After 20 weeks of therapy with ampreloxetine (Theravance Biopharma, South San Francisco, CA) participants in a phase 2 clinical trial (NCT02705755) had sustained improvements in symptoms from neurogenic orthostatic hypotension (nOH). In the phase 2 study, participants with nOH who completed a single ascending dose study (1-20 mg/day) were treated with ampreloxetine (5, 10, or 20 mg/day) on an open-label basis. After 4 weeks of treatment, 16 participants had a mean reduction in symptom severity of 2.4 points on the Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 that measures dizziness, lightheadedness, or the sensation of being about to black out.
For the 13 individuals who were symptomatic at baseline, the mean symptom reduction measured after 4 weeks of treatment was 3.8 points. Treatment with ampreloxetine increased standing systolic blood pressure to normal levels at the 3-minute assessment in participants who were symptomatic at the beginning of the study. A mean increase of more than 20 mm Hg was seen at all visits after the fourth week of treatment. After another 16 weeks of treatment, the 11 individuals who remained in the trial durable improvements in symptom severity.
Discontinuation of treatment resulted in a return of symptoms at a level comparable to participants baseline levels. No drug-related serious adverse events reported during the active treatment phase of the study and ampreloxetine was generally well tolerated.
"The magnitude and durability of symptom improvement among this group of seriously debilitated patients is cause for optimism as it relates to the potential for ampreloxetine to serve as a much-needed treatment option in the area of nOH. Noting that an improvement of just one point in OHSA#1 is minimally clinically important, the sustained multi-point improvements witnessed in this study are impressive," stated Horacio Kaufmann, MD, Felicia B. Axelrod Professor of Dysautonomia Research, Department of Neurology at New York University School of Medicine.
A phase 3 registrational trial (NCT03750552) is underway including a randomized double-blind placebo-controlled study with a 4-week endpoint, a 4-mont open label phase, and a 6-week randomized, placebo-controlled withdrawal study. Ampreloxetine is an investigational, once-daily norepinephrine reuptake inhibitor (NRI) with high affinity for norepinephrine transporters. By blocking the action of these transporters, ampreloxetine causes an increase in extracellular concentrations of norepinephrine.