Open-label phase 2 study to explore durability of effect and safety of once-daily oral ampreloxetine (TD-9855), a norepinephrine reuptake inhibitor, for symptomatic treatment of neurogenic orthostatic hypotension in subjects with synucleinopathies

Objective: To explore the durability of effect and safety of once-daily oral ampreloxetine for the symptomatic treatment of neurogenic orthostatic hypotension (nOH) in subjects with synucleinopathies. Background: Inadequate norepinephrine (NE) release in nOH causes blood pressure to fall on standing and debilitating symptoms of cerebral hypoperfusion. Ampreloxetine, a novel, longer-acting, NE reuptake inhibitor, potentiates the effects of endogenous NE, and may improve symptoms of nOH. Design/Methods: In an open-label, phase 2, exploratory, multicenter study, subjects received open-label ampreloxetine (3–20 mg) once-daily for up to 20 weeks, with 4-week follow-up after stopping ampreloxetine and restarting alternative pressor agents. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 (OHSA#1; dizziness, lightheadedness, feeling faint; OHSA and Orthostatic Hypotension Daily Activities Scale (OHDAS) composite scores, and Patient Global Impression of Severity and Change (PGI-S, PGI-C, respectively). Results: Seventeen symptomatic subjects (baseline OHSA#1 score \u003e4) were enrolled (mean age, 65 years). At Week 4, mean (SD) improvement on OHSA#1 was −3.8 (3.1) points; ~77% of subjects reported ≥1-point improvement (minimal clinically important difference). At Week 20, mean improvement was −3.1 (3.0) points; ~86% reported ≥1-point improvement. Symptom improvement was observed as early as Week 1 and was sustained throughout the study. Deterioration to baseline symptom severity was seen by the end of the 4-week follow-up period. Similar trends were seen in OHSA and OHDAS composite scores, PGI-S, and PGI-C. Most common adverse events were urinary tract infection (24%), hypertension (19%), and headache (14%), with no study-drug related serious adverse events. Conclusions: Ampreloxetine showed durable symptom improvement in symptomatic subjects with nOH over 20 weeks, with return to baseline symptom severity after stopping ampreloxetine. Ampreloxetine was well tolerated with a favorable safety profile. These encouraging open label findings are being evaluated further in ongoing Phase 3, double blind, confirmatory studies in subjects with nOH and synucleinopathies. Disclosure: Dr. Kaufmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Lundbeck, Theravance Biopharma US Inc, and Biogen. Dr. Kaufmann has received personal compensation in an editorial capacity for Clinical Autonomic Research. Dr. Kaufmann has received research support from Theravance Biopharma US Inc.Dr. Biaggioni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Lundbeck, Theravance Biopharma, US, Inc.. Dr. Biaggioni has received research support from Lundbeck (investigator-initiated grant) and Theravance Biopharma, US, Inc. (Clinical Trial). Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Theravance Biopharma US, Inc.. Dr. Wang holds stock and/or stock options in Theravance Biopharma, Inc.. Dr. Haumann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Theravance Biopharma US Inc. Dr. Haumann holds stock and/or stock options in Theravance Biopharma Inc.Dr. Vickery has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Theravance Biopharma Ireland Limited. Dr. Vickery holds stock and/or stock options in Theravance Biopharma, Inc..