Objective: To assess the efficacy and durability using validated symptom questionnaire OHQ, and safety of ampreloxetine, given once-daily to treat neurogenic orthostatic hypotension (nOH) in subjects with synucleinopathies.

Background: nOH is due to failure of the autonomic nervous system to adequately increase synaptic norepinephrine (NE) to maintain upright blood pressure (BP). A norepinephrine reuptake inhibitor (NRI) could 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 24-week open-label Phase 2 multicenter study of subjects with nOH. After a single-dose escalation phase, responders were treated with ampreloxetine (3 to 20 mg) taken orally once-daily for up to 20 weeks and followed for 4 weeks thereafter. Primary endpoint for efficacy was OHSA#1 at Week 4, durability was assessed at Week 20 and following withdrawal of treatment at Week 24.

Results: 21 subjects were enrolled in the open-label phase (mean age 64 years; 57% MSA). Of these, 16 (76%) completed the Week 4 assessment, 11 (52%) completed Week 20 and 10 (48%) were assessed at Week 24. The mean [SD] improvement from baseline in OHSA#1, OHSA and OHDAS composite scores are provided below. Table 1 Table 2 The most frequently reported AEs were urinary tract infection (24%), hypertension (19%), and headache (14%). Two subjects (10%) discontinued treatment due to AEs and 5 (24%) reported SAEs, none considered related to the study medication.

Conclusion: In subjects with nOH, ampreloxetine demonstrated clinically meaningful improvements in OHSA#1 at Week 4. The improvement in OHSA#1 was sustained through Week 20. Symptoms reverted back to baseline during the 4-week withdrawal. A similar trend was observed in OHSA and OHDAS composite scores.  Ampreloxetine was generally well-tolerated.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-2-study-of-the-efficacy-durability-and-safety-of-ampreloxetine-td-9855-a-norepinephrine-reuptake-inhibitor-given-once-daily-to-treat-neurogenic-orthostatic-hypotension-noh-in-subjects-w/