Theravance Biopharma, Inc. announced new ampreloxetine data in neurogenic orthostatic hypotension (nOH) will be presented at the 2023 International Congress of Parkinson's Disease and Movement Disorders (MDS), taking place August 27-31, 2023, in Copenhagen, Denmark. Findings Presented at the 2023 MDS Congress: Ampreloxetine demonstrated the following benefits in MSA (multiple system atrophy) patients from studies 0169 [SEQUOIA] and 0170 [REDWOOD]: Clinically-meaningful and nominally statistically significant (p< 0.05) improvements over placebo were observed in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score [LS mean difference: -1.6 (95% CI: -2.7, -0.5)] and in the overall Orthostatic Hypotension Questionnaire (OHQ) composite score [LS mean difference: -1.2 (95%CI: -2.3, -0.2)] in Study 0170. Post-hoc analysis of Study 0170 indicated a consistent benefit of ampreloxetine relative to placebo across MSA subgroups including MSA sub-type (MSA-P and MSA-C), sex, age, time since MSA diagnosis, time since nOH onset, and the global MSA disability scale (UMSARS Part IV).

Subgroup benefits of ampreloxetine ranged from 0.5 to 2.2 point improvements relative to placebo across all subgroup categories and were demonstrated on the OHSA and OHQ composite scores. Ampreloxetine was well-tolerated with similar adverse event rates compared to placebo during the placebo-controlled periods of both Study 0169 and Study 0170. In a separate single-center study evaluating ampreloxetine's effects on cardiac repolarization compared to placebo, 72 healthy subjects were enrolled in a randomized, double-blind, placebo-controlled fashion.

At therapeutic (10 mg QD) and supratherapeutic (40 mg QD) doses of ampreloxetine, no clinically relevant effect on the Q-Tc interval, a measure of heart rhythm, was observed in this study, further supporting the cardiovascular safety of ampreloxetine. Study 0197 (NCT05696717) is currently enrolling. This is a registrational Phase 3, multi-center, randomized withdrawal study to evaluate the efficacy and durability of ampreloxetine in participants with MSA and symptomatic nOH after 20 weeks of treatment; the primary endpoint of the study is change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score.

The Study includes four periods: screening, open label (12-week period, participants will receive a single daily 10 mg dose of ampreloxetine), randomized withdrawal (eight-week period, double-blind, placebo-controlled, participants will receive a single daily 10 mg dose of placebo or ampreloxetine), and a long-term treatment extension. Secondary outcome measures include change from baseline in Orthostatic Hypotension Daily Activity Scale (OHDAS) item 1 (activities that require standing for a short time) and item 3 (activities that require walking for a short time). Study 0170 (NCT03829657) was a 22-week Phase 3 study comprised of a 16-week open-label period and a 6-week double-blind, placebo-controlled, randomized withdrawal period.

This study followed study 0169, a Phase 3, four week randomized, double-blind, placebo-controlled, parallel-group study of ampreloxetine in patients with symptomatic nOH. The primary endpoint for Study 0170 of treatment failure at week 6 was defined as a worsening of both Orthostatic Hypotension Symptom Assessment Scale (OHSA) question #1 and Patient Global Impression of Severity (PGI-S) scores by 1.0 point. After Study 0169 did not meet its primary endpoint, the Company took actions to close out the ongoing clinical program including Study 0170.

The study was more than 80% enrolled (n=128/154 planned) despite stopping early. The primary endpoint was not statistically significant for the overall population of patients which included patients with Parkinson's disease, pure autonomic failure and MSA (odds ratio=0.6; p-value=0.196). The pre-specified subgroup analysis by disease type suggests the benefit seen in patients receiving ampreloxetine was largely driven by MSA patients (n=40).

An odds ratio of 0.28 (95% CI: 0.05, 1.22) was observed in MSA patients indicating a 72% reduction in the odds of treatment failure with ampreloxetine compared to placebo.