NET-Inhibition with Ampreloxetine, Blood Pressure, and Catecholamines in Patients with Neurogenic Orthostatic Hypotension
Valeria Iodice1, Meredith Bryarly2, Tadhg Geurin3, Ross Vickery3, Lucy Norcliffe-Kaufmann3, Italo Biaggioni4, Horacio Kaufmann5
1National Hospital for Neurology and Neurosurgery, 2UT Southwestern, 3Theravance Biopharma, 4Vanderbilt, Professor of Medicine and Pharmacology, David Robertson Professor in Autonomic Disorders, 5NYU Langone Health - NYU Dysautonomia Center
Objective:
To determine the impact of ampreloxetine (oral, 10 mg/day) on orthostatic blood pressures (BP) and venous norepinephrine levels in patients with alpha-synucleinopathies.
Background:
In most patients with neurogenic orthostatic hypotension (nOH), adequate symptomatic relief is not achieved with available pressor agents. Ampreloxetine is a novel, long-acting, norepinephrine reuptake inhibitor being tested as a treatment for nOH in phase III trials.
Design/Methods:
We conducted 2 back-to-back trials of ampreloxetine, including a phase III placebo-controlled randomized withdrawal study in 203 subjects with symptomatic nOH caused by alpha-synucleinopathies (NCT 03829657). After 16-weeks of open-label treatment subjects were randomized 1:1 to 6-weeks of placebo or ampreloxetine. BP measurements were obtained supine and standing. Plasma catecholamine levels and metabolites were measured.
Results:
Across studies, after 4-weeks on ampreloxetine, venous norepinephrine levels were significantly increased compared to placebo (geometric mean ratio [GMR]±SE): 1.47+0.11), whereas venous DHPG, the main intraneuronal metabolite, were decreased (GMR±SE: 0.78±0.04). Of the 128 subjects that maintained symptomatic improvement at the end of the open-label period, 64 were assigned to continue ampreloxetine and 64 were withdrawn to placebo. Age/sex and diagnostic subtype were equally distributed between the assigned treatment groups. After 6-weeks of randomization, standing BP at 3-minutes of standing was significantly lower than at the end of open-label treatment in the group assigned to placebo (systolic: -7.9±2.90, diastolic -4.0±1.87 mmHg), whereas BP remained unchanged from the end of open-label in the group assigned to continue on ampreloxetine (systolic: 0.7±2.86 p=0.0303, diastolic: 0.9±1.85, p=0.0540).
Conclusions:
The catecholamine profile observed on treatment with ampreloxetine showed target engagement of NE transporter-inhibition. After 16-weeks of open-label treatment, withdrawal of ampreloxetine was associated with a fall in standing BP. norepinephrine reuptake inhibition with ampreloxetine resulted in a sustained improvement in orthostatic BP, which was lost in patients that withdrew to placebo.
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