First Huntington’s patient dosed in large trial of oral therapy votoplam
Main goal is to show that it tops a placebo at slowing disease progression
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The first participant has been dosed in a large clinical trial testing the experimental oral therapy votoplam (formerly PTC518) in adults with early-stage Huntington’s disease.
That’s according to a press release from PTC Therapeutics, the therapy’s original developer, announcing its latest financial results and business updates. Novartis is now leading votoplam’s clinical development and owns the therapy’s manufacturing and commercial rights after entering into a license and collaboration agreement with PTC in late 2024.
The Novartis-sponsored Phase 3 study, dubbed INVEST-HD (NCT07326709), is currently enrolling up to 770 participants, ages 21 to 70, at sites in the U.S., Canada, and the U.K. Participants will be randomly assigned to take either votoplam (10 mg) or a placebo, once daily for up to three years.
The study’s main goal is to show that votoplam is superior to the placebo at slowing disease progression, as assessed using a standard measure called the Composite Unified Huntington’s Disease Ratings Scale (cUHDRS). It is expected to end in 2030.
Votoplam aims to halt production of healthy, mutant versions of protein
Huntington’s disease is caused by mutations in the HTT gene, leading to the production of an abnormal version of the huntingtin protein, which is thought to drive the disease. Votoplam aims to shut down the production of both healthy and mutant versions of this protein by targeting HTT’s messenger RNA, an intermediate molecule produced when the gene is read to make protein.
The previous Phase 2 PIVOT-HD clinical trial (NCT05358717) tested two votoplam doses (5 mg and 10 mg daily) against a placebo in people with stage 2 or 3 Huntington’s, corresponding to early- and late-intermediate stages.
The trial met its main goal, showing that votoplam was better than the placebo at reducing blood levels of the huntingtin protein after about three months, with sustained reductions observed after one year.
Participants who completed the yearlong placebo-controlled portion of PIVOT-HD could enter into a Phase 2b extension study (NCT06254482), in which all are being treated with votoplam for at least 2.5 years. Those originally given votoplam continued on the drug at the same dose, while those on the placebo were randomly assigned to start votoplam at one of the two doses tested.
Of note, study participants and investigators remain blinded, meaning neither group knows whether patients received votoplam or the placebo in the original study.
Stage 2 patients on votoplam had significantly slower progression
In a separate press release, PTC also announced results from an interim analysis of the extension study. Results from patients treated with votoplam for two years in PIVOT-HD and its extension were compared with data from a group of matched untreated Huntington’s patients participating in an observational study called Enroll-HD (NCT01574053).
According to PTC, stage 2 patients on votoplam had significantly slower progression as measured by the cUHDRS — by 28% with the lower dose and by 52% with the higher dose that’s now in Phase 3 testing — compared with matched untreated patients.
“Potential signals of slowing of progression were observed” among stage 3 patients, the release stated, but no specific numbers were provided at this time.
PTC also noted that mean levels of neurofilament light chain (NfL), a marker of nerve damage, were lower after two years on either dose of votoplam than at the start of PIVOT-HD. This contrasts with the typical progression of Huntington’s, in which NfL levels increase over time.
Votoplam’s long-term safety profile has been consistent with early findings, according to the company.
“These results give us confidence in the potential for votoplam to deliver long-term meaningful effect on slowing Huntington’s disease progression,” said Matthew B. Klein, MD, PTC’s CEO. “In particular, the evidence of dose-dependent slowing of progression on the cUHDRS disease rating scale in the Stage 2 study participants supports the Novartis-initiated Phase 3 INVEST-HD study. We look forward to continuing to review the data and aligning on potential regulatory interactions based on the results with our partner Novartis.”
