PTC518 treatment shows benefits for Huntington’s in PIVOT-HD trial
Oral therapy safely lowers HTT levels in Phase 2a study: Early data
PTC Therapeutics’ Huntington’s disease treatment candidate PTC518 is well-tolerated and lowers blood levels of the huntingtin protein (HTT) in people with the neurodegenerative disorder.
That’s according to interim three-month data from the Phase 2a PIVOT-HD trial (NCT05358717), which found that use of the investigational oral therapy did not lead to any sudden increases in neurofilament light chain, known as NfL, a marker of nerve cell damage. The analysis also showed evidence of PTC518 in the cerebrospinal fluid, or CSF, the liquid that surrounds the brain and spinal cord, as intended.
“We are very pleased with the encouraging data from the PIVOT-HD interim analysis demonstrating dose-dependent HTT lowering, desired [PTC518] CSF exposure and a favorable tolerability profile without evidence of treatment-related serious adverse events or CSF NfL spikes,” Matthew Klein, MD, CEO of PTC, said in a company press release.
As enrolled participants continue treatment for up to one year, the global study is still recruiting additional Huntington’s patients at sites across Europe and in Australia. Patients must be age 25 or older, and can not have undergone treatment within 90 days prior to screening. Some will receive a third, higher dose of the therapy.
U.S. enrollment in the trial — which began in April 2022 — remains paused after regulatory authorities requested additional preclinical data late last year. The company hopes the new data will support renewed U.S. enrollment.
Treatment now being tested in stage 2 Huntington’s patients
Huntington’s disease is caused by mutations in the HTT gene, driving the production of a mutant form of the HTT protein (mHTT) that leads to nerve cell death.
PTC518 is an oral small molecule that works to disrupt production of all forms of the HTT protein, including mHTT, by modifying a cellular process called RNA splicing.
RNA splicing is one part of the complex chain of events through which the information contained in DNA gives rise to a functional protein. Ultimately, by interfering with that process, PTC518 causes the degradation of an intermediate molecule needed to produce HTT, called messenger RNA, or mRNA.
In an earlier Phase 1 trial, PTC518 was found to dose-dependently reduce HTT mRNA by 30%-50% among healthy adults.
Now, the Phase 2a PIVOT-HD trial is testing the treatment candidate against a placebo in up to 162 adults with Huntington’s.
The study initially recruited Huntington’s patients with stage 2 disease, which corresponds to an early-intermediate disease phase. It has since opened recruitment to patients in early stage 3, who have slightly more advanced disease.
All participants are being randomly assigned to receive tablets of either PTC518 — at doses of 5 mg or 10 mg — or a placebo once per day for one year. All countries in which the trial is active have also cleared enrollment for a higher, 20 mg dose group.
The goal of the trial’s first part, spanning three months, was to assess the treatment’s pharmacology, pharmacodynamics (effects on the body), and distribution within the body. In terms of pharmacodynamic effects, scientists were looking for how well PTC518 could lower HTT mRNA and protein levels.
The new interim findings, which Klein presented in a recent company update, concerned three-month data from the first 33 participants in PIVOT-HD. The 17 men and 16 women, who had a mean age of 46.8, all had stage 2 disease.
These results showed a dose-dependent reduction in HTT protein in blood cells with PTC518 relative to the study’s start. Those levels dropped by 21% in the 5 mg group and by 30% in the 10 mg group. In turn, patients given the placebo saw their HTT levels increase by 12% over three months.
Similar dose-dependent effects were seen for HTT mRNA levels at three months, with a drop of 27% with the lower dose and 29% with the higher dose.
Reductions in the levels of mHTT specifically also were “similar, as expected given that PTC518 is not selective” for either form, Klein said.
Ultimately, the company hopes to see comparable mHTT reductions in the cerebrospinal fluid — with the ultimate target HTT protein reduction in the CSF being between 30%-50%, Klein noted.
Treatment lowers blood HTT levels in Huntington’s patients by 30%
Previous Phase 1 trial data involving the healthy volunteers indicated that PTC518 levels were higher in the CSF than in the blood, confirming that the therapy is able to reach the brain and that it does not flow back out — “an incredibly important requisite for treating a whole-brain disease like [Huntington’s],” Klein said.
While CSF HTT levels have not been measured yet in treated Huntington’s patients, PTC518 itself reached concentrations that are about 50% higher in the CSF than in the blood at its 10-mg dose, the data showed.
“With a 30% reduction in HTT protein recorded in peripheral blood cells at the 10 mg dose level, and the approximately 50% higher drug exposure levels in the [CSF],” HTT protein reduction “could be as high as 45%,” Klein said.
The therapy was generally well-tolerated, with no reports of serious treatment-related adverse events, no treatment discontinuations due to adverse events, and no signs of nerve damage outside the brain and spinal cord.
We … look forward to the 12-month data readout of these initial subjects, at which time we can learn more about the longer-term effects of PTC518 treatment on key disease biomarkers.
The most common adverse events in the PTC518 and placebo groups were respiratory tract infection and headache.
NfL level reductions are a known marker of a treatment’s efficacy, but a spike in the protein can also reflect unintended nerve cell damage caused by a treatment. Three-month data showed that CSF NfL levels were not increased with PTC518, and in fact tended to decrease with treatment.
“This is an interesting, potentially meaningful treatment benefit finding that of course will be followed over the longer course of the study,” Klein said.
“In summary, all key objectives of this interim data analysis were met,” Klein added.
In the trial’s second part, participants will be followed for nine more months, during which HTT, mHTT, and NfL levels will be measured in bodily fluids, as well brain volume by MRI — which is reduced with Huntington’s.
“We … look forward to the 12-month data readout of these initial subjects, at which time we can learn more about the longer-term effects of PTC518 treatment on key disease biomarkers,” Klein said.
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