Objective: To present results in the subset of patients with multiple system atrophy (MSA) and relevant MSA subgroups from two ampreloxetine phase 3 trials for the treatment of neurogenic orthostatic hypotension (nOH) in patients with synucleinopathies.

Background: Approximately 80% of patients with MSA are impacted by nOH and despite available treatment options many remain symptomatic. Ampreloxetine, a selective norepinephrine reuptake inhibitor has a distinct mechanism of action and may be particularly suited to patients with MSA.

Method: A longitudinal analysis was performed on MSA patients who enrolled in the Phase 3 ampreloxetine program. Patients were allowed to roll over from a 4-week randomized placebo-controlled study (SEQUOIA) to a 22-week study (REDWOOD) comprised of a 16-week open-label period and a 6-week randomized withdrawal (RW) period. Key outcome assessments were the Orthostatic Hypotension Questionnaire (OHQ) which includes the Orthostatic Hypotension Symptom Assessment (OHSA and the Orthostatic Hypotension Daily Activities Scale (OHDAS); and the orthostatic standing test. Safety and tolerability were also examined.

Results: 68 MSA patients received ampreloxetine across the program with 40 randomized into the RW period. The 40 patients had a mean reduction of -2.6 points in the OHSA composite score over 20 weeks from the start of SEQUOIA to RW entry. During the 6-week RW period there was a benefit for ampreloxetine over placebo in the OHSA composite score of -1.6 points (p-value = 0.0056), the OHQ composite score (-1.2 points; p-value = 0.0250), OHDAS item 1 (-2.0 points; p-value = 0.0147) and the 3-min standing systolic blood pressure which was 15.7 mmHg higher than placebo (p-value = 0.0157). Post hoc analyses suggest a consistent benefit across subgroups (sex, age, MSA subtype, Unified MSA Rating Scale Part IV, time since MSA diagnosis and time since nOH onset), with treatment differences ranging from 0.5 to 2.2 points in favor of ampreloxetine on the OHSA and OHQ composite scores. Ampreloxetine was well tolerated in MSA patients across the program with similar adverse event rates to placebo during each of the placebo-controlled periods.

Conclusion: Ampreloxetine may be an effective treatment for symptomatic nOH in patients with MSA, with consistent benefits observed across key subgroups including MSA subtype, disease duration, sex and age.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/an-analysis-of-subgroups-of-multiple-system-atrophy-patients-from-ampreloxetine-phase-3-trials/