An Investigational Monograph on Ampreloxetine (DB15348): A Precision Approach to Neurogenic Orthostatic Hypotension in Multiple System Atrophy

I. Executive Summary

Ampreloxetine (developmental code name TD-9855) is an investigational, orally active, small molecule drug being developed as a highly selective norepinephrine reuptake inhibitor (NRI). Its defining pharmacological characteristic is a prolonged plasma half-life of 30–40 hours, which supports a convenient once-daily dosing regimen and provides sustained, stable inhibition of the norepinephrine transporter (NET). This pharmacokinetic profile is central to its therapeutic potential and distinguishes it from existing treatments for neurogenic orthostatic hypotension (nOH).

The clinical development of ampreloxetine has been marked by a critical strategic pivot. Initially investigated for a broad range of nOH etiologies, including Parkinson's disease (PD) and pure autonomic failure (PAF), early Phase 3 trials failed to meet their primary endpoints in the overall population. However, pre-specified subgroup analyses revealed a robust and statistically significant efficacy signal exclusively in patients with nOH secondary to multiple system atrophy (MSA). This finding reshaped the entire development program, transforming ampreloxetine into a candidate for a precision medicine approach. The rationale for this specificity lies in the distinct pathophysiology of MSA, which involves central autonomic failure with relative sparing of the peripheral sympathetic neurons—the precise target for a norepinephrine reuptake inhibitor.