The Huntington’s disease space saw a flurry of activity Wednesday as PTC and uniQure released data from their respective mid-phase trials.
A Background Neural blueprint network/iStock, Clayton Machado Gallego
Huntington’s disease patients haven’t had a lot of therapeutic progress to cheer about in recent years. Wednesday brought a dose of optimism—and possibly confusion—as PTC Therapeutics and uniQure released mid-phase data from their respective programs.
Huntington’s disease is caused by a CAG repeat in the first exon of the huntingtin (HTT) gene. This mutation causes brain cells to die, leading to a host of progressive cognitive, psychiatric and movement disorders, including the jerky motions (chorea) characteristic of the disease.
New Jersey–based PTC reported interim data from the II PIVOT-HD trial, showing that 10 mg of PTC518 led to a 30% reduction in mutant huntingtin (HTT) levels.
PTC518—an oral, small molecule drug developed on PTC’s splicing platform—was well-tolerated, with no treatment-related serious adverse events, the company stated in its announcement. There were also no treatment-related spikes in neurofilament light chain protein (NfL) in the cerebral spinal fluid (CSF). NfL is a widely accepted marker of neurodegeneration that has recently been validated as a surrogate biomarker in ALS.
Recently, NfL has been used as a marker of drug safety in clinical trials as treatment-related increases may reflect neuronal cell injury resulting from either on-target or off-target drug effect, Matthew Klein, PTC’s CEO, told BioSpace in an email. “This is an interesting and potentially meaningful finding that will be followed over the longer course of the study,” he said.
The PIVOT-HD study was paused in the U.S. in October 2022, with the FDA requesting additional data to support the proposed dosing and duration in the 12-month trial. Klein said PTC plans to share these data—including safety data—with the FDA to support renewed enrollment of U.S. patients in the study. PIVOT-HD is continuing in Europe.
Also on Wednesday, Dutch biotech uniQure announced an update from the U.S.-based Phase I/II trial of AMT-130, which is intended to be a one-time gene therapy for Huntington’s. AMT-130 is the first adeno-associated virus (AAV) gene therapy for Huntington’s to enter clinical trials.
Patients treated with low-dose AMT-130 saw their NfL levels fall below baseline and NfL levels were declining toward baseline after 12 months in the high-dose cohort. uniQure also reported that patients in both low- and high-dose groups saw clinical benefits compared to natural history data.
But the therapy’s effect on mutant huntingtin (mHTT) was a different story. Almost exactly year ago, uniQure reported 12-month data from the first four patients showing an average 53.8% decline in mHTT in the CSF. At 24 months, however, the reduction was just 8.1%. And in the high-dose cohort, mHTT actually increased by 39.7%, compared to 4.7% in the control group, according to Wednesday’s press release.
“We really don’t understand the noise in the high-dose cohort,” Ricardo Dolmetsch, uniQure’s president of R&D, told STAT News. AMT-130 is injected into the striatum, the region in the brain where Huntington’s is believed to manifest, and uniQure CEO Matthew Kapusta suggested that mHTT might be lowered there while continuing to be produced elsewhere, according to STAT.
Up next, uniQure expects to present new clinical data from its Phase I/II program of AMT-130, including additional follow-up data from the U.S. trial and 12-month follow-up data from low-dose patients in an adjacent EU trial.
The company expects to engage with regulators in both the U.S. and EU to discuss the data and a path to further development of AMT-130 by the first quarter of 2024.
Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.
