Trial results on Huntington’s treatment PTC518 expected soon
Findings follow FDA request for additional data, company says
One-year results from the Phase 2 PIVOT-HD clinical trial testing PTC Therapeutics’ Huntington’s disease treatment PTC518 are expected in the second quarter.
That’s according to an update from PTC, which also noted that in a December meeting with the U.S. Food and Drug Administration (FDA), the agency requested additional trial data to support the company’s plans to seek PTC518’s accelerated approval. The company expects findings from PIVOT-HD (NCT05358717) to help address that request.
With accelerated approval, regulators conditionally allow a treatment to be marketed based on preliminary data suggesting it will benefit patients. But developers need to provide additional trial data confirming the treatment does indeed lead to clinical gains for patients.
While PTC is currently in control of moving the Phase 2 trial forward, the company closed a license and collaboration agreement with Novartis in January. Under the agreement, Novartis will assume responsibility for PTC518’s development, manufacturing, and commercialization once PIVOT-HD’s placebo-controlled part is completed, which is expected by June.
Huntington’s is caused by mutations in the HTT gene that lead to production of an abnormally long huntingtin (HTT) protein that forms toxic clumps inside cells, leading to nerve cell death.
Huntington’s treatment aims to lower protein production
PTC518 is an oral small molecule designed to promote the degradation of HTT’s messenger RNA, an intermediate molecule derived from DNA that’s used as a template for protein production.
In doing so, it aims to lower production of all forms of the HTT protein, including the mutant version that drives neurodegeneration in Huntington’s, thereby easing Huntington’s symptoms and slowing disease progression.
In the December meeting, PTC shared with the FDA its plans to use reductions in HTT levels as a surrogate measure to support accelerated approval of PTC518 in the U.S. Accelerated approval relies on a surrogate outcome measure that doesn’t directly evaluate the therapy’s clinical benefit, but which is known to correlate with clinical outcomes for that patient group.
Previous Phase 1 trial data involving healthy adults and interim findings from the Phase 2 PIVOT-HD trial have demonstrated the therapy’s ability to reduce HTT levels.
While the FDA agreed on the scientific rationale for using HTT level reductions as a surrogate measure, it asked that PTC provide more clinical data, such as those being collected in PIVOT-HD, to demonstrate that lowering HTT levels correlates with clinical change in Huntington’s patients, the company said.
PIVOT-HD, launched in 2022, enrolled 252 adults, ages 25 and older, with stage 2 or 3 Huntington’s, corresponding to early- and late-intermediate stages of disease, respectively.
Participants were randomly assigned to take oral tablets of either PTC518 (5 mg or 10 mg) or a placebo, once a day for one year. It was later recommended that a third, 20-mg dosing group be added to the study.
In addition to safety, the study’s main goal was to evaluate changes in blood HTT levels after three months.
Data from the first 33 participants in the two lower-dose groups showed that the Huntington’s treatment was well tolerated and led to dose-dependent reductions in mutant HTT levels in the blood after three months.
Interim one-year findings demonstrated that the treatment continued to dose-dependently reduce levels of the faulty protein in both the blood and cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, over time.
Early evidence also showed a dose-dependent slowing of motor symptom progression and positive trends in other clinical outcome measures.
PTC518 continued to be well tolerated with longer treatment, without signs of treatment-related increases of neurofilament light chain, a marker of nerve cell damage, in the blood or CSF.
According to a company webcast, one-year data from about 100 more participants are expected in the second quarter.
Patients who complete PIVOT-HD may choose to enroll in a long-term extension Phase 2b study (NCT06254482) in which all will receive PTC518 for two years.
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