Objective: To assess the long-term safety and tolerability of ampreloxetine in patients with synucleinopathies (MSA, PD, and PAF) and symptomatic neurogenic orthostatic hypotension (nOH) from the OAK study (NCT04095793).

Background: Ampreloxetine, a selective norepinephrine reuptake inhibitor, has been investigated in patients with nOH due to MSA, PD, and PAF within a Phase 3 trial program, concluding with the 182-week OAK long-term extension study. Preceding Phase 3 studies, SEQUOIA and REDWOOD, established ampreloxetine’s safety profile for up to 26 weeks.

Method: This open-label extension study included patients with nOH and synucleinopathies (MSA, PD, or PAF) who completed treatment in the REDWOOD Phase 3 randomized controlled trial. Participants were administered an open-label once-daily dose of 10mg ampreloxetine. Comprehensive safety assessments were conducted during the initial 26 weeks with subsequent monitoring of adverse events, concomitant medication usage and dosing information captured beyond that timeframe. Exploratory endpoints included the EQ-5D-5L quality of life measure.

Results: The OAK study was terminated prematurely by the sponsor due to the short-term SEQUOIA trial not meeting its primary endpoint. At the time of termination, 110 patients had been enrolled, with median and maximum treatment durations of 247.5 and 735 days, respectively. Treatment discontinuation occurred in seven (6.4%) participants (3 from adverse events and 4 from patient withdrawal). Eleven (10.0%) patients experienced ≥1 drug-related treatment-emergent adverse event (TEAE), with a single case (0.9%) deemed serious. The most frequent TEAEs (>5%) were urinary tract infections (8.2%) and headaches (5.5%). Additional safety evaluations, including electrocardiograms, vital signs, laboratory parameters, and the Columbia-suicide severity scale, remained stable over the initial 26 weeks. Quality of life, as measured by the EQ-5D-5L, also remained stable throughout the same period.

Conclusion: The safety findings in this long-term study were consistent with the existing safety profile for ampreloxetine, with minimal incidences of related TEAEs and serious TEAEs. The low dropout rate and continuation of treatment for up to two years in this open-label extension study further supports the long-term safety and tolerability of ampreloxetine.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/long-term-safety-of-ampreloxetine-in-patients-with-symptomatic-neurogenic-orthostatic-hypotension/