Results from Theravance’s Second Phase 3 Study Has Company Narrowing Indication for Drug Once Again

Theravance Biopharma said results from the second phase 3 study, Study 0170, assessing ampreloxetine compared to placebo for the treatment of symptomatic neurogenic orthostatic hypotension, a rare and debilitating drop in blood pressure, found it failed to demonstrate statistical significance on the primary endpoint for patients overall, but showed that it did benefit a subset of patients with multiple system atrophy.

Photo: Rick Winningham, CEO of Theravance Biopharma

Neurogenic orthostatic hypotension (nOH) is a rare disorder defined as a sustained fall in blood pressure within three minutes of standing. Severely affected patients are unable to stand for more than a few seconds because of their decrease in blood pressure, leading to cerebral hypoperfusion and syncope. The condition results in a range of symptoms including dizziness, lightheadedness, fainting, fatigue, blurry vision, weakness, trouble concentrating, and head and neck pain. nOH is caused by autonomic nervous system malfunction and is associated with several underlying medical conditions including multiple system atrophy, pure autonomic failure, and Parkinson’s disease.

Multiple system atrophy (MSA) is a rare, rapidly progressive, severely debilitating, and fatal neurodegenerative disease that leads to death within a median of seven to 10 years after the onset of symptoms. MSA shares many Parkinson’s disease-like symptoms, such as slow movement, rigid muscles, and poor balance. The primary sign of multiple system atrophy is postural (orthostatic) hypotension. A person with MSA can also develop dangerously high blood pressure levels while lying down (supine hypertension). Other manifestations include urinary and bowel dysfunction, constipation, incontinence, sweating abnormalities, sleep disorders, sexual dysfunction, cardiovascular problems, and psychiatric problems. The most common causes of death in MSA are infection and cardiopulmonary complications. Currently, MSA patients receive only symptomatic and palliative therapies as there are no disease-modifying treatments and no cure.

Ampreloxetine is an experimental therapy discovered by Theravance that is a potent, long-acting, oral, once-daily norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension (nOH).

The study 0170 was a 22-week phase 3 study comprised of a 16-week open-label period followed by a six-week double-blind, placebo-controlled, randomized withdrawal period. The primary endpoint of treatment failure at week six of the randomized withdrawal period was defined as a worsening of both Orthostatic Hypotension Symptom Assessment Scale (OHSA) question #1 and Patient Global Impression of Severity (PGI-S) scores by 1.0 point.

The primary endpoint was not statistically significant for the overall population of patients, which included patients with Parkinson’s disease, pure autonomic failure and multiple system atrophy. The odds ratio suggests that patients receiving ampreloxetine had a 40 percent reduction in the odds of treatment failure compared to placebo.

The pre-specified subgroup analysis by disease type suggests the benefit seen in patients receiving ampreloxetine was largely driven by multiple system atrophy patients. An odds ratio of 0.28 was observed in MSA patients indicating a 72 percent reduction in the odds of treatment failure with ampreloxetine compared to placebo. The benefit to MSA patients was observed in multiple endpoints including OHSA composite, Orthostatic Hypotension Daily Activities Scale (OHDAS) composite, Orthostatic Hypotension Questionnaire (OHQ) composite and OHSA #1.

Patients withdrawn to placebo had a clinically relevant decrease in standing blood pressure; there was no decrease for patients remaining on ampreloxetine. While the same benefit was not apparent in patients with Parkinson’s disease or pure autonomic failure, the company continues to analyze the data to better understand this observation. Throughout the study, there was no indication of worsening of supine hypertension based on 24-hour monitoring. Data suggest that ampreloxetine was well-tolerated and no new safety signals were identified.

“MSA is a devastating and debilitating disease with no effective disease modifying treatment. There is an urgency to treat MSA patients suffering with nOH due to the impact on quality of life and the extreme caregiver burden,” said Roy Freeman, professor of Neurology, and director of the Center for Autonomic and Peripheral Nerve Disorders at Beth Israel Deaconess Medical Center, who assisted in the design and interpretation of the study. “Ampreloxetine appears to improve a narrow, but critically important group of symptoms related to blood pressure control, and along with the safety profile, may represent a potential therapy for MSA patients.”

Rick Winningham, CEO of Theravance Biopharma, said given the unmet need for MSA patients suffering from symptomatic nOH, the company is engaging potential partners and planning health authority interactions to determine a path forward in hopes of expediting ampreloxetine as a possible treatment option for people with MSA.

Author: Rare Daily Staff