rapastinel · program

Rapastinel for Major depressive disorder

DiscontinuedDiscontinuedAllergan plc
  • FDA Fast Track (MDD; Granted 2014)
  • FDA Breakthrough Therapy (Adjunctive Treatment Of MDD; Announced 2016-01-29)

Rapastinel (GLYX-13), a weekly intravenous NMDA-receptor modulator (glycine-site functional partial agonist), for major depressive disorder — one of the largest rapid-acting-antidepressant programs of its era and a landmark Phase 3 failure. After single-dose Phase 2 studies showed rapid (24-hour) antidepressant effects without psychotomimetic side effects, FDA granted Fast Track (2014) and Breakthrough Therapy designation (January 2016), and Allergan acquired originator Naurex (2015, $560M upfront). The pivotal program comprised three acute adjunctive studies (RAP-MD-01/-02/-03, ~1,550 randomized patients with partial response to antidepressants; primary endpoint MADRS change at Week 3), an adjunctive relapse-prevention study (RAP-MD-04, n=1,304), a long-term safety study (RAP-MD-06), an acute + relapse-prevention monotherapy program (RAP-MD-30/-31/-32/-33), and a Phase 2 study in MDD with suicidality (RAP-MD-20). On 2019-03-06 Allergan announced that none of the three acute adjunctive studies differentiated from placebo on primary or key secondary endpoints and that the RAP-MD-04 interim indicated failure; rapastinel was well tolerated with no psychotomimetic signal. The remaining monotherapy and suicidality studies were terminated between 2019-06-21 and 2019-07-11 as a 'business decision to stop the program', ending development. Never approved anywhere.

Data current as of

Development timeline

DiscontinuedJul 2019
  1. Program-wide stop. Allergan issued no dedicated discontinuation press release; the stop is documented on ClinicalTrials.gov, where every remaining study was terminated with whyStopped 'Business decision to stop the program': RAP-MD-20 (suicidality, 2019-06-21), RAP-MD-99 (open-label extension, 2019-07-03), RAP-MD-32 (acute monotherapy, 2019-07-08), RAP-MD-30 and RAP-MD-33 (monotherapy acute + relapse prevention, 2019-07-11), and RAP-MD-31 withdrawn before enrollment. 2019-07-11 is the latest termination date (upper bound of the wind-down).
  2. Trial terminatedAllergan terminates all remaining rapastinel studies, ending the program
Phase 3Oct 2016 – Mar 2019
  1. missedRAP-MD-01 pivotal adjunctive Phase 3: rapastinel did not differentiate from placebo on the primary endpoint (MADRS change at Week 3) or key secondary endpoints↗
  2. missedRAP-MD-04 adjunctive relapse-prevention Phase 3: interim analysis indicated primary and key secondary endpoints would not be met↗
  3. missedRAP-MD-02 pivotal adjunctive Phase 3: rapastinel did not differentiate from placebo on primary or key secondary endpoints↗
  4. missedRAP-MD-03 pivotal adjunctive Phase 3: rapastinel did not differentiate from placebo on primary or key secondary endpoints↗
  5. First pivotal adjunctive Phase 3 study RAP-MD-01 (NCT02932943) started, ten months after FDA Breakthrough Therapy designation (announced 2016-01-29, which described rapastinel as 'Phase III ready'). RAP-MD-02, RAP-MD-03 and the relapse-prevention study RAP-MD-04 all started within the following month.
Phase 2May 2011 – Jan 2016
  1. Breakthrough TherapyFDA Breakthrough Therapy designation for rapastinel as adjunctive treatment of MDD↗
  2. AcquisitionAllergan completes acquisition of Naurex, gaining rapastinel (GLYX-13) and NRX-1074↗
  3. Fast TrackFDA grants Fast Track designation to rapastinel (GLYX-13) for major depressive disorder↗
  4. Phase 2 single-IV-dose proof-of-concept GLYX13-C201 (NCT01234558) started in MDD patients with inadequate response to antidepressants (registry month precision: May 2011). Published as Preskorn et al., J Psychiatr Pract 2015 — rapid antidepressant effect within 24 hours at 5 and 10 mg/kg without psychotomimetic effects. The repeated-dose Phase 2b GLYX13-C-202 (NCT01684163, n=369) followed from November 2012.
Phase 1Nov 2009
  1. First-in-human single-ascending-dose study GLYX13-C-101 (NCT01014650) started (registry month precision: November 2009; day is an anchor).

