Small Molecule · TD-9855

Ampreloxetine

DiscontinuedTheravance Biopharma, Inc.
  • FDA Orphan Drug Designation (Symptomatic NOH In Patients With MSA; Announced May 2023)

Oral, once-daily, long-acting monoamine reuptake inhibitor discovered by Theravance (code TD-9855) and developed by Theravance Biopharma. First studied as a norepinephrine and serotonin reuptake inhibitor (NSRI) for CNS conditions (adult ADHD Phase 2 failed 2013; fibromyalgia Phase 2 positive at 20 mg in 2014), then repositioned as a selective norepinephrine reuptake inhibitor for symptomatic neurogenic orthostatic hypotension (nOH) in multiple system atrophy (MSA), where it received FDA Orphan Drug Designation (May 2023). Three Phase 3 studies failed their primary endpoints (SEQUOIA 2021, REDWOOD 2022, CYPRESS 2026-03-03) and Theravance wound the program down; Zymeworks acquired Theravance Biopharma on 2026-09-23 with a contingent value right tied to any future monetization of ampreloxetine. Human in vitro binding pKi 8.8 at NET and 8.5 at SERT; human PET showed high NET occupancy at doses above 4 mg with ~25% SERT occupancy at 20 mg.

Also known as: TD-9855, TD 9855, ampreloxetine, 1227056-84-9, 4-[2-[(2,4,6-trifluorophenoxy)methyl]phenyl]piperidine

Data current as of

Key facts

Modality
Small molecule
Chemical class
piperidine, fluoroarene
Chemistry
Achiral
Mechanism
NET Reuptake inhibitor
Highest phase
Discontinued
Lead indication
Multiple System Atrophy
Developer
Theravance Biopharma, Inc.
Designations
FDA Orphan Drug Designation (Symptomatic NOH In Patients With MSA; Announced May 2023)
Trials
7 tracked · 285 sites

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).

TargetActionAffinity
NETprimarySLC6A2Reuptake inhibitorpKi 8.8ⓘ
SERTSLC6A4Reuptake inhibitorpKi 8.5ⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
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.
OralOnce daily—

Development timeline#

201520202025TodayPhase 29 Sept 2017 — phase change — Phase 2 study 0145 (NCT02705755) in nOH (MSA, PD, PAF) started per ClinicalTrials.gov.30 Apr 2014 — readout (met) — TD-9855 20 mg met the primary endpoint (change in average daily pain score) and FIQ/PGIC secondaries vs placebo in fibromyalgia; 5 mg missed the primary.1 Nov 2012 — phase change — NCT01693692 started (month precision per CT.gov).1 Dec 2011 — phase change — NCT01458340 started (month precision per CT.gov).Discontinued3 Mar 2026 — readout (missed) — 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.3 Mar 2026 — phase change — Inferred: Theravance announced complete wind-down of its R&D organization and the ampreloxetine program. Upper bound — de facto inactivity dates from ~2014.3 Mar 2026 — Trial terminated — Theravance winds down ampreloxetine after Phase 3 CYPRESS miss13 Nov 2013 — readout (missed) — TD-9855 did not meet the primary endpoint (AISRS total score vs placebo) at 5 mg or 20 mg in adult ADHD; ADHD program not continued.13 Nov 2013 — Trial terminated — Theravance ends TD-9855 ADHD program after Phase 2 missPhase 327 Jun 2023 — phase change — 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).15 May 2023 — Orphan Drug — FDA grants Orphan Drug Designation to ampreloxetine for symptomatic nOH in MSA15 Jul 2022 — Financing — Royalty Pharma invests up to $40M in ampreloxetine for MSA30 Apr 2022 — readout (missed) — 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.30 Sept 2021 — readout (missed) — SEQUOIA 4-week Phase 3 RCT in symptomatic nOH did not meet its primary endpoint; no supine-hypertension signal.24 Jan 2019 — phase change — SEQUOIA (NCT03750552, Study 0169) first participant enrolled 2019-01-24 — start of the Phase 3 program.
Phase change Readout Event UpcomingHover a marker for details.
DiscontinuedNov 2013 – Mar 2026
  1. 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.Multiple System Atrophy↗
  2. Inferred: Theravance announced complete wind-down of its R&D organization and the ampreloxetine program. Upper bound — de facto inactivity dates from ~2014.Fibromyalgia↗
  3. Trial terminatedTheravance winds down ampreloxetine after Phase 3 CYPRESS missMultiple System Atrophy↗
  4. missedTD-9855 did not meet the primary endpoint (AISRS total score vs placebo) at 5 mg or 20 mg in adult ADHD; ADHD program not continued.Attention-deficit/hyperactivity disorder↗
  5. Trial terminatedTheravance ends TD-9855 ADHD program after Phase 2 missAttention-deficit/hyperactivity disorder↗
Phase 3Jan 2019 – Jun 2023
  1. 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).Multiple System Atrophy
  2. Orphan DrugFDA grants Orphan Drug Designation to ampreloxetine for symptomatic nOH in MSAMultiple System Atrophy↗
  3. FinancingRoyalty Pharma invests up to $40M in ampreloxetine for MSAMultiple System Atrophy↗
  4. 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.Multiple System Atrophy↗
  5. missedSEQUOIA 4-week Phase 3 RCT in symptomatic nOH did not meet its primary endpoint; no supine-hypertension signal.Multiple System Atrophy↗
  6. SEQUOIA (NCT03750552, Study 0169) first participant enrolled 2019-01-24 — start of the Phase 3 program.Multiple System Atrophy
Phase 2Dec 2011 – Sept 2017
  1. Phase 2 study 0145 (NCT02705755) in nOH (MSA, PD, PAF) started per ClinicalTrials.gov.Multiple System Atrophy
  2. metTD-9855 20 mg met the primary endpoint (change in average daily pain score) and FIQ/PGIC secondaries vs placebo in fibromyalgia; 5 mg missed the primary.Fibromyalgia↗
  3. NCT01693692 started (month precision per CT.gov).Fibromyalgia
  4. NCT01458340 started (month precision per CT.gov).Attention-deficit/hyperactivity disorder

