Theravance Biopharma presented promising new analyses from its Phase 3 program evaluating ampreloxetine for neurogenic orthostatic hypotension (nOH) at the 77th Annual Meeting of the American Academy of Neurology in San Diego. The data highlights the drug's potential as a first-in-class therapy for multiple system atrophy (MSA) patients suffering from symptomatic nOH.
The analyses, presented on April 7, 2025, focused on ampreloxetine's pharmacodynamic effects and safety profile, particularly regarding supine hypertension—a common concern with existing treatments.
Selective Mechanism Shows Durable Target Engagement
Ampreloxetine, a selective norepinephrine reuptake inhibitor, demonstrated significant pharmacodynamic effects in patients with symptomatic nOH. In Study 0169, patients receiving ampreloxetine experienced a mean 58% increase in venous plasma norepinephrine levels after 4 weeks of treatment, with MSA patients showing the most pronounced response (79% increase).
"There is a persistent unmet need for effective long-term treatments for nOH in patients with MSA," said Dr. Valeria Iodice, Honorary Associate Professor in Neurology at the National Hospital for Neurology and Neurosurgery, UCL, London. "Inadequately treated nOH is associated with rapid functional decline, and many patients fail to respond despite trials of two to three different antihypotensive agents."
The data showed that ampreloxetine's mechanism resulted in target inhibition and reduced pre-synaptic uptake of norepinephrine. During the randomized withdrawal period in Study 0170, patients who continued on ampreloxetine maintained improvements in orthostatic blood pressure, while those switched to placebo lost this benefit—confirming the drug's physiological effect.
No Worsening of Supine Hypertension
A significant finding from the analyses was ampreloxetine's favorable safety profile regarding supine hypertension. Currently, all FDA-approved pressor agents for orthostatic hypotension carry black box warnings about the risk of exacerbating supine hypertension.
Patients in Study 0169 underwent both in-clinic blood pressure measurements and remote ambulatory blood pressure monitoring. Key findings revealed:
- No worsening of supine hypertension during in-clinic visits for patients on ampreloxetine
- No worsening of overnight supine hypertension compared to placebo during home monitoring
- No difference in maximal blood pressure excursion during 24-hour monitoring between ampreloxetine and placebo groups
"nOH is a difficult condition to treat, as available pressor agents also raise blood pressure while patients are lying down, which we know increases the risk of hypertensive organ damage to the heart, brain, and kidney," explained Dr. Lucy Norcliffe-Kaufmann, Theravance Biopharma's Executive Director of Clinical Science. "This new analysis of ambulatory blood pressure data, which is the 'gold-standard' method for detection, is very promising."
MSA Patients Show Strongest Response
The previous Phase 3 program included two trials (Study 0169 and Study 0170) in patients with symptomatic nOH across multiple conditions, including MSA, Parkinson's Disease, and pure autonomic failure. While Study 0169 did not meet its primary endpoint in the overall population, pre-specified subgroup analysis revealed that MSA patients derived the greatest benefit.
In Study 0170, MSA patients showed an odds ratio of 0.28 (95% CI: 0.05, 1.22), indicating a 72% reduction in the odds of treatment failure with ampreloxetine compared to placebo. This benefit was observed across multiple endpoints, including OHSA composite, OHDAS composite, OHQ composite, and OHSA #1.
These findings supported the initiation of the ongoing CYPRESS study (NCT05696717), a registrational Phase 3 trial specifically focused on patients with nOH and MSA.
About Multiple System Atrophy and nOH
MSA is a progressive brain disorder affecting movement, balance, and autonomic nervous system function. Approximately 50,000 MSA patients in the US experience nOH symptoms at a rate of 70-90%. Neurogenic orthostatic hypotension is defined as a fall in systolic blood pressure of ≥20 mm Hg or diastolic blood pressure of ≥10 mm Hg within 3 minutes of standing.
Severely affected patients cannot stand for more than a few seconds due to decreased blood pressure, leading to cerebral hypoperfusion and syncope. The condition causes debilitating symptoms including dizziness, lightheadedness, fainting, fatigue, blurry vision, weakness, trouble concentrating, and head and neck pain.
The CYPRESS Study
The ongoing CYPRESS study is a registrational Phase 3, multi-center, randomized withdrawal study evaluating ampreloxetine's efficacy and durability in MSA patients with symptomatic nOH. The primary endpoint is change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score after 20 weeks of treatment.
The study includes four periods: screening, a 12-week open-label period with 10 mg daily ampreloxetine, an 8-week randomized withdrawal period (double-blind, placebo-controlled), and a long-term treatment extension.
Theravance Biopharma has received Orphan Drug Designation for ampreloxetine for treating symptomatic nOH in MSA patients and plans to file an NDA for full approval if the CYPRESS study results are supportive.
Potential First-in-Class Therapy
Ampreloxetine has the potential to become a first-in-class therapy for MSA patients with symptomatic nOH. Its unique benefits include increased norepinephrine levels, favorable impact on blood pressure, clinically meaningful and durable symptom improvement, and no signal for worsening supine hypertension.
"Ampreloxetine's unique mechanism of action suggests that it may be an effective therapy for relieving symptomatic nOH without the side effect of high blood pressure in the supine position," noted Dr. Norcliffe-Kaufmann.
For MSA patients who currently lack effective long-term treatment options, ampreloxetine represents a promising therapeutic approach that could address a significant unmet medical need while avoiding the safety concerns associated with existing treatments.
