Ampreloxetine fails to meet the primary endpoint in the Phase 3 CYPRESS trial for neurogenic orthostatic hypotension in multiple system atrophy, prompting Theravance Biopharma to discontinue the program while focusing on respiratory assets YUPELRI and TRELEGY.
Written By: Sana Khan BPharm
Reviewed By: Pharmacally Editorial Team
Theravance Biopharma has reported topline results from the Phase 3 CYPRESS study evaluating ampreloxetine for the treatment of symptomatic neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA). The trial did not meet its primary efficacy endpoint, prompting the company to discontinue further development of the investigational therapy.
The Phase 3 CYPRESS study assessed the efficacy and durability of ampreloxetine, a once-daily norepinephrine reuptake inhibitor designed to increase norepinephrine signaling and improve blood pressure control in patients with neurogenic orthostatic hypotension. The primary endpoint measured the change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score at Week 8 during the double-blind randomized withdrawal phase.
According to the topline results, the trial failed to demonstrate a statistically significant improvement in the OHSA composite score compared with placebo. Secondary endpoints, including measures from the Orthostatic Hypotension Daily Activity Scale (OHDAS) evaluating daily activities requiring standing or short-distance walking, showed similar trends at Week 8.
Despite the lack of clinical efficacy, physiological markers suggested that the drug remained pharmacologically active. Changes in blood pressure, heart rate, and norepinephrine levels indicated a consistent pressor effect. Ampreloxetine was also generally well tolerated, and the safety profile remained consistent with previous studies, with no new safety signals reported, including no evidence of worsening supine hypertension.
Given the failure to achieve the primary endpoint, Theravance Biopharma has decided to wind down the ampreloxetine development program. The company stated that additional analyses of the CYPRESS dataset will be conducted with external experts to determine whether any aspects of the data could support further regulatory discussions, although no additional development plans have been announced.
Commenting on the results, Rick E. Winningham, Chief Executive Officer of Theravance Biopharma, acknowledged the disappointment surrounding the outcome, particularly for patients with this rare neurological disorder who were hoping for new treatment options.
While the ampreloxetine program is being discontinued, the company continues to derive value from its commercial respiratory portfolio. YUPELRI® (revefenacin) inhalation solution, a once-daily nebulized long-acting muscarinic antagonist approved in the United States for maintenance treatment of chronic obstructive pulmonary disease (COPD), remains a key revenue-generating asset. The product recorded U.S. net sales of $70.6 million in the fourth quarter of 2025, representing a 6% year-over-year increase, with full-year 2025 sales reaching $266.6 million, up 12% compared with 2024.
Theravance also maintains exposure to TRELEGY, the blockbuster triple-therapy inhaler marketed by GSK for COPD and asthma. Global TRELEGY sales reached approximately $3.91 billion in 2025, triggering milestone payments to the company. Continued strong commercial performance of both respiratory therapies remains central to the company’s financial outlook following the discontinuation of the ampreloxetine program.
The CYPRESS study (NCT05696717) was a registrational Phase 3, multi-center randomized withdrawal trial designed to evaluate the efficacy of ampreloxetine in patients with symptomatic neurogenic orthostatic hypotension associated with multiple system atrophy after 20 weeks of treatment.
Reference
Theravance Biopharma Reports Phase 3 CYPRESS Study Did Not Meet Primary Endpoint; Board Accelerates Strategic Review and Announces Cost Reduction Actions, 03 March 2026, https://investor.theravance.com/news-releases/news-release-details/theravance-biopharma-reports-phase-3-cypress-study-did-not-meet
Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic nOH in Participants with Multiple System Atrophy (CYPRESS), ClinicalTrials.gov ID NCT05696717, https://clinicaltrials.gov/study/NCT05696717
About Writer
Sana Jamil Khan, B.Pharm
She is a pharmacy graduate with a keen interest in clinical research, pharmacovigilance, and medical writing, with a growing focus on publication and scientific content development. In her words, she is passionate about translating complex medical data into clear, evidence-based communication.