Background Pridopidine is a safe, well tolerated oral drug candidate in clinical development for HD and ALS. Pridopidine selectively activates the Sigma-1 receptor (S1R). S1R activation is neuroprotective, regulating vital cellular processes impaired in neurodegenerative diseases. Post-hoc analysis of the PRIDE-HD Ph2 trial shows pridopidine 45 mg bid maintains functional capacity at 52 weeks in early HD patients (TFC 7-13) (Δ vs. placebo 1.16, p=0.0003).
Neurons release neurofilament light (NfL) protein upon neuronal injury. In HD, NfL levels in plasma and CSF increase with disease progression, correlating with longitudinal decline in function, cognition, and brain atrophy. NfL is a biomarker of disease progression in HD. A decrease in NfL is associated with clinical effectiveness of treatment in neurodegenerative diseases (i.e. Multiple Sclerosis). To date, no treatment has shown maintenance or a decrease in NfL levels of HD patients.
Aim Evaluate the effect of pridopidine on plasma NfL levels, and whether this effect associates with TFC in PRIDE-HD.
Methods Plasma samples from early HD patients, treated with placebo (n=34) or 45 mg bid (n=31), were analyzed for NfL levels at baseline and wk 52 (by Simoa methodology). The relationship between NfL and TFC was modelled by a linear mixed model.
Results The placebo group shows an increase in NfL (Δ NfL 0.05 log2 pg/ml), similar to the reported annual increase from the observational TRACK HD study (Δ NfL 0.057 log2 pg/ml). The 45 mg bid group shows stabilization of NfL levels, with -0,06 log2 pg/ml Δ NfL.
In the placebo group, an inverse correlation between NfL and TFC is obtained, showing an increase in NfL with a decrease in TFC (ΔTFC -1 and ΔNfL 0.05 log2 pg/ml, p=0.02). In the 45 mg bid group, stabilization of plasma NfL associates with maintenance of TFC (ΔTFC + 0.09 and ΔNfL -0.06 log2 pg/ml).
Conclusions Pridopidine 45 mg bid stabilizes plasma NfL levels in association with maintenance of TFC in early HD.
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