TD-9855 · program
Ampreloxetine for Multiple System Atrophy
- FDA Orphan Drug Designation (Symptomatic NOH In Patients With MSA; Announced May 2023)
Indications for TD-9855: Multiple System Atrophy · Discontinued Fibromyalgia · Discontinued Attention-deficit/hyperactivity disorder · Discontinued
Ampreloxetine (TD-9855), a once-daily norepinephrine reuptake inhibitor, for symptomatic neurogenic orthostatic hypotension (nOH) in multiple system atrophy.
Development timeline
- missedPhase 3 CYPRESS did not meet its primary endpoint (change in OHSA composite score at Week 8 of the double-blind randomized-withdrawal period); secondary endpoints showed similar trends; consistent pressor effect, generally well tolerated, no supine-hypertension signal.↗
- After SEQUOIA and REDWOOD missed in the mixed population, the program narrowed to MSA: CYPRESS (NCT05696717) start date per ClinicalTrials.gov (the 10-Q says initiated Q1 2023; registry start date used).
- missedREDWOOD Phase 3 did not meet its primary endpoint in the overall nOH population (PD, PAF, MSA); prespecified subgroup analysis suggested benefit driven by MSA patients.↗
- missedSEQUOIA 4-week Phase 3 RCT in symptomatic nOH did not meet its primary endpoint; no supine-hypertension signal.↗
- SEQUOIA (NCT03750552, Study 0169) first participant enrolled 2019-01-24 — start of the Phase 3 program.
- Phase 2 study 0145 (NCT02705755) in nOH (MSA, PD, PAF) started per ClinicalTrials.gov.
Readouts
- 2026-03-03ReportedTopline datamissedNCT05696717
Phase 3 CYPRESS did not meet its primary endpoint (change in OHSA composite score at Week 8 of the double-blind randomized-withdrawal period); secondary endpoints showed similar trends; consistent pressor effect, generally well tolerated, no supine-hypertension signal. ↗
- 2022-04-30ReportedTopline datamissedNCT03829657
REDWOOD Phase 3 did not meet its primary endpoint in the overall nOH population (PD, PAF, MSA); prespecified subgroup analysis suggested benefit driven by MSA patients. ↗
- 2021-09-30ReportedTopline datamissedNCT03750552
SEQUOIA 4-week Phase 3 RCT in symptomatic nOH did not meet its primary endpoint; no supine-hypertension signal. ↗
Clinical trials in Multiple System Atrophy
NCT056967170197Phase 3Activen=102
Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic nOH in Participants With Multiple System Atrophy (CYPRESS)
NCT040957930171Phase 3Discontinuedn=110
Phase 3 Open-Label Extension Study of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure (OAK)
NCT038296570170Phase 3Discontinuedn=203
Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure (REDWOOD)
NCT037505520169Phase 3Completedn=195
Clinical Effect of Ampreloxetine (TD-9855) for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure (SEQUOIA)
NCT027057550145Phase 2Completedn=34
TD-9855 Phase 2 in Neurogenic Orthostatic Hypotension (nOH)
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Ampreloxetine oral once-daily ADHD Phase 2: 5 mg once daily, or 10 mg titrated to 20 mg once daily (oral capsules), 42 days. Fibromyalgia Phase 2: 5 mg or 20 mg once daily up to 6 weeks. nOH Phase 2 (NCT02705755): escalating doses over 5 days, median 10 mg once daily over 20 weeks. CYPRESS dose not verified from an opened source. | Oral | Once daily | — |
Mechanism of action
Inhibitor of the norepinephrine transporter (NET, SLC6A2) with lesser serotonin transporter (SERT, SLC6A4) activity and weak dopamine transporter activity. Human recombinant transporter binding: pKi 8.8 (NET), 8.5 (SERT), 6.7 (DAT); uptake inhibition pIC50 8.6 (NET), 8.0 (SERT), 6.8 (DAT), i.e. 4- to 10-fold functional selectivity for NET. Brain-penetrant: human PET estimated NET plasma EC50 1.21 ng/mL with projected >75% steady-state NET occupancy above 4 mg, and ~25% SERT occupancy after 20 mg. Originally positioned as an NSRI for CNS indications (ADHD, fibromyalgia); in nOH it is described as a selective NRI whose rationale is peripheral — blocking NE reuptake at residual postganglionic sympathetic neurons, which are relatively spared in MSA, to raise vasoconstrictor tone (plasma NE +71%, DHPG -22% on treatment).
| Target | Action | Affinity |
|---|---|---|
| NETprimarySLC6A2 | Reuptake inhibitor | pKi 8.8ⓘ |
| SERTSLC6A4 | Reuptake inhibitor | pKi 8.5ⓘ |
← Full TD-9855 compound page (identity, identifiers, all indications)
Sources
- Lo A et al. Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic nOH. Clin Auton Res 2021;31(3):395-403 — Clinical Autonomic Research / PubMed
- NCT02705755 — Study 0145 Phase 2 of TD-9855 in neurogenic orthostatic hypotension — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT03750552 — SEQUOIA (Study 0169) Phase 3 study of ampreloxetine in symptomatic nOH (MSA/PD/PAF) — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT03829657 — REDWOOD (Study 0170) Phase 3 randomized withdrawal durability study in symptomatic nOH — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT04095793 — OAK (Study 0171) Phase 3 open-label extension in symptomatic nOH — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT05696717 — CYPRESS (Study 0197) Phase 3 randomized withdrawal study of ampreloxetine in MSA with symptomatic nOH — ClinicalTrials.gov (U.S. National Library of Medicine)
- Smith JA et al. Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor. Int J Neuropsychopharmacol 2015;18(2):pyu027 — Int J Neuropsychopharmacol (OUP) via PubMed Central
- Theravance Biopharma 8-K Ex.99.1 (2026-03-03): Phase 3 CYPRESS study did not meet primary endpoint; ampreloxetine program wound down — Theravance Biopharma / SEC EDGAR
- Theravance Biopharma Form 10-Q for the quarter ended 2026-06-30 (program history, orphan designation, Zymeworks merger agreement and ampreloxetine CVR) — Theravance Biopharma / SEC EDGAR