Precision therapy with ampreloxetine for neurogenic orthostatic hypotension in multiple system atrophy

ObjectiveA pre-specified subgroup analysis of ampreloxetine (oral, 10 mg/once-per-day) for neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA). BackgroundThe degeneration of the central autonomic network underlies neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA), which leads to disability. The pathology shows relative sparing of the peripheral autonomic neurons. Despite adherence to treatment many patients remain symptomatic. Ampreloxetine is a novel, long-acting, selective, norepinephrine re-uptake inhibitor that allows for once daily dosing to precisely target residual peripheral autonomic neurons. Based on the hypothesis that MSA patients would be most responsive to ampreloxetine, we performed a pre-specified subgroup analysis of the MSA cohort. MethodsREDWOOD (NCT03829657) was an IRB-approved, phase 3, placebo-controlled, randomized withdrawal trial conducted at 76 international clinics. The trial had a 16-week open-label period with responders continuing into a double-blind 1:1 randomized 6-week withdrawal phase. Outcome measures included symptom burden captured on the 10-item OH-Questionnaire (OHQ), blood pressures, and catecholamine assays. The pre-specified subgroup analysis included all randomly assigned MSA patients. ResultsIn total, 73 MSA patients entered the program. Forty (61%) met enrichment criteria and went on to randomize. At the end of the open-label phase, their average OHQ symptom assessment (OHSA) composite score improved by 2.6 points from the pre-treatment baseline values. At week 6 of randomization, symptoms remained stable in the ampreloxetine group but worsened on placebo (mean difference OHSA composite score: -1.6 points; p=0.0056). Walking for a short time showed similar changes favoring ampreloxetine (-2.0 points; p=0.0147). Standing 3-minute blood pressure remained unchanged from open-label in the ampreloxetine group (systolic: 5.6{+/-}4.14; diastolic: 3.7{+/-}2.89 (SE) mmHg), but dropped in the group withdrawn to placebo (systolic: -10.0{+/-}4.45, diastolic -6.0{+/-}3.09 mmHg). The catecholamine profile showed target engagement of norepinephrine transporter-inhibition by ampreloxetine. There were no safety concerns nor observed increases in supine blood pressure. ConclusionIf the ongoing phase 3 study confirms the safety and efficacy, ampreloxetine would be the first example of a precision medicine approach for the treatment of nOH in MSA.