PTC518 lowers mutant HTT, slows disease progression: Interim data

PIVOT-HD showed no spikes from treatment in NfL, a nerve cell damage marker

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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An investigational oral therapy from PTC Therapeutics called PTC518 safely and effectively reduces levels of the mutant huntingtin protein (mHTT) in Huntington’s disease patients, while being linked to trends of slower disease progression.

That’s according to one-year interim data from the ongoing Phase 2a PIVOT-HD clinical trial (NCT05358717), which also showed there were no treatment-related spikes in neurofilament light chain (NfL), a marker of nerve cell damage.

“The evidence of both [biomarker] and early clinical effects at month 12 along with the continued favorable tolerability profile supports the promise of PTC518 to address the need for an effective and safe disease-modifying therapy for patients living with Huntington’s disease,” PTC CEO Matthew B. Klein, MD, said in a company press release.

Based on these promising data, PTC plans to begin designing a Phase 3 trial, Klein said in a recent company webcast where he shared the findings.

The new results also prompted the U.S. Food and Drug Administration to lift its partial clinical hold on the trial’s enrollment in the U.S., which remained active in Australia and Europe.

In Huntington’s, mutations in the HTT gene lead to a mutant form of the huntingtin protein that’s thought to form toxic clumps and drive nerve cell death.

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What is PTC518 doing to mHTT levels?

PTC518 is an oral small molecule designed to disrupt the production of all forms of huntingtin, including mHTT. It works by promoting the degradation of HTT’s messenger RNA (mRNA), the intermediate molecule derived from DNA that guides protein production.

Data from a previous Phase 1 trial in healthy adults showed PTC518 reduced levels of HTT mRNA by 30% to 50%.

PIVOT-HD is evaluating the therapy’s safety and efficacy against a placebo in up to 252 adults with stage 2 Huntington’s, an early-intermediate disease phase, or early stage 3, which represents slightly more advanced disease.

Participants are being randomly assigned to receive tablets of either one of two PTC518 doses (5 or 10 mg), or a placebo, once daily for a year. Based on safety data from these two doses, the study’s drug safety monitoring board may recommend testing a 20 mg dose.

Meeting the trial’s three-month goals, interim findings from the first 33 participants, all with stage 2 Huntington’s, showed the therapy was well tolerated, reduced blood mHTT levels in a dose-dependent manner, and could access the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord.

Newly presented data concerned the first 32 stage 2 patients who completed one year in the trial — 10 were given the low dose, 12 were treated with the high dose, and 10 were given a placebo.

Blood mHTT levels dropped by 22% in the 5 mg group and by 43% in the 10 mg group, and remained stable after six to nine months. Blood mHTT levels in the placebo group rose by 14%.

Paralleling this, CSF mHTT levels dropped by 9% in the placebo group, 21% in the 5 mg group, 43% in the 10 mg group.

Over the whole year, there were no treatment-related spikes in blood or CSF NfL levels, with blood levels actually dropping by 3 to 7% across all three groups.

“Based on natural history studies, [blood] NfL increases on average 10 to 12% per year in stage 2 patients” with fluctuations over time, Klein said in the webcast.

Slowing disease progression

PTC518 treatment also showed a dose-dependent slowing of motor symptom progression, as indicated by the Total Motor Score (TMS). TMS worsened by 4.9 points with the placebo, 2 points in the 5 mg group, and 1.3 points in the 10 mg group, representing a reduced TMS progression of more than 70% compared with placebo, Klein said.

“In stage 2 patients, the TMS is one of the disease measures that tend to be the most relevant in measuring disease progression, and to see this signal of favorable [brain and spinal cord] clinical effect in such a small number of subjects at month 12 is clearly encouraging,” Klein said.

PTC518 also was associated with positive trends on other key clinical scales of overall functional capacity, including the composite Unified Huntington’s Disease Rating Scale (cUHDRS) and total functional capacity. Particularly, mean cUHDRS scores worsened by 0.91 points in the placebo group, by 0.62 points in the 5 mg group, and 0.47 points in the 10 mg group.

“The PTC518 treatment effect relative to placebo in this initial group of subjects is notable,” Klein said.

PTC518 continued to be well tolerated after a year, with no dose-limiting toxicities. The most common adverse events included common cold, influenza, headache, and falls, with similar rates across all groups, including the placebo.

Klein also presented available data from the 36 stage 2 patients and 45 stage 3 patients who completed three months of the trial. In these patients, the therapy also safely resulted in a dose-dependent lowering of mHTT protein in the blood.

Patients completing PIVOT-HD may enter an open-label extension study (NCT06254482), where all will receive the therapy for up to about 2.5 years.