Theravance Biopharma has reached a critical milestone in developing a potential first-in-class treatment for a devastating neurological condition, announcing completion of enrollment in its pivotal Phase 3 CYPRESS study of ampreloxetine for symptomatic neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA). The company expects topline results in Q1 2026 and plans an expedited NDA submission with priority FDA review if data prove supportive.
Addressing Critical Unmet Medical Need
Multiple system atrophy affects approximately 50,000 patients in the United States, with 70-90% experiencing nOH symptoms. The condition is characterized by sudden drops in blood pressure upon standing, leading to dizziness, fainting, and blurry vision that can result in falls, disability, and loss of independence. Despite its severity, effective and durable treatment options specifically designed for nOH in MSA patients remain lacking.
"nOH is one of the most debilitating manifestations of MSA, which affects about 40,000 patients in the U.S. alone. Yet current therapies often fail to provide lasting symptoms relief, require frequent dosing and carry a boxed warning for supine hypertension," said Dr. Horacio Kaufmann, F.B. Axelrod Professor of Neurology and Professor of Medicine at NYU Grossman School of Medicine.
Promising Early Results Drive Optimism
Ampreloxetine demonstrated compelling efficacy signals in the earlier Study 0170, where MSA patients showed a 72% reduction in the odds of treatment failure compared to placebo (odds ratio of 0.28; 95% CI: 0.05, 1.22). The benefit was observed across multiple endpoints including OHSA composite, Orthostatic Hypotension Daily Activities Scale composite, Orthostatic Hypotension Questionnaire composite, and OHSA #1.
"Ampreloxetine is designed to address the underlying cause of nOH. In Study 0170, it showed compelling improvement in OHSA composite score without worsening supine hypertension," Dr. Kaufmann noted. "If these benefits are confirmed, I would expect to use ampreloxetine in the majority of my patients living with nOH due to MSA."
Innovative Study Design and Mechanism
The CYPRESS study (NCT05696717) represents the first randomized-withdrawal trial designed specifically for the MSA population. The global, multi-center study enrolled patients across four continents in a 12-week open-label portion, followed by an eight-week randomized-withdrawal phase where responders are randomized 1:1 to continue ampreloxetine or switch to placebo. The primary endpoint measures change in orthostatic hypotension symptom assessment (OHSA) composite score from randomized-withdrawal baseline to Week 8.
Ampreloxetine works as a selective norepinephrine reuptake inhibitor, targeting the root cause driving MSA-associated nOH. The once-daily dosing regimen of 10 mg offers potential advantages over current therapies that require frequent dosing and carry boxed warnings for supine hypertension.
Regulatory Pathway and Market Potential
The drug has received Orphan Drug Designation in the United States, underscoring the significant unmet medical need in symptomatic nOH due to MSA. If approved, ampreloxetine could address a critical gap as the first therapy with potential to provide durable benefit for the estimated 40,000 U.S. patients with symptomatic nOH in MSA.
"Completing enrollment in CYPRESS marks a major step toward bringing this potentially transformative therapy to patients with symptomatic nOH due to MSA – an underserved patient population in dire need for a new, effective and durable treatment with a favorable safety profile," said Áine Miller, Ph.D., Head of Development at Theravance Biopharma.
Previous Trial Context
The CYPRESS study builds on lessons learned from earlier trials. Study 0169, a Phase 3 four-week study in 195 patients with symptomatic nOH, did not meet its primary endpoint for the overall population including Parkinson's disease, pure autonomic failure, and MSA patients (odds ratio=0.6; p-value=0.196). However, pre-specified subgroup analysis revealed that benefits were largely driven by MSA patients, leading to the focused CYPRESS trial design.
The unique benefits of ampreloxetine treatment reported in MSA patients from Study 0170 included increased norepinephrine levels, favorable impact on blood pressure, clinically meaningful and durable symptom improvement, and no signal for worsening of supine hypertension.
