Phase 2a Randomized Controlled Trial of TPN-101, A Nucleoside Reverse Transcriptase Inhibitor, in Progressive Supranuclear Palsy.

BACKGROUND: Preclinical and human brain postmortem studies indicate that progressive supranuclear palsy (PSP) is associated with increased expression of the retrotransposon Long Interspersed Nuclear Element-1 (L1Hs). L1Hs activity initiates an innate immune response that leads to neuroinflammation and neurodegeneration, which can be attenuated by inhibiting the L1Hs-encoded reverse transcriptase. TPN-101 is a potent inhibitor of the L1Hs reverse transcriptase. OBJECTIVE: The objective of this study was to assess the safety, pharmacokinetics, and biomarker and clinical effects of TPN-101 in patients with PSP. METHODS: A double-blind, placebo-controlled, parallel-group study randomly assigned patients with probable PSP to receive TPN-101 100, 200, or 400 mg, or placebo daily for 24 weeks. Following the double-blind period, all patients received open-label TPN-101 400 mg daily for 24 weeks. The primary outcome was the incidence and severity of treatment-emergent adverse events. Biomarker, clinical, and TPN-101 pharmacokinetic assessments were conducted throughout the study. RESULTS: Forty-two patients were randomly assigned to TPN-101 100 mg (N = 11), 200 mg (N = 10), 400 mg (N = 11), or placebo (N = 10). TPN-101 was well tolerated, with no notable safety differences between any drug dose and placebo. Greater reductions in cerebrospinal fluid levels of neurofilament light chain with increasing dose were seen in patients taking TPN-101 during the double-blind period, compared with an increase in the placebo arm. There were no differences among the treatments on the Progressive Supranuclear Palsy Rating Scale during the double-blind period. CONCLUSIONS: The safety, pharmacokinetics, and reductions in biomarkers of neuroinflammation and neurodegeneration warrant future trials powered to detect clinical effects of TPN-101 in PSP. © 2026 International Parkinson and Movement Disorder Society.