Objective: To assess the acute effects of ampreloxetine on the pressor response, improvement of symptoms and safety in a daily, single, escalating doses.

Background: nOH is due to failure of the autonomic nervous system to adequately increase synaptic norepinephrine (NE) and maintain upright blood pressure (BP) following postural change. Norepinephrine reuptake inhibitors (NRI) may augment local synaptic concentrations of tonically released NE, at the vascular sympathetic neuroeffector junction, resulting in increased BP and reduced symptoms of orthostatic hypotension. Ampreloxetine is a novel NRI being investigated for the treatment of subjects with symptomatic nOH.

Method: This was a multicenter, 2 part, single-blind (Part A) and randomized, double-blind (Part B) study of ampreloxetine versus placebo. Part A was a daily, single, escalating dose design starting with placebo on Day 1, followed by escalating doses of ampreloxetine to a maximum dose of 20 mg. Escalation was based on safety, tolerability, pressor effect using seated systolic blood pressure (SBP) and change in symptoms. Part B was designed to confirm Part A results using a randomized, placebo–controlled, double-blind parallel design.

Results: 34 subjects (mean age 66 years) were enrolled in Part A of the study. 29 (85%) completed all dosing level. At 4 hrs post dose the mean [SD] of change between placebo and 10 mg dose, for standing duration was 1.6 [3.6] minutes; seated SBP was 4.9 [20.1] mmHg. The most frequently reported AEs were headache and urinary tract infection; one subject discontinued treatment due to an AE; no SAEs were reported. In Part B, 10 subjects, 5 each in the ampreloxetine and placebo arms, were enrolled. The mean and 95% CI difference in seated SBP between ampreloxetine and placebo at 4 hrs post dose was 29.9 [7.6, 52.3].

Conclusion: In subjects with nOH, single doses of ampreloxetine resulted in an acute increase in seated SBP at 4 hrs post dose and improvement in the ability to stand relative to baseline. Ampreloxetine was generally well tolerated. These results support further assessment of ampreloxetine in a multiple dose study evaluating the longer term effects on symptoms of nOH.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-2-dose-escalation-study-of-ampreloxetine-td-9855-a-norepinephrine-reuptake-inhibitor-given-once-daily-to-treat-neurogenic-orthostatic-hypotension-noh-in-subjects-with-synucleinopathies/