Fully Enrolled CYPRESS Phase 3 Trial to Test Ampreloxetine in Symptomatic Neurogenic Orthostatic Hypotension of MSA

Horacio Kaufmann, MD

A new phase 3 study, dubbed CYPRESS (NCT05696717), testing the therapeutic potential of ampreloxetine (Theravance Biopharma) in patients with symptomatic neurogenic orthostatic hypotension (nOH) due to multiple system atrophy (MSA), has completed enrollment. If successful, data from the study is expected to fuel a new drug application (NDA) submission, coming in early 2026.¹

nOH is one of the most common and disabling autonomic symptoms in MSA, a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia, and widespread autonomic dysfunction. CYPRESS, a large-scale trial, is a multicenter study testing the efficacy and durability of ampreloxetine, a once-daily, selective norepinephrine reuptake inhibitor, in a cohort of 102 patients with symptomatic nOH due to clinically diagnosed MSA.

CYPRESS includes a screening period, 12-weekl open-label period, an 8-week randomized, double-blind withdrawal period, and a long-term extension. Investigators will use change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score as the primary outcome, with secondary outcomes that include change in Orthostatic Hypotension Daily Activity Scale (OHDAS) item 1 (activities that require standing for a short time) and item 3 (activities that require walking for a short time).

"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," Horacio Kaufmann, F.B. Axelrod Professor of Neurology and Professor of Medicine at the NYU Grossman School of Medicine, said in a statement.¹ "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."

Prior to CYPRESS, Ampreloxetine was previously tested in 2 phase 3 studies, dubbed SEQUOIA (Study 0169; NCT03750552) and REDWOOD (Study 0170; NCT03829657). Both studies assessed the efficacy and safety of ampreloxetine in symptomatic nOH, but Study 0169 was a short, 4-week placebo-controlled trial focused on initial efficacy and safety, whereas Study 0170 followed as a longer 22-week study with an open-label phase and randomized withdrawal to evaluate sustained benefit.

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All told, Study 0169 did not meet its primary end point, forcing the company to voluntarily step in and close out the ongoing clinical program, which included Study 0170. In Study 0169, treatment with ampreloxetine failed to separate itself from placebo (OR, 0.6; P = .196) on the primary end point of OHSA item 1 in the overall population, which included patients with Parkinson disease, pure autonomic failure, and MSA.²

A greater look into the subgroups of Study 0169 revealed that the benefit from ampreloxetine was largely driven by those with MSA (n = 40). Using multiple end points, including OHSA composite, OHDAS composite, Orthostatic Hypotension Questionnaire composite, and OHSA item 1, the study authors recorded an odds ratio of 0.28 (95% CI, 0.05-1.22) in patients with MSA, indicating a 72% reduction in the odds of treatment failure with ampreloxetine relative to placebo.

Kaufmann added, "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."¹

CYPRESS accepts those aged 30 and older with a confirmed diagnosis of possible or probable MSA, either parkinsonian or cerebellar subtype, who also meet diagnostic criteria for nOH. Eligible participants must demonstrate a sustained blood pressure drop on standing or tilt-table testing, have moderate functional impairment (UMSARS Part IV ≤4), report significant symptoms of dizziness/lightheadedness (OHSA item 1 ≥4), and be able to provide informed consent while adhering to study requirements, including contraception if applicable.³

Patients are excluded if they have systemic illnesses causing autonomic neuropathy (except well-controlled type 2 diabetes meeting strict criteria), unstable or severe cardiovascular disease, glaucoma, significant psychiatric or cognitive impairment, or recent neurological events. Additional exclusions include use of prohibited medications (MAOIs, strong CYP1A2 modulators, >1 preventive migraine therapy), recent changes to orthostatic hypotension treatment, substance abuse, uncontrolled comorbidities, active malignancy, abnormal labs indicating organ dysfunction, or prior hypersensitivity to ampreloxetine.

REFERENCES
1. Theravance Biopharma Completes Enrollment in Pivotal Phase 3 CYPRESS Study of Ampreloxetine in Patients with Symptomatic Neurogenic Orthostatic Hypotension due to Multiple System Atrophy. News release. Theravance Biopharma. August 25, 2025. Accessed August 27, 2025. https://www.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
2. Theravance Biopharma, Inc. Announces Top-line Results from a Phase 3 Study of Ampreloxetine in Patients with Symptomatic Neurogenic Orthostatic Hypotension. News release. Theravance Biopharma. September 15, 2021. Accessed August 27, 2025. https://investor.theravance.com/news-releases/news-release-details/theravance-biopharma-inc-announces-top-line-results-phase-3
3. Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic NOH in Participants with Multiple System Atrophy (CYPRESS). Clinicaltrials.gov. Updated December 27, 2024. Accessed August 27, 2025. https://clinicaltrials.gov/study/NCT05696717