Small Molecule · Centanafadine

Centanafadine

ApprovedOtsuka Pharmaceutical Co., Ltd. (4578)
  • Priority Review

A first-in-class norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) in development for attention-deficit/hyperactivity disorder (ADHD) across the lifespan. A triple monoamine reuptake inhibitor with greatest potency at the norepinephrine transporter (NET) and secondary inhibition of the dopamine (DAT) and serotonin (SERT) transporters. Originated at DOV Pharmaceutical (as EB-1020), developed by Euthymics/Neurovance, and acquired by Otsuka Pharmaceutical in 2017.

Also known as: Centanafadine, SIMTRIYO, EB-1020, CTN, 924012-43-1, (1R,5S)-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane

Data current as of

Key facts

Modality
Small molecule
Chemical class
azabicyclohexane, Naphthalene
DEA schedule
Unscheduled
Chemistry
Single enantiomer
Mechanism
NET Reuptake inhibitor
Highest phase
Approved
Lead indication
Attention-deficit/hyperactivity disorder
Developer
Otsuka Pharmaceutical Co., Ltd. (4578)
Designations
Priority Review
Trials
4 tracked · 4 sites

Mechanism of action#

Triple monoamine reuptake inhibitor (norepinephrine, dopamine, and serotonin reuptake inhibitor; NDSRI). It inhibits reuptake at NET, DAT, and SERT with in vitro IC50 values of 6 nM, 38 nM, and 83 nM respectively (rank order of potency NET > DAT > SERT), increasing synaptic availability of all three monoamines.

1 nM10 nM100 nMNETNET — Reuptake inhibitor — IC50 6 nMIC50 6 nMDATDAT — Reuptake inhibitor — IC50 38 nMIC50 38 nMSERTSERT — Reuptake inhibitor — IC50 83 nMIC50 83 nM
Binding affinity on a log scale — further left is more potent. Values from the sourced literature (see table).
TargetActionAffinity
NETprimarySLC6A2Reuptake inhibitorIC50 6 nMⓘ
DATSLC6A3Reuptake inhibitorIC50 38 nMⓘ
SERTSLC6A4Reuptake inhibitorIC50 83 nMⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
Centanafadine sustained-release tabletsustained-release tablet
200-400 mg total daily dose, divided twice daily (morning and 4-6 h later); titrated from 200 mg TDD to target 400 mg TDD
OralTwice dailyt½ 4.5 h · Tmax 2 h

Development timeline#

20182020202220242026TodayApproved24 Jul 2026 — readout (met) — FDA approved SIMTRIYO (centanafadine) on the 2026-07-24 PDUFA date for ADHD in adults and pediatric patients aged 6+24 Jul 2026 — FDA approval — FDA approves SIMTRIYO (centanafadine) for ADHD in adults and pediatric patients aged 6+ (>=20 kg)1 May 2022 — readout (met) — Adult Phase 3 trial (NCT03605836) met AISRS primary endpoint at both doses; published Adler et al. 2022, J Clin Psychopharmacol.1 May 2022 — readout (met) — Adult Phase 3 trial (NCT03605680) met AISRS primary endpoint at both doses; published Adler et al. 2022, J Clin Psychopharmacol.30 Jun 2017 — Acquisition — Otsuka acquires Neurovance, gaining centanafadine (CTN / EB-1020) for ADHDPhase 327 Oct 2023 — readout (met) — Adolescent Phase 3 trial (13-17) met ADHD-RS-5 primary endpoint at week 6 (high dose); positive topline announced Oct 27, 2023.27 Oct 2023 — readout (met) — Pediatric Phase 3 trial (children 4-12) met ADHD-RS-5 primary endpoint at week 6; positive topline announced Oct 27, 2023.Filed (NDA)25 Jun 2026 — readout (met) — Phase 3b topline: centanafadine XR 280 mg met primary endpoint in adults with ADHD and comorbid anxiety (AISRS LS mean change -18.5 vs -12.6 placebo at week 8)27 Jan 2026 — phase change — FDA accepted the NDA and granted priority review; PDUFA target action date set for July 24, 2026.25 Nov 2025 — phase change — Otsuka submitted the NDA to the U.S. FDA for centanafadine for the treatment of ADHD in children, adolescents, and adults.
Phase change Readout Event UpcomingHover a marker for details.
ApprovedJun 2017 – Jul 2026
  1. metFDA approved SIMTRIYO (centanafadine) on the 2026-07-24 PDUFA date for ADHD in adults and pediatric patients aged 6+↗
  2. FDA approvalFDA approves SIMTRIYO (centanafadine) for ADHD in adults and pediatric patients aged 6+ (>=20 kg)↗
  3. metAdult Phase 3 trial (NCT03605836) met AISRS primary endpoint at both doses; published Adler et al. 2022, J Clin Psychopharmacol.
  4. metAdult Phase 3 trial (NCT03605680) met AISRS primary endpoint at both doses; published Adler et al. 2022, J Clin Psychopharmacol.
  5. AcquisitionOtsuka acquires Neurovance, gaining centanafadine (CTN / EB-1020) for ADHD↗
Filed (NDA)Nov 2025 – Jun 2026
  1. metPhase 3b topline: centanafadine XR 280 mg met primary endpoint in adults with ADHD and comorbid anxiety (AISRS LS mean change -18.5 vs -12.6 placebo at week 8)↗
  2. FDA accepted the NDA and granted priority review; PDUFA target action date set for July 24, 2026.↗
  3. Otsuka submitted the NDA to the U.S. FDA for centanafadine for the treatment of ADHD in children, adolescents, and adults.↗
Phase 3Oct 2023
  1. metAdolescent Phase 3 trial (13-17) met ADHD-RS-5 primary endpoint at week 6 (high dose); positive topline announced Oct 27, 2023.↗
  2. metPediatric Phase 3 trial (children 4-12) met ADHD-RS-5 primary endpoint at week 6; positive topline announced Oct 27, 2023.↗

