Theravance Biopharma to Present New Ampreloxetine Data at the 34th International Symposium on The Autonomic Nervous System
"The results of this anchor-based analysis of prior ampreloxetine studies underscore the clinical relevance of the Orthostatic Hypotension Symptom Assessment domain of the Orthostatic Hypotension Questionnaire and further substantiate its use as a primary endpoint in clinical studies," said
Data will be presented in a poster session on
- Kaufmann H, et al. Poster #95
Evaluating clinically meaningful changes in the Orthostatic Hypotension Symptom Assessment domain of the Orthostatic Hypotension Questionnaire
Data Presented at the 2023 AAS Annual Meeting:
Key observations from this anchor-based analysis of the ampreloxetine Phase 3 studies, Study 0169 [SEQUOIA] and Study 0170 [REDWOOD], include the following:
- Two measures of patient clinical status served as anchors to the Orthostatic Hypotension Symptom Assessment (OHSA) composite score for the analysis. Patient global assessment of change (PGI-C) at Week 4 served as an anchor in Study 0169 and patient global assessment of severity (PGI-S) at Week 6 of the randomized withdrawal period served as an anchor in Study 0170.
- The OHSA composite score was shown to correlate with both PGI-C and PGI-S, providing additional support for its use as an appropriate endpoint when evaluating nOH symptoms.
- Clinically meaningful thresholds of an improvement of 0.9 to 1.3 points and a worsening of 0.7 to 1.1 points in the OHSA composite score were identified.
The 1.6 point benefit demonstrated by ampreloxetine relative to placebo in multiple system atrophy (MSA) patients during the randomized withdrawal period of Study 170 exceeds the OHSA composite score thresholds established in the presented analysis.2
The OHSA composite score was chosen as the primary efficacy endpoint in the Phase 3 CYPRESS study, which is currently enrolling patients. This anchor-based analysis model will aid in the interpretation of clinically meaningful changes to the OHSA composite score observed in CYPRESS. Further, establishment of an anchor-based, clinically meaningful change in the OHSA composite primary endpoint will be important for clinicians, regulators, and payors.
Ampreloxetine, an investigational, once-daily norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA). The unique benefits of ampreloxetine treatment reported in MSA patients from Study 0170 included an increase in norepinephrine levels, a favorable impact on blood pressure, clinically meaningful and durable symptom improvement, and no signal for supine hypertension. The company has been granted an orphan drug designation in the US and, if results support it, plans to file an NDA for full approval based on the Phase 3 CYPRESS study.
About CYPRESS (Study 0197), a Phase 3 Study
Study 0197 (NCT05696717) is currently enrolling. This is a registrational Phase 3, multi-center, randomized withdrawal study to evaluate the efficacy and durability of ampreloxetine in participants with MSA and symptomatic nOH after 20 weeks of treatment; the primary endpoint of the study is change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score. The Study includes four periods: screening, open label (12-week period, participants will receive a single daily 10 mg dose of ampreloxetine), randomized withdrawal (eight-week period, double-blind, placebo-controlled, participants will receive a single daily dose of placebo or 10 mg ampreloxetine), and a long-term treatment extension. Secondary outcome measures include change from baseline 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).
About Study 0170, a Phase 3 Study
Study 0170 (NCT03829657) was a 22-week Phase 3 study comprised of a 16-week open-label period and a 6-week double-blind, placebo-controlled, randomized withdrawal period. This study followed study 0169, a Phase 3, four week randomized, double-blind, placebo-controlled, parallel-group study of ampreloxetine in patients with symptomatic nOH. The primary endpoint for Study 0170 of treatment failure at week 6 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. After Study 0169 did not meet its primary endpoint, the Company took actions to close out the ongoing clinical program including Study 0170. The study was more than 80% enrolled (n=128/154 planned) despite stopping early. The primary endpoint was not statistically significant for the overall population of patients which included patients with Parkinson's disease, pure autonomic failure and MSA (odds ratio=0.6; p-value=0.196). The pre-specified subgroup analysis by disease type suggests the benefit seen in patients receiving ampreloxetine was largely driven by MSA patients (n=40). An odds ratio of 0.28 (95% CI: 0.05, 1.22) was observed in MSA patients indicating a 72% 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 (read more about the data here).
About Multiple System Atrophy (MSA) and Symptomatic Neurogenic Orthostatic Hypotension (nOH)
MSA is a progressive brain disorder that affects movement and balance and disrupts the function of the autonomic nervous system. The autonomic nervous system controls body functions that are mostly involuntary. One of the most frequent autonomic symptoms associated with MSA is a sudden drop in blood pressure upon standing (nOH).3 There are approximately 50,000 MSA patients in the US4 and 70-90% of MSA patients experience nOH symptoms.5 Despite available therapies, many MSA patients remain symptomatic with nOH.
Neurogenic orthostatic hypotension (nOH) is a rare disorder defined as a fall in systolic blood pressure of ⩾20 mm Hg or diastolic blood pressure of ⩾10 mm Hg, within 3 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. A debilitating condition, nOH results in a range of symptoms including dizziness, lightheadedness, fainting, fatigue, blurry vision, weakness, trouble concentrating, and head and neck pain.
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2 Data from MSA patients at week 6 of the randomized withdrawal period of Study 0170.
5 Delveinsight MSA Market Forecast (2023); Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple systems atrophy, CJ Mathias (1999).
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