Ampreloxetine for Multiple System Atrophy#

DiscontinuedDiscontinuedMultiple System Atrophy indication →

Ampreloxetine (TD-9855), a once-daily norepinephrine reuptake inhibitor, for symptomatic neurogenic orthostatic hypotension (nOH) in multiple system atrophy.

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. ↗

Ampreloxetine for Attention-deficit/hyperactivity disorder#

DiscontinuedDiscontinuedAttention-deficit/hyperactivity disorder indication →

TD-9855 (later ampreloxetine), then positioned as a norepinephrine and serotonin reuptake inhibitor, in adult ADHD. A Phase 2 randomized, double-blind, placebo-controlled proof-of-concept study (NCT01458340, n=295 adult males; 5 mg or 10->20 mg once daily for 6 weeks) did not meet its primary endpoint (change in AISRS total score vs placebo). Theravance, Inc. announced on 2013-11-13 that it would not continue TD-9855 in ADHD. Generally well tolerated with no serious adverse events.

Readouts

  • 2013-11-13ReportedTopline datamissedNCT01458340

    TD-9855 did not meet the primary endpoint (AISRS total score vs placebo) at 5 mg or 20 mg in adult ADHD; ADHD program not continued. ↗

Ampreloxetine for Fibromyalgia#

DiscontinuedDiscontinuedFibromyalgia indication →

TD-9855 (ampreloxetine), as a norepinephrine and serotonin reuptake inhibitor, in fibromyalgia. A Phase 2 randomized, double-blind, placebo-controlled study (NCT01693692, n=392; 5 mg or 20 mg once daily up to 6 weeks) met its primary endpoint (change in average daily pain) at 20 mg, with significant FIQ and PGIC secondary benefits, while 5 mg missed; both doses were generally well tolerated (reported 2014-04-30). The program never advanced to Phase 3; the molecule was repositioned to neurogenic orthostatic hypotension, and Theravance wound down its R&D function in March 2026. No explicit fibromyalgia discontinuation announcement was found.

Readouts

  • 2014-04-30ReportedTopline datametNCT01693692

    TD-9855 20 mg met the primary endpoint (change in average daily pain score) and FIQ/PGIC secondaries vs placebo in fibromyalgia; 5 mg missed the primary. ↗

Clinical trials#

NCT056967170197Phase 3Activen=102

Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic nOH in Participants With Multiple System Atrophy (CYPRESS)

Started Jun 2023· Primary completion Jan 2026

NCT040957930171Phase 3Discontinuedn=110

Phase 3 Open-Label Extension Study of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure (OAK)

Started Sept 2019· Primary completion Nov 2021· 55 sites across 18 countries

United StatesItalyRussiaPoland

NCT038296570170Phase 3Discontinuedn=203

Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure (REDWOOD)

Started Feb 2019· Primary completion Nov 2021· 82 sites across 19 countries

United StatesItalyUnited KingdomPoland

NCT037505520169Phase 3Completedn=195

Clinical Effect of Ampreloxetine (TD-9855) for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure (SEQUOIA)

Started Jan 2019· Primary completion Jul 2021· 125 sites across 19 countries

United StatesItalySpainRussia

NCT027057550145Phase 2Completedn=34

TD-9855 Phase 2 in Neurogenic Orthostatic Hypotension (nOH)

Started Sept 2017· Primary completion Jul 2018· 6 sites across 1 country

United States

Show all 7 trials

NCT016936920092Phase 2Completedn=392

Phase 2 Study of TD-9855 to Treat Fibromyalgia

Started Nov 2012· Primary completion Jan 2014

NCT014583400085Phase 2Completedn=295

A Study of TD-9855 in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)

Started Dec 2011· Primary completion Oct 2013· 17 sites across 1 country

United States

Sources#

  1. 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
  2. NCT01458340 — Study 0085 Phase 2 proof-of-concept of TD-9855 in adults with ADHD — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT01693692 — Study 0092 Phase 2 of TD-9855 in fibromyalgia — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT02705755 — Study 0145 Phase 2 of TD-9855 in neurogenic orthostatic hypotension — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT03750552 — SEQUOIA (Study 0169) Phase 3 study of ampreloxetine in symptomatic nOH (MSA/PD/PAF) — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT03829657 — REDWOOD (Study 0170) Phase 3 randomized withdrawal durability study in symptomatic nOH — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT04095793 — OAK (Study 0171) Phase 3 open-label extension in symptomatic nOH — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT05696717 — CYPRESS (Study 0197) Phase 3 randomized withdrawal study of ampreloxetine in MSA with symptomatic nOH — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. 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
  10. 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
Show all 13 sources
  1. 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
  2. Theravance reports positive Phase II trial results of fibromyalgia drug candidate TD-9855 (2014-04-30) — Clinical Trials Arena
  3. Theravance, Inc. 8-K (2013-11-13): TD-9855 did not meet primary endpoint in adult ADHD Phase 2; ADHD program not continued — Theravance, Inc. / SEC EDGAR