Centanafadine for Attention-deficit/hyperactivity disorder#

ApprovedApprovedAttention-deficit/hyperactivity disorder indication →

NDA for centanafadine (once-daily extended-release capsule) for the treatment of ADHD in children, adolescents, and adults accepted by the FDA with priority review on January 27, 2026; PDUFA target action date July 24, 2026. Supported by four pivotal Phase 3 trials (two adult, one pediatric ages 4-12, one adolescent ages 13-17), all of which met their primary efficacy endpoint. Approved by the FDA on July 24, 2026 (the PDUFA action date) as SIMTRIYO, a once-daily extended-release capsule for ADHD in adults and pediatric patients aged 6+ weighing at least 20 kg.

Readouts

  • 2026-07-24ReportedRegulatorymet

    FDA approved SIMTRIYO (centanafadine) on the 2026-07-24 PDUFA date for ADHD in adults and pediatric patients aged 6+ ↗

  • 2026-06-25ReportedTopline datamet

    Phase 3b topline: centanafadine XR 280 mg met primary endpoint in adults with ADHD and comorbid anxiety (AISRS LS mean change -18.5 vs -12.6 placebo at week 8) ↗

  • 2023-10-27ReportedTopline datametNCT05257265

    Adolescent Phase 3 trial (13-17) met ADHD-RS-5 primary endpoint at week 6 (high dose); positive topline announced Oct 27, 2023. ↗

  • 2023-10-27ReportedTopline datametNCT05428033

    Pediatric Phase 3 trial (children 4-12) met ADHD-RS-5 primary endpoint at week 6; positive topline announced Oct 27, 2023. ↗

  • 2022-05-01ReportedFull resultsmetNCT03605836

    Adult Phase 3 trial (NCT03605836) met AISRS primary endpoint at both doses; published Adler et al. 2022, J Clin Psychopharmacol.

  • 2022-05-01ReportedFull resultsmetNCT03605680

    Adult Phase 3 trial (NCT03605680) met AISRS primary endpoint at both doses; published Adler et al. 2022, J Clin Psychopharmacol.

Clinical trials#

NCT05428033Phase 3Completedn=574

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Determine the Efficacy and Safety of Once Daily Centanafadine Capsules for the Treatment of Children With Attention-deficit/Hyperactivity Disorder (ADHD)

Started Jul 2022· Primary completion Mar 2025· 1 site across 1 country

United States

metprimaryChange from baseline in ADHD-RS-5 symptoms total raw score at Week 6 (children ages 4-12) — Average of both doses vs placebo p=0.0039; high dose p=0.0008 (average p=0.0039; high dose p=0.0008)

Once-daily centanafadine capsules met the primary endpoint in children: statistically significant improvement in ADHD-RS-5 at week 6 vs placebo (average of both doses and high dose); low dose did not reach significance. Topline reported Oct 27, 2023.

