Objective: To confirm: 1) clinical efficacy and safety of once-daily oral ampreloxetine in a 4-week double-blind (DB), placebo-controlled (PC) study (NCT03750552); 2) durability of efficacy and safety in a 22-week ampreloxetine study (16 weeks open-label [OL], 6-week DB/PC, randomized withdrawal [RW]) (NCT03829657).

Background: Impaired sympathetic response to upright posture occurs in synucleinopathies, with decreased norepinephrine (NE) release, blood pressure (BP) fall on standing (neurogenic orthostatic hypotension; nOH) and cerebral hypoperfusion. By inhibiting NE reuptake at the neurovascular junction, ampreloxetine increases NE availability on sympathetic activation. In Phase 2 studies, ampreloxetine has shown durable improvement from baseline in standing BP and nOH symptoms.

Method: 1) 4-week DB study (target enrollment=188): Eligible subjects are those diagnosed with nOH due to multiple system atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure; >30 yrs; lightheadedness/dizziness symptom burden >4 on Orthostatic Hypotension Symptom Assessment Item 1 (OHSA #1); residual post-ganglionic sympathetic function (plasma NE >100 pg/ml). Subjects are randomized to placebo or ampreloxetine 10 mg for 4 weeks. 2) 22-week OL/RW study (target enrollment=258): Completers of the 4-week study and new subjects are eligible. Continued eligibility will be assessed by ≥2-point OHSA #1 improvement after 4 weeks of OL ampreloxetine, study-drug compliance, and OHSA #1 score <7 prior to entering RW period. Subjects may continue ampreloxetine for ≤3.5 years in OL extension (NCT04095793).

Results: Key endpoints for 4-week DB study are change in OHSA #1, falls, and Patient Global Impression of Change (PGI-C); for OL/RW study, composite of OHSA #1 and Patient Global Impression of Severity (PGI-S), and daily activity. Other assessments include BP, MSA-/PD-specific measures, quality of life, and safety.

Conclusion: Ampreloxetine Phase 3 studies: 1) are complementary in their objectives (efficacy vs durability), duration (4 vs 22 weeks), and design (DB/PC vs OL/RW with responder enrichment); 2) enroll subjects most likely to benefit from NE reuptake inhibition; 3) offer robust testing to confirm ampreloxetine efficacy, safety and durability in nOH. Enrollment is ongoing.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ampreloxetine-td-9855-a-long-acting-norepinephrine-reuptake-inhibitor-nri-for-the-treatment-of-neurogenic-orthostatic-hypotension-noh-in-subjects-with-synucleinopathies-phase-3-clinical-progr/