Theravance Biopharma Reports New Data from Phase 2 Study of Ampreloxetine (TD-9855) in Presentation at 2019 International Association of Parkinsonism and Related Disorders (IAPRD) World Congress
Ampreloxetine is an investigational, once-daily norepinephrine reuptake inhibitor (NRI) in development for the treatment of patients with symptomatic nOH.
The IAPRD presentation reported data from the Company's completed Phase 2 clinical study, which evaluated the efficacy, durability and safety of once-daily oral ampreloxetine in patients with nOH. Following the completion of the single ascending dose portion of the study, patients entered the open-label extension phase, which was designed to evaluate improvement in patients' symptoms and impact on blood pressure.
A total of 21 patients entered the open-label extension phase of the study. As previously reported, 16 subjects completed the first four weeks of treatment and demonstrated evidence of improved nOH symptom severity by the end of four weeks of treatment. The mean reduction in symptom severity in these 16 subjects was 2.4 points at four weeks, as measured by Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 (OHSA#1, a measure of dizziness, lightheadedness or the sensation of being about to black out). Importantly, the mean symptom reduction was greatest (3.8 points) in the 13 subjects who were categorized as symptomatic due to their reporting of dizziness symptoms (OHSA#1 > 4) at baseline. The pre-defined regulatory and clinical threshold of OHSA#1 > 4 is being applied as an inclusion criterion in the ongoing Phase 3 ampreloxetine program.
New data reported at the 2019
Study data also demonstrated that ampreloxetine treatment increased symptomatic patients' standing systolic blood pressure (SBP) to normal levels at the three-minute assessment at all time points on all weekly clinic visits compared to the low pre-treatment baseline for these patients. The mean increase in standing SBP compared to baseline was > 7mmHg at the end of Week 4 and > 20mmHg at all subsequent assessment time points throughout the study. There were no drug-related serious adverse events reported during the active treatment phase of the study and ampreloxetine was generally well tolerated. Based on these results, the Company initiated registrational Phase 3 clinical trials of ampreloxetine in symptomatic nOH patients in
"The magnitude and durability of symptom improvement among this group of seriously debilitated patients is cause for optimism as it relates to the potential for ampreloxetine to serve as a much-needed treatment option in the area of nOH. Noting that an improvement of just one point in OHSA#1 is minimally clinically important, the sustained multi-point improvements witnessed in this study are impressive," stated
"We are gratified by the totality of data collected from this important study, which we believe highlights the promising therapeutic potential of ampreloxetine. These results are encouraging, even in a small number of symptomatic patients in an exploratory open-label study, and we hope that they will translate into a potential therapeutic benefit in our ongoing placebo-controlled registrational Phase 3 program for ampreloxetine. Importantly, the 3.8 point reduction in OHSA#1 score that was observed at Week 4 in symptomatic patients was critical to our pre-Phase 3 discussions with the
About the Phase 2 Study in nOH
The Phase 2 study of ampreloxetine consisted of three parts. Part A was a single ascending dose (from 1 mg up to 20 mg based on patient response) designed to evaluate impact on blood pressure and standing time for ampreloxetine as compared to placebo. Part B was a double-blind, single dose study designed to evaluate impact on blood pressure and standing time for ampreloxetine as compared to placebo. Part B was discontinued when the trial was amended to include Part C, following the enrollment of ten patients in Part B (five on ampreloxetine; five on placebo). Part C was an open label extension to Part A designed to evaluate improvement in patients' symptoms and impact on blood pressure. Responders in Part A were eligible to enroll in Part C at up to their highest tolerated Part A dose, which included 5 mg, 10 mg and 20 mg. The primary endpoint of the study was measured after four weeks, although patients were able to continue to receive medication for up to five months.
Neurogenic orthostatic hypotension (nOH) is a rare disorder defined as a sustained orthostatic fall in systolic blood pressure (SBP) of ≥ 20 mm Hg or diastolic blood pressure (DBP) of ≥ 10 mm Hg 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. A debilitating condition, nOH results in a range of symptoms including dizziness, lightheadedness, fainting, fatigue, blurry vision, weakness, trouble concentration and head and neck pain. nOH is caused by autonomic nervous system (ANS) malfunction and is associated with several underlying medical conditions including multiple system atrophy (MSA), pure autonomic failure (PAF) and Parkinson's disease (PD).
OHSA #1 is an endpoint which is part of the Orthostatic Hypotension Questionnaire, a validated scale assessing the presence of a range of hypotension-related symptoms including dizziness, weakness, problems with vision, fatigue, trouble concentrating and head/neck discomfort. It is based on a scale from 0 (no symptoms) to 10 (worst possible severity of a symptom), with reductions in OHSA points indicating symptom improvement and increases in OHSA score indicating symptom worsening. OHSA #1 specifically measures patients' dizziness, lightheadedness, feeling faint, or feeling like they might black out. OHSA #1 has been accepted as a suitable endpoint in the investigation of neurogenic orthostatic hypotension by
About Ampreloxetine (TD-9855)
Ampreloxetine is an investigational, once-daily norepinephrine reuptake inhibitor (NRI) being developed for the treatment of patients with symptomatic neurogenic orthostatic hypotension (nOH). The compound has high affinity for binding to norepinephrine transporters. By blocking the action of these transporters, ampreloxetine causes an increase in extracellular concentrations of norepinephrine.
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