PTC Says Experimental Huntington Therapy Met Primary Endpoint in Phase 2 Study

Rare Daily Staff

PTC Therapeutics said its experimental therapy PTC518 met its primary endpoint in a phase 2 study in people with stage 2 and stage 3 Huntington’s disease by reducing blood levels of a key biomarker at week 12.

Huntington’s disease (HD) is a rare, hereditary, genetic disorder of the central nervous system. It is caused by a defective gene. This gene produces a protein, called huntingtin, which is involved in the functioning of the neurons in the brain. When the gene is defective, it produces an abnormal (or mutated) huntingtin protein that is toxic and causes neuron damage and neuron death.

PTC518 is a small molecule splicing modifier that acts via a unique mechanism to promote the inclusion of a novel pseudoexon containing a premature termination codon, thus triggering huntingtin (HTT) mRNA degradation and subsequent reduction in HTT protein levels. PTC518 was discovered from PTC’s validated splicing platform.

The phase 2 PIVOT-HD study was designed as a 12-month placebo-controlled trial to assess pharmacodynamic effect and safety of PTC518 at two dose levels—5mg and 10mg—relative to placebo. Initially, the study included only Stage 2 patients. A Stage 3 cohort of similar size was subsequently added to help identify the best study population for future studies.

The primary endpoints of PIVOT-HD were total blood HTT lowering at 12 weeks and safety events. Secondary endpoints included 12-month blood HTT levels and other blood and central nervous system biomarkers, as well as changes in the Composite Unified Huntington’s Disease Rating Scale.

The 12-month data from PIVOT-HD trial stage 2 patients were consistent with the previously reported dose-dependent lowering of HTT protein and dose-dependent trends across clinical scales.

Results from the full 12-month cohort demonstrate dose-dependent lowering in blood HTT levels, with 23% at the 5mg dose level for both Stage 2 and 3 patients and 39% and 36% at the 10mg dose level for Stage 2 and 3 patients, respectively.

For Stage 2 patients, there were dose-dependent trends of benefit on clinical scales, including the Composite Unified Huntington’s Disease Rating Scale and Total Motor Score subscale. For Stage 3 patients, trends favored the 5mg dose group relative to placebo, but not the 10mg dose group, suggesting that the treatment effect may differ in Stage 3 patients relative to Stage 2 patients.

PTC518 showed a favorable safety and tolerability profile for all dose levels and disease stages with no treatment-related serious adverse events or neurofilament light chain protein spikes.

“These PIVOT-HD results confirm that PTC518 lowers huntingtin protein and shows early signals of clinical benefit with a favorable safety profile,” said Matthew Klein, CEO of PTC Therapeutics.

The company expects to discuss the potential for accelerated approval as it meets with regulators.