TD-9855 · program

Ampreloxetine for Attention-deficit/hyperactivity disorder

DiscontinuedDiscontinuedTheravance Biopharma, Inc.

Indications for TD-9855: Multiple System Atrophy · Discontinued Fibromyalgia · Discontinued Attention-deficit/hyperactivity disorder · Discontinued

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.

Data current as of

Development timeline

DiscontinuedNov 2013
  1. 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.↗
  2. Trial terminatedTheravance ends TD-9855 ADHD program after Phase 2 miss↗
Phase 2Dec 2011
  1. NCT01458340 started (month precision per CT.gov).

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. ↗

Clinical trials in Attention-deficit/hyperactivity disorder

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)

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—

Mechanism of action (compound-wide)

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ⓘ

← Full TD-9855 compound page (identity, identifiers, all indications)

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. 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
  4. 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