Topline Findings
- Phase III CYPRESS Enrollment Completed: Theravance Biopharma finishes open-label patient enrollment in the pivotal trial evaluating ampreloxetine for neurogenic orthostatic hypotension in multiple system atrophy.
- Trial Design Focuses on Durability and Efficacy: The multi-center randomized-withdrawal study is assessing both short- and long-term symptom improvement, using orthostatic hypotension symptom assessment and Orthostatic Hypotension Daily Activities Scale endpoints to measure treatment impact.
- Regulatory Pathway and Next Steps: Theravance plans to release topline Phase III data in early 2026 and is preparing for an expedited NDA submission with potential priority FDA review, highlighting strategic focus on high-impact rare disease therapies.
Theravance Biopharma has announced the completion of enrollment in the open-label portion of its pivotal Phase III CYPRESS trial (NCT05696717), which is evaluating ampreloxetine for the treatment of symptomatic neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA).
The treatment has previously shown clinical evidence of improving symptoms without exacerbating hypertension. Theravance noted that the CYPRESS study represents the first randomized-withdrawal trial designed specifically for MSA patients with nOH.1
How Could Ampreloxetine Change the Treatment Paradigm of MSA Patients with nOH?
"nOH is one of the most debilitating manifestations of MSA, which affects about 40,000 patients in the US alone,” said Horacio Kaufmann, FB Axelrod professor of neurology, professor of Medicine, NYU Grossman School of Medicine, in a press release. “Yet current therapies often fail to provide lasting symptoms relief, require frequent dosing and carry a boxed warning for supine hypertension. 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.1 If these benefits are confirmed, I would expect to use ampreloxetine in the majority of my patients living with nOH due to MSA. I am encouraged that enrollment in CYPRESS, the first randomized-withdrawal trial designed specifically for the MSA population, has been completed, and I look forward to seeing the data early next year."
CYPRESS Trial Design and Endpoints
- The multi-center, randomized-withdrawal CYPRESS trial will evaluate the efficacy and durability of ampreloxetine in approximately 102 patients with symptomatic nOH due to clinically diagnosed MSA.
- The trial includes a 12-week open-label phase followed by an eight-week randomized withdrawal phase to rigorously assess durability of benefit.
- The primary endpoint of the trial is change in orthostatic hypotension symptom assessment composite score from randomized-withdrawal baseline to week eight.
- Key secondary endpoints included change from baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) item 1 at week eight post-randomization and change from baseline in OHDAS item 3 at week eight post-randomization.1,2
Disease Background and Patient Population
- According to Orphanet, patients with MSA have a median survival range of six to nine years.
- The prevalence is estimated to be between one in every 20,000 people and one in every 50,000 people.
- The most common age of onset is between the ages of 55 and 60 years.3 nOH affects approximately 80% of patients with MSA.3
- In the United States, there are an estimated 50,000 people living with MSA.1
Next Steps and Regulatory Plans
Theravance expects to release topline Phase III CYPRESS data in early 2026 and, if results are positive, plans to pursue an expedited New Drug Application submission to the FDA with a potential priority review designation.1
"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, PhD, head of Development, Theravance Biopharma, in the press release.
"Ampreloxetine is intended to target the root cause driving MSA-associated nOH by selectively inhibiting norepinephrine reuptake and demonstrated benefit in this patient population in Study 0170. The CYPRESS randomized withdrawal trial was designed with insights from Study 0170, and we are confident that, along with our careful study execution, this derisked program strongly positions us to evaluate ampreloxetine's full potential in this patient population."
References
- Theravance Biopharma Completes Enrollment in Pivotal Phase 3 CYPRESS Study of Ampreloxetine in Patients with Symptomatic Neurogenic Orthostatic Hypotension due to Multiple System Atrophy. PR Newswire. August 25, 2025. Accessed August 25, 2025. https://prnmedia.prnewswire.com/news-releases/theravance-biopharma-completes-enrollment-in-pivotal-phase-3-cypress-study-of-ampreloxetine-in-patients-with-symptomatic-neurogenic-orthostatic-hypotension-due-to-multiple-system-atrophy-302537380.html
- Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic NOH in Participants with Multiple System Atrophy (CYPRESS). Clinicaltrials.gov. Accessed August 25, 2025. https://clinicaltrials.gov/study/NCT05696717?term=CYPRESS&intr=multiple%20system%20atrophy&rank=1
- Multiple system atrophy. Orphanet. Accessed August 25, 2025. https://www.orpha.net/en/disease/detail/102
