To determine the impact of ampreloxetine (oral, 10 mg/day) on supine hypertension as assessed by ambulatory blood pressure (BP) monitoring.

Subjects with nOH due to alpha-synucleinopathies (n=186) were recruited into a 4-week double-blind placebo-controlled parallel-group trial (NCT 03829657).  Supine hypertension was assessed with two methods: 1) in-office after 10-mins supine rest and 2) throughout the night (nocturnal) using ambulatory BP monitoring at three time points: screening (pre-treatment) and day-7 and day-21 in the randomized phase; then graded as: absent <140, mild 140-159, moderate 160-179, or severe >180 mmHg.

Satisfactory ambulatory BP recordings at two or more timepoints were available in 80 subjects (n=48 Parkinson disease, n=22 multiple system atrophy, n=10 pure autonomic failure). Diagnostic subtype and age/sex were similar in the placebo (n=50) and ampreloxetine (n=30) groups. Mean pre-treatment nocturnal BP was not different (127.2±17.0 vs. 127.3±16.9 mmHg, respectively). In the randomized phase, nocturnal BP was unchanged from baseline in both the ampreloxetine-treated and placebo-treated groups at day-7 and day-21. Shift table analysis showed no worsening in the severity of supine hypertension on ampreloxetine. No significant differences were observed in office supine BP.

We saw no signal for worsening of supine hypertension on ampreloxetine in patients with alpha-synucleinopathies and nOH. This suggests that, if the ongoing phase 3 study confirms safety and efficacy, ampreloxetine may be the first drug to treat nOH without exacerbating supine hypertension, which should not worsen intravascular volume loss overnight or add to the risk of target organ damage.