NCT05257265Phase 3Completedn=459

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Determine the Efficacy and Safety of Once Daily Centanafadine Capsules for the Treatment of Adolescents With Attention-deficit/Hyperactivity Disorder

Started Feb 2022· Primary completion Sept 2023· 1 site across 1 country

United States

metprimaryChange from baseline in ADHD-RS-5 symptoms total raw score at Week 6 (adolescents ages 13-17) — Centanafadine 328.8 mg: -18.50 vs placebo -14.15 (LS mean); high-dose p=0.0006; average of both doses p=0.0099 (high dose (328.8 mg) p=0.0006; 164.4 mg did not meet)

Once-daily centanafadine capsules met the primary endpoint in adolescents: high dose (328.8 mg) significantly improved ADHD-RS-5 at week 6 vs placebo; low dose (164.4 mg) did not. Published in JAACS/JAACAP 2025.

NCT03605680Phase 3Completedn=604

A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel-group Trial Evaluating the Efficacy, Safety, & Tolerability of Centanafadine Sustained-release Tablets in Adults With Attention-deficit/Hyperactivity Disorder

Started Jan 2019· Primary completion Apr 2020· 1 site across 1 country

United States

metprimaryChange from baseline in Adult ADHD Investigator Symptom Rating Scale (AISRS) total score at Day 42 — Centanafadine 200 mg: -10.1; 400 mg: -9.73; placebo: -6.98 (LS mean change) (200 mg p=0.0193; 400 mg p=0.0392)

Both centanafadine doses (200 mg and 400 mg total daily dose, BID) significantly reduced AISRS scores vs placebo at Day 42. Primary endpoint met for both doses (Adler et al. 2022, J Clin Psychopharmacol).

NCT03605836Phase 3Completedn=590

A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel-group Trial Evaluating the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release Tablets in Adults With Attention-deficit/Hyperactivity Disorder

Started Jan 2019· Primary completion May 2020· 1 site across 1 country

United States

metprimaryChange from baseline in ADHD Investigator Symptom Rating Scale (AISRS) total score at Day 42 — Centanafadine 200 mg: -12.1; 400 mg: -12.5; placebo: -8.07 (LS mean change); LS mean difference -4.01 (200 mg) and -4.42 (400 mg) (200 mg p=0.0021; 400 mg p=0.0009)

Both centanafadine doses significantly reduced AISRS scores vs placebo at Day 42. Primary endpoint met for both doses (Adler et al. 2022, J Clin Psychopharmacol).

Conference coverage#

Centanafadine appears in 5 CNS Pulse conference abstracts:

Sources#

  1. 52-Week Open-Label Safety and Tolerability Study of Centanafadine Sustained Release in Adults With Attention-Deficit/Hyperactivity Disorder — PMC / Journal
  2. Centanafadine for Attention-Deficit/Hyperactivity Disorder in Adolescents: A Randomized Clinical Trial — Journal of the American Academy of Child & Adolescent Psychiatry
  3. Centanafadine SR Tablets in Adults With ADHD (NCT03605680) — ClinicalTrials.gov
  4. Centanafadine SR Tablets in Adults With ADHD (NCT03605836) — ClinicalTrials.gov
  5. Once Daily Centanafadine Capsules in Adolescents With ADHD (NCT05257265) — ClinicalTrials.gov
  6. Once Daily Centanafadine Capsules in Children With ADHD (NCT05428033) — ClinicalTrials.gov
  7. Otsuka Announces FDA Acceptance and Priority Review of New Drug Application for Centanafadine for the Treatment of ADHD in Children, Adolescents, and Adults — Otsuka Pharmaceutical
  8. Otsuka Announces Positive Phase 3b Results for Centanafadine in Adults with ADHD and Comorbid Anxiety — Otsuka Pharmaceutical Co., Ltd.
  9. Otsuka Pharmaceutical Announces Positive Topline Results from Two Pivotal Phase 3 Trials of Centanafadine as a Treatment for Adolescents and Children with ADHD — Otsuka Pharmaceutical
  10. Otsuka Pharmaceutical Submits New Drug Application to U.S. FDA for Centanafadine for the Treatment of ADHD in Children, Adolescents, and Adults — Otsuka Pharmaceutical
Show all 13 sources
  1. Otsuka Pharmaceutical to Acquire Neurovance, Inc. — Otsuka Pharmaceutical
  2. Otsuka Receives FDA Approval for First-in-Class SIMTRIYO (centanafadine) for the Treatment of Attention-Deficit Hyperactivity Disorder (ADHD) in Adults and Pediatric Patients Aged 6 Years and Older — Otsuka Pharmaceutical Co., Ltd.
  3. Structural basis for pharmacotherapeutic action of triple reuptake inhibitors — Nature Communications (PMC)