PIVOT-HD met its primary endpoint with significant dose-dependent reductions in blood HTT levels. How meaningful is this biomarker in establishing a disease-modifying effect, and is HTT suppression alone sufficient for regulatory consideration?

Stage 2 patients receiving PTC518 showed favorable trends in motor and functional scores over 12 and 24 months. How clinically relevant are these early changes in cUHDRS, TFC, and SDMT when compared to natural history benchmarks?

Stage 3 patients showed some inconsistencies in dose response. How should these findings be interpreted in the context of disease stage, and could disease progression stage influence future patient stratification in trials?

PTC518 lowered plasma neurofilament light (NfL) by up to 14% without spikes, suggesting neuronal protection. How reliable is NfL as a predictive biomarker for long-term outcomes in HD, and how does this data compare with other investigational agents?

The study reported no treatment-related serious adverse events or NfL spikes across 24 months. How critical is this safety consistency in a disease where patients may require lifelong therapy?

PTC518 uses a pseudoexon splicing strategy to reduce mutant HTT mRNA, following the splicing platform used in Evrysdi® for SMA. What are the implications of this splicing-based mechanism in CNS diseases like HD?

The study leveraged both placebo and ENROLL-HD natural history cohorts. How strong is the scientific rationale for using matched observational data, and can it support future regulatory filings or accelerated approval pathways?

Given the totality of biomarker and clinical data, what are the critical milestones PTC needs to reach for an accelerated approval filing? Could Stage 2 patients be the primary focus for a confirmatory trial?