The investigational agent was well-tolerated, with no new safety signals and no indication of worsening of supine hypertension based on 24-hour monitoring.
Despite a failure to meet the overall primary end point, a subanalysis from the phase 3 Study 0170 (NCT03829657) showed that treatment with ampreloxetine (Theravance Biopharma) reduced the odds of treatment failure in patients with multiple system atrophy (MSA) who suffer from symptomatic neurogenic orthostatic hypotension (nOH).1
In a prespecified subgroup analysis consisting solely of patients with MSA, ampreloxetine, a long-acting, oral, once-daily norepinephrine reuptake inhibitor, resulted in an odds ratio of 0.28 (95% 0.05-1.22) relative to placebo, indicating a 72% reduction in the odds of treatment failure. Overall, there was no indication of worsening of supine hypertension or emergence of any new safety signals.
"MSA is a devastating and debilitating disease with no effective disease-modifying treatment. There is an urgency to treat MSA patients suffering with nOH due to the impact on quality of life and the extreme caregiver burden,” Roy Freman, MBChB, professor of neurology, director, Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, said in a statement. “Ampreloxetine appears to improve a narrow, but critically important group of symptoms related to blood pressure control, and along with the safety profile, may represent a potential therapy for MSA patients." Freeman assisted in the design and interpretation of the study.1
Study 0170 was a 22-week trial comprised of a 16-week open-label period and a 6-week double-blind, placebo-controlled, randomized withdrawal period. Investigators used treatment failure, 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, at the end of the double-blind period as the primary end point. With more than 80% (128 of 154) of the cohort enrolled before stopping early, the final sample included patients with MSA (n = 40), Parkinson disease (PD, n = 68), and pure autonomic failure (PAF, n = 20).
When factoring in all 3 cohorts of patients, ampreloxetine did not meet its primary end point of statical significance at the end of the 6-week period (odds ratio (OR), 0.6; P = .196). The OR suggested that patients receiving the study drug had a 40% reduction in the odds of treatment failure compared with placebo.
Patients with MSA, who represented the largest treatment benefit among the subgroups, demonstrated benefit from the active drug on several end points, including OHSA composite (least square [LS] mean difference, -1.6; 95% CI, -2.7 to -0.5), Orthostatic Hypotension Daily Activities Scale (OHDAS) composite (LS mean difference, -0.8; 95% CI, -2.1 to 0.4), and OHSA question #1 (LS mean difference, (LS mean difference, -1.5; 95% CI, -3.2 to 0.2). Amprelexetine-treated patients also showed benefits on Orthostatic Hypotension Questionnaire (OHQ) composite (LS mean difference, -1.2; 95% CI, -2.3 to -0.2), which included OHSA and OHDAS domains.2
At the end of the 16-week open-label period, 53% (n = 103) of patients experienced treatment-emergent adverse events (AEs), a majority of which were mild to moderate. Furthermore, 8% (n = 16) of patients reported serious AEs, although none of them were related to ampreloxetine. Supine hypertension, myocardial infarction, and atrial arrythmia were all documented as AEs of special interest. Notably, there were 5 deaths in the study, none related to study drug.
In the 6-week double-blind randomized withdrawal period, there were 4 serious AEs reported in the amprelexetine treatment group, 2 of which were related to study drug. There were 2 deaths recorded, 1 which was unrelated to study drug and another that was unknown and imputed as related. In the placebo group, 1 of 2 serious AEs were reported as study drug-related. Between the 2 arms, treatment-emergent AEs were similar during this period, most of which were mild to moderate. There were no AEs of special interest and no clinically significant difference in laboratory values, ECG, ambulatory blood pressure monitoring, and vital signs.
"At Theravance Biopharma, we are guided by patient outcomes. Given the clear unmet need for MSA patients suffering from symptomatic nOH, we are engaging potential partners and planning health authority interactions to determine a path forward in hopes of expediting ampreloxetine as a possible treatment option for people with MSA," Rick E. Winningham, chief executive officer, Theravance Biopharma, said in a statement.1