Neurogenic orthostatic hypotension (NOH) is a rare, chronic, and debilitating drop in blood pressure upon standing that is associated with Parkinson’s disease, multiple-system atrophy, and pure autonomic failure. Droxidopa (Northera, Chelsea Therapeutics) is a synthetic amino acid precursor of norepinephrine indicated for the treatment of orthostatic dizziness or lightheadedness in adult patients with symptomatic NOH caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Droxidopa was approved as oral therapy in February 2014 under the FDA’s accelerated approval program.
As a norepinephrine precursor, droxidopa is metabolized to norepinephrine by dopa-decarboxylase, causing an increase in blood pressure by inducing peripheral and venous vasoconstriction. Clinical studies examined the efficacy of droxidopa in both short- and long-term periods. Two studies in the package insert showed a treatment effect of droxidopa at week one, but none of the studies demonstrated continued efficacy beyond two weeks of treatment.
Study 306B was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 147 subjects with symptomatic NOH and Parkinson’s disease. Eligible patients had symptoms of NOH and a decrease of at least 20 mm Hg systolic or 10 mm Hg diastolic within three minutes after standing. A two-week dose titration period, in which subjects received either placebo or 100 or 600 mg of droxidopa three times a day, was followed by an eight-week treatment period. Efficacy was measured using the Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 score (dizziness, lightheadedness, feeling faint, and feeling like you might black out) at week one. At week one, subjects showed a statistically significant mean 0.9-unit decrease in dizziness with droxidopa versus placebo (p=0.028); however, the effect did not persist beyond week one.
Study 301 was a multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study that included an initial open-label dose titration period, a seven-day washout period, and a randomized, double-blind, seven-day treatment period. Eligibility criteria were the same as for study 306B, but subjects also had to be considered a responder. Efficacy was measured using the Orthostatic Hypotension Questionnaire (OHQ), a patient-reported outcome that measures symptoms of NOH and their impact on the patient’s ability to perform daily activities that require standing and walking. A statistically significant treatment effect was not demonstrated on OHQ (treatment effect of 0.4 unit, p=0.19). Patients showed a 0.7-unit decrease in their dizziness score on OHSA Item #1 with droxidopa versus placebo (p=0.06).