PTC518 found to reduce huntingtin protein levels in 1 year in trial
Early clinical benefit seen with treatment in Huntington's Phase 2 study
One year of treatment with PTC518 safely lowered blood levels of huntingtin, the protein that’s faulty in Huntington’s disease, in a dose-dependent manner in people with early- and late-intermediate stages of the neurodegenerative condition.
That’s according to new data from the Phase 2 PIVOT-HD clinical trial (NCT05358717), which is testing the treatment candidate in more than 250 individuals with Huntington’s. The data also showed dose-dependent trends — linked to the two different doses being evaluated — in terms of clinical benefits in early-intermediate stage patients.
“These PIVOT-HD results confirm that PTC518 lowers Huntingtin protein and shows early signals of clinical benefit with a favorable safety profile,” Matthew Klein, MD, CEO of PTC Therapeutics, the therapy’s original developer, said in a company press release. The release noted that, “for all dose levels and disease stages, PTC518 showed a favorable safety and tolerability profile with no treatment-related serious adverse events.”
With this clinical trial now complete, PTC518’s development will shift to Novartis under a collaboration agreement reached by the two companies late last year.
Targeting disease-causing mutations in the HTT gene
Huntington’s disease is caused by mutations in the HTT gene, which provides instructions to make the huntingtin protein. Huntington’s-causing mutations give rise to an abnormal form of the protein that is thought to be centrally involved in driving the disease.
When the HTT gene is read to make huntingtin, the genetic code is copied from a cell’s DNA into an intermediary molecule called messenger RNA, which is then used as a template to make protein.
PTC518 is an oral medicine designed to target this intermediary molecule, thereby reducing the production of all forms of huntingtin protein — including the mutant version that drives Huntington’s neurodegeneration.
The PIVOT-HD trial enrolled Huntington’s patients with stage 2 or 3 disease, corresponding to early- and late-intermediate stages, respectively. Participants were randomly assigned to take either PTC518 at doses of 5 or 10 mg/day or a placebo, for one year.
The trial’s main goals were to assess the therapy’s safety and its ability to lower blood huntingtin protein levels after three months. Top-line three-month data showed the study met that goal, with PTC518 being superior to the placebo at reducing huntingtin levels.
Reductions in mutant huntingtin protein seen at 1 year
The newly announced data showed sustained huntingtin reductions after one year — by 23% with the low PTC518 dose, and 36% with the high dose. Huntingtin reductions were broadly similar in patients with stage 2 or 3 disease. According to a company webcast, huntingtin levels were also decreased in the fluid that surrounds the brain and spinal cord.
Among stage 2 patients, blood levels of NfL, a marker of nerve damage, tended to decrease in those given PTC518, but were largely unchanged for those on the placebo. For the stage 3 patients, NfL levels decreased slightly in those given the low PTC518 dose, but tended to increase in those given the high dose or the placebo. Measures of brain shrinkage, or atrophy, did not show any notable difference among the three groups.
“Twelve months may be too early to see clear treatment effects on NfL” and on “brain volume changes,” Klein said in the webcast.
Scores on the Composite Unified Huntington’s Disease Rating Scale (cUHDRS), a measure of disease severity, did not show statistically significant differences between the groups.
However, there was a trend toward dose-dependent effects among stage 2 patients, with cUHDRS scores dropping the most in the placebo group and the least in the high dose group — which is broadly what might be expected if the therapy was slowing disease progression, according to the researchers.
Among stage 3 patients however, cUHDRS scores worsened similarly for individuals given the placebo or the low PTC518 dose, but worsened more for those given the high dose.
“These data support that optimal clinical effect at 12 months may be better understood in the less severe stage 2 patients,” Klein said, noting that this will be important for planning future studies.
Novartis to now take over development of PTC518
PTC518 was well tolerated, without reports of serious side effects. The most commonly reported adverse events were symptoms of the common cold, flu, headache, and falls.
After completing PIVOT-HD, participants had the option to continue into a Phase 2b extension study (NCT06254482), in which all are being treated with PTC518 for at least 2.5 years.
Data from 21 patients already treated with PTC518 for two years — 10 at the 5 mg/day dose and 11 at the 10 mg/day dose — were compared with those from untreated patients in an observational study on Huntington’s. That study, Enroll-HD (NCT01574053), is the world’s largest observational study.
The results indicated that cUHDRS scores worsened significantly more slowly, and NfL levels decreased, in PTC518-treated patients compared with untreated patients. A measure of functionality called the Total Function Capacity (TFC) and a measure of cognition called the Symbol Digit Modalities Test (SDMT) also showed better outcomes with PTC518.
“In terms of safety … importantly, we continue to see a favorable safety and tolerability profile,” Klein said.
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.
Klein also noted, in the release, that researchers saw, at the two-year mark, “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.”
Now that PIVOT-HD is completed, Novartis will assume responsibility for PTC518’s further development, manufacturing, and commercialization. That’s all part of a license and collaboration agreement reached with PTC in December 2024.
For PTC’s part, Klein last year said the company — which is eligible for as much as $1.9 billion in revenues if certain development, regulatory and sales milestones are met — is “excited to collaborate with Novartis.”
Now, he added: “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.”
Accelerated, or conditional, approval allows a therapy to be brought to market based on early clinical data while requiring drug makers to run additional trials to prove the therapy offers clinical benefit.
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