Ampreloxetine Data in Neurogenic Orthostatic Hypotension to be Presented at the 33rd International Symposium on the Autonomic Nervous System
- Totality of Evidence from the Phase 3 Clinical Program Demonstrates Ampreloxetine was Effective in Treating Symptoms and Improving Activities of Daily Living in MSA Patients with Neurogenic Orthostatic Hypotension
- Safety Profile of Ampreloxetine was Similar to that of Placebo
"These ampreloxetine data are encouraging for patients with MSA suffering with neurogenic orthostatic hypotension. There is an urgency to treat MSA patients with nOH due to the impact on quality of life and the extreme caregiver burden. Ampreloxetine appears to broadly impact a critical group of symptoms related to blood pressure control and may represent a potential therapy for MSA patients," said
Disclosure: Dr. Freeman is a consultant serving as an advisor for drug development and clinical trial design for Theravance Biopharma.
Study results presented at the 2022 AAS meeting, session 1 include:
Clinical Effectiveness of Ampreloxetine
- Clinically meaningful and nominal statistically significant (p < 0.05) differences relative to placebo in MSA patients on the following endpoints in Study 0170:
- Orthostatic Hypotension Symptom Assessment Scale (OHSA) composite score (LS mean difference: -1.6 [95% CI: -2.7, -0.5])
- Orthostatic Hypotension Questionnaire (OHQ) composite score (LS mean difference: -1.2 [95% CI: -2.3, -0.2])
- Orthostatic Daily Activities Scale (OHDAS) Item 1 – Standing a short time (LS mean difference: -2.0 [95% CI: -3.6, -0.4])
- Symptomatic improvement in patients with MSA was broadly demonstrated on the individual components of the OHSA composite in Study 0170 including:
- dizziness (LS mean difference: -1.5 [95% CI: -3.2, 0.2])
- vision (LS mean difference: -1.7 [95% CI: -3.2, -0.3])
- weakness (LS mean difference: -0.7 [95% CI: -2,3, 0.9])
- fatigue (LS mean difference: -1.5 [95% CI: -3.1, 0.1])
- trouble concentrating (LS mean difference -1.8 [95% CI: -3.3, -0.4])
- head/neck discomfort (LS mean difference: -2.2 [95% CI: -3.7, -0.7])
- Durability of clinical effect was demonstrated by ampreloxetine in MSA patients as reflected in the reduction of the OHSA composite score and OHDAS item 1 over the course of 20 weeks (5 months) across the Phase 3 program (studies 0169 and 0170 open-label period).
Blood Pressure and Pharmacodynamics
- Standing systolic blood pressure across all studied patients (including MSA, Parkinson's disease and Pure Autonomic Failure) with nOH was maintained by ampreloxetine and worsened after withdrawal to placebo [treatment difference: 8.6 mm Hg; p<0.05] during the randomized withdrawal phase of study 0170. The benefit was most pronounced in patients with MSA [treatment difference: 15.7 mm Hg; p < 0.05].
- Ampreloxetine increased levels of plasma norepinephrine (NE) [47%; p< 0.05] and decreased levels of dihydroxyphenyl glycol (DHPG) [-22%; p < 0.05] over the course of 4 weeks in patients with nOH, consistent with its mechanism of action. The increase in NE [57%; p< 0.05] was especially notable in the sub-group of patients with MSA.
Safety and Tolerability
- Ampreloxetine was generally well-tolerated in patients with nOH, including in the sub-group of MSA patients. Treatment-emergent adverse events were similar between the placebo and ampreloxetine groups with no clinically significant differences in laboratory parameters, ECG changes, ambulatory BP monitoring, and vital signs.
- No adverse events of supine hypertension were observed in the Phase 3 randomized withdrawal period (Study 0170).
Ampreloxetine (TD-9855) is an investigational, once-daily norepinephrine reuptake inhibitor in development for the treatment of symptomatic nOH in patients with multiple system atrophy (MSA). Phase 3 results (Study 0170) showed a benefit to MSA patients in the study that was observed in multiple endpoints including Orthostatic Hypotension Symptom Assessment (OHSA) composite, Orthostatic Hypotension Daily Activities Scale (OHDAS) composite, Orthostatic Hypotension Questionnaire (OHQ) composite and OHSA #1. The Company held a Type C meeting with the FDA in
Patients with MSA may benefit from ampreloxetine treatment due to the presence of central autonomic pathway degeneration and intact peripheral postganglionic fibers that is specific to MSA. As a NET re-uptake inhibitor, ampreloxetine may enhance the function of the residual sympathetic nerves resulting in increases in norepinephrine levels, standing BP, and reduction in symptoms of nOH in patients with MSA.
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. The primary endpoint 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 (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).1 There are approximately 50,000 MSA patients in the US2 and 70-90% of MSA patients experience nOH symptoms.3 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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Chief Financial Officer
2 2019 IQVIA Claims Analysis;
3 Mathias CJ, et al. J Neurol 1999 Oct;246(10):893-8
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