages, PTC518 showed a favorable safety and tolerability profile with no treatment-related serious adverse events or neurofilament light chain protein (NfL) spikes.

In addition, 24-month treatment data from the patients on whom data were shared last year (N=21) demonstrate signals of dose-dependent trends on the cUHDRS, Total Function Capacity (TFC) and Symbol Digit Modalities Test (SDMT) subscales when compared to a propensity matched natural history cohort from the ENROLL-HD Registry. At Month 24, there was also dose-dependent lowering of plasma NfL from baseline of -8.9% (nominal p=0.12) for the 5mg dose level and -14% (nominal p=0.03) for 10mg dose level.

Conference Call and Webcast Details:
PTC will hold a conference call at 8:00 am ET today to discuss this news. To access the call by phone, please click here to register and you will be provided with dial-in details. To avoid delays, we recommend participants dial in to the conference call 15 minutes prior to the start of the call. The webcast conference call can be accessed on the Investor section of the PTC website at https://ir.ptcbio.com/events-presentations. A replay of the call will be available approximately two hours after completion of the call and will be archived on the company's website for 30 days following the call.

About PIVOT-HD
PIVOT-HD was designed as a 12-month placebo-controlled trial to assess pharmacodynamic effect and safety of PTC518 at two dose levels--5mg and 10mg, relative to placebo. Initially, the study included only Stage 2 patients. A Stage 3 cohort of similar size was subsequently added to help identify the best study population for future studies. The primary endpoints of PIVOT-HD were total blood Huntingtin (HTT) lowering at 12 weeks and safety events. Secondary endpoints included 12-month blood HTT levels, and other blood-and central nervous system (CNS) biomarkers as well as changes in Composite Unified Huntington's Disease Rating Scale (cUHDRS).

Following 12 months, patients were eligible to enroll in a long-term extension study in which all subjects would receive PTC518. Those originally randomized to 5mg and 10mg would continue at that dose level; those initially randomized to placebo would be randomized 1:1 to 5mg or 10mg. All subjects and investigators remain blinded to initial treatment assignment.

Presentation of study results is expected at a scientific meeting later in the year.

About PTC518
PTC518 is a small molecule splicing modifier that acts via a unique mechanism to promote the inclusion of a novel pseudoexon containing a premature termination codon, thus triggering Huntingtin (HTT) mRNA degradation and subsequent reduction in HTT protein levels. PTC518 was discovered from PTC's validated splicing platform, following the successful discovery and development of Evrysdi^® (risdiplam) for spinal muscular atrophy (SMA).

About Huntington's Disease
Huntington's disease (HD) is a fatal, hereditary, genetic disorder of the central nervous system.¹  It is caused by a defective gene. This gene produces a protein, called Huntingtin (HTT), which is involved in the functioning of the nerve cells in the brain (neurons). When the gene is defective, it produces an abnormal (or mutated) HTT protein that is toxic and causes neuron damage and neuron death.²  HD usually presents in people who are in their 30s or 40s. Symptoms can present earlier in life, and this is called Juvenile HD.^2,3  There are also cases of infantile HD, when symptoms develop in children who are younger than 10 years old.²  While symptoms vary from person to person, the disease primarily affects the brain and results in abnormal movements, difficulties with speech, swallowing and walking, as well as a number of other symptoms including behavioral, cognitive and motor symptoms.^4,5  While there are therapies approved for specific disease symptoms, currently, there is no cure for HD and there are no approved drugs that delay the onset or slow disease progression.

About PTC Therapeutics, Inc.
PTC is a global biopharmaceutical company that discovers, develops and commercializes clinically differentiated medicines that provide benefits to children and adults living with rare disorders. PTC's ability to innovate new therapies and to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines. To learn more about PTC, please visit www.ptcbio.com and follow on Facebook, X, and LinkedIn.

For More Information:

Investors:
Ellen Cavaleri
+1 (615) 618-6228
ecavaleri@ptcbio.com

Media:
Jeanine Clemente
+1 (908) 912-9406
jclemente@ptcbio.com 

Forward-Looking Statement:
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this press release, other than statements of historic fact, are forward-looking statements, including statements with respect to the future expectations, plans and prospects for PTC, PTC's strategy, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses and other matters, future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions.

PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; expectations with respect to PTC's license and collaboration agreement with Novartis Pharmaceuticals Corporation including its right to receive development, regulatory and sales milestones, profit sharing and royalty payments from Novartis; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; the sufficiency of PTC's cash resources and its ability to obtain adequate financing in the future for its foreseeable and unforeseeable operating expenses and capital expenditures; and the factors discussed in the "Risk Factors" section of PTC's most recent Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors.

As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory or prove to be commercially successful. 

The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law. 

References:

1. World Health Organization, 2020. 8A01.10 Huntington disease. Available at: https://icd.who.int/browse10/2019/en#/G10. Accessed October 2021.
2. Gatto EM, González Rojas N, Persi G, et al. Clin Parkinsonism Rel Disord 2020;3:100056.
3. Tabrizi SJ, Flower MD, Ross CA, et al. Nat Rev Neurol 2020;16(10):529–546.
4. Roos RAC. Orphanet J Rare Dis 2010; 5:40.
5. Kirkwood SC, Su JL, Conneally P, et al. Arch Neurol 2001;58(2):273–278.

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SOURCE PTC Therapeutics, Inc.

FAQ

What were the main results of PTCT's PIVOT-HD Phase 2 trial for PTC518?

The trial met its primary endpoint with significant dose-dependent blood HTT protein reduction at Week 12 (p<0.0001), showing 23% reduction at 5mg and up to 39% at 10mg, with favorable safety profile and clinical benefits in Stage 2 patients.

How did PTC518 perform in terms of safety in the PIVOT-HD study?

PTC518 demonstrated a favorable safety and tolerability profile with no treatment-related serious adverse events or neurofilament light chain protein spikes across all dose levels and disease stages.

What was the HTT protein reduction achieved by PTC518 in the PIVOT-HD trial?

The study showed dose-dependent HTT reduction of 23% at 5mg dose for both Stage 2 and 3 patients, and 39% and 36% reduction at 10mg dose for Stage 2 and 3 patients, respectively.

What were the 24-month results for PTC518 in Huntington's disease?

24-month data showed dose-dependent improvements in clinical scales versus natural history and plasma NfL reductions of 8.9% (5mg) and 14% (10mg) from baseline.

Is PTC518 effective in all stages of Huntington's disease?

The drug showed better efficacy in Stage 2 patients, while Stage 3 patients showed limited response, particularly at the 10mg dose, suggesting treatment effects may differ by disease stage.