Theravance Biopharma announced that the Phase III CYPRESS study evaluating ampreloxetine in patients with symptomatic neurogenic orthostatic hypotension (nOH) associated with multiple system atrophy (MSA) failed to meet its primary endpoint, prompting the company to wind down development of the drug and accelerate a strategic review.
The registrational trial assessed whether once-daily ampreloxetine, a selective norepinephrine reuptake inhibitor, could improve symptoms of orthostatic hypotension in patients with MSA. The study’s primary endpoint was the change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score, a patient-reported outcome measure evaluating dizziness, weakness, fatigue, and other symptoms related to blood pressure drops upon standing.
According to the company, the trial did not show a statistically significant improvement in the OHSA composite score compared with placebo. As a result, Theravance said it will wind down the ampreloxetine program.
Following the setback, the board’s Strategic Review Committee is accelerating its evaluation of options to maximize shareholder value, which may include a potential sale of the company or other strategic transactions. The company also announced cost-reduction measures, including the wind-down of its research and development organization and significant workforce reductions, expected to reduce the firm’s cost base by 60%-70%, equating to around USD 70 million in savings.
Theravance said it will continue to focus on its commercial respiratory product Yupelri (revefenacin) and expects additional milestone payments from its partnered COPD therapy Trelegy Ellipta.
Research context
Ampreloxetine had been the company’s lead late-stage pipeline candidate and was being developed for symptomatic nOH, a disabling condition caused by autonomic nervous system dysfunction that leads to dangerous drops in blood pressure when standing. The condition occurs in several neurodegenerative diseases, including Parkinson’s disease, pure autonomic failure, and multiple system atrophy (MSA), where degeneration of autonomic neurons disrupts norepinephrine signaling needed to maintain vascular tone.
Current pharmacologic options for nOH are limited to symptomatic relief. Ampreloxetine was designed as a once-daily norepinephrine reuptake inhibitor intended to increase synaptic norepinephrine and improve autonomic blood pressure control. Earlier mid-stage studies suggested potential benefits in patients with MSA-associated nOH, a subgroup with particularly severe autonomic impairment and limited treatment options.
However, late-stage development in the indication has historically proven challenging. Disease heterogeneity, variability in patient-reported symptom measures such as the Orthostatic Hypotension Symptom Assessment (OHSA) score, and the progressive neurodegeneration underlying MSA complicate demonstration of sustained clinical benefit.