Pridopidine maintenance of Total Functional Capacity (TFC) is associated with stabilization of plasma Neurofilament Light (NfL) levels

Michal Geva1, Deniz Akinc Abdulhayoglu2, Noga Gershoni-Emek1, Y. Paul Goldberg1, Bruno Boulanger2 and Michael R. Hayden1,3

1 Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
2 National eHealth Living Lab, Leiden University Medical Center, Leiden, the Netherlands
3 Huntington Center Topaz Overduin, Katwijk, the Netherlands
4 Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands
5 Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands

Background
Pridopidine is an oral drug candidate in clinical development for HD and ALS. Pridopidine selectively binds and activates the Sigma-1 receptor (S1R), which enhances several neuroprotective pathways that are impaired in neurodegenerative diseases. In the PRIDE-HD Ph2 trial, pridopidine 45 mg bid maintained Total Functional Capacity (TFC) 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 or degeneration. In HD, biofluid NfL levels increase with disease progression, serving as a biomarker that correlates with longitudinal decline in function, cognition, and brain atrophy. Reductions in NfL associate with clinical effectiveness of treatment (e.g. Multiple Sclerosis). To date, no treatment has shown maintenance or decrease of NfL levels in HD.

Aim
Evaluate the effect of pridopidine on plasma NfL levels, and its association with TFC in early HD patients from PRIDE-HD at 52 weeks.

Methods
Available 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 week 52 (by Simoa methodology). The association between NfL and TFC (available TFC data from placebo n=41, pridopidine n=37) was modelled by a linear mixed model.

Results
At baseline, both placebo and pridopidine groups show similar demographics, CAG repeat number and plasma NfL levels. Higher CAG repeats correlate with higher baseline NfL levels (p=0.003). Pridopidine treatment demonstrates maintenance in TFC vs. placebo at 52 weeks (ΔTFC +0.09, vs. -1.0, p=0.0006). Placebo shows an annual increase in NfL (ΔNfL +0.05 log2 pg/ml), similar to the annual increase in the TRACK-HD observational study (ΔNfL +0.06 log2 pg/ml). Pridopidine 45 mg bid shows stabilization of NfL levels at 52 weeks (ΔNfL -0.06 log2 pg/ml). In placebo, the increase in NfL correlates with a decrease (worsening) in TFC (p=0.02). In the pridopidine 45 mg bid group, stabilization of plasma NfL is associated with maintenance of TFC.

Conclusion
Pridopidine 45 mg bid stabilizes plasma NfL levels in association with maintenance of TFC in early HD patients. The effect of pridopidine on plasma NfL is a pre-specified endpoint in the ongoing Ph3 PROOF-HD trial.