Readouts

  • 2019-03-06ReportedTopline datamissedNCT02932943

    RAP-MD-01 pivotal adjunctive Phase 3: rapastinel did not differentiate from placebo on the primary endpoint (MADRS change at Week 3) or key secondary endpoints ↗

  • 2019-03-06ReportedInterim analysismissedNCT02951988

    RAP-MD-04 adjunctive relapse-prevention Phase 3: interim analysis indicated primary and key secondary endpoints would not be met ↗

  • 2019-03-06ReportedTopline datamissedNCT02943564

    RAP-MD-02 pivotal adjunctive Phase 3: rapastinel did not differentiate from placebo on primary or key secondary endpoints ↗

  • 2019-03-06ReportedTopline datamissedNCT02943577

    RAP-MD-03 pivotal adjunctive Phase 3: rapastinel did not differentiate from placebo on primary or key secondary endpoints ↗

Clinical trials in Major depressive disorder

NCT03814733RAP-PK-18Phase 1Completedn=107

Assessment of Effect of Rapastinel on Driving Performance (RAP-PK-18)

Started Nov 2018· Primary completion Mar 2019

NCT03799900RAP-PK-12Phase 1Completedn=72

Assessment of Abuse Potential of Rapastinel in Humans (RAP-PK-12)

Started Nov 2018· Primary completion Mar 2019

NCT03675776RAP-MD-30Phase 3Discontinuedn=50

Study of Rapastinel as Monotherapy in Patients With Major Depressive Disorder (RAP-MD-30)

Started Oct 2018· Primary completion Jul 2019· 📍 23 sites across 5 countries (Japan, Slovakia, Russia, Hungary)

NCT03668600RAP-MD-99Phase 3Discontinuedn=230

Study of Adjunctive or Monotherapy Rapastinel Treatment in Patients With Major Depressive Disorder (Open-label Extension, RAP-MD-99)

Started Aug 2018· Primary completion Jul 2019· 📍 74 sites across 1 country (United States)

NCT03614156RAP-MD-33Phase 3Discontinuedn=363

Study of Monotherapy Rapastinel in the Prevention of Relapse in Patients With Major Depressive Disorder (RAP-MD-33)

Started Aug 2018· Primary completion Jul 2019· 📍 52 sites across 5 countries (United States, Japan, Slovakia, Poland)

NCT03560518RAP-MD-32Phase 3Discontinuedn=439

Study of Rapastinel as Monotherapy in Patients With MDD (RAP-MD-32)

Started Jun 2018· Primary completion Jul 2019· 📍 40 sites across 1 country (United States)

NCT03352453RAP-MD-20Phase 2Discontinuedn=138

A Study of Rapastinel for Rapid Treatment of Symptoms of Depression and Suicidality in Adult Patients With Major Depressive Disorder (RAP-MD-20)

Started Dec 2017· Primary completion Jun 2019· 📍 17 sites across 1 country (United States)

NCT03002077RAP-MD-06Phase 3Completedn=617

Long-term Safety Study of Rapastinel as Adjunctive Therapy in Patients With Major Depressive Disorder

Started Feb 2017· Primary completion Dec 2018· 📍 128 sites across 1 country (United States)

NCT02951988RAP-MD-04Phase 3Completedn=1304

A Study of Rapastinel as Adjunctive Therapy in the Prevention of Relapse in Patients With Major Depressive Disorder (RAP-MD-04)

Started Nov 2016· Primary completion Feb 2019· 📍 137 sites across 1 country (United States)

missedprimaryTime to relapse (adjunctive rapastinel vs placebo)

Interim analysis (announced 2019-03-06) indicated the primary and key secondary endpoints would not be met.

NCT02943577RAP-MD-03Phase 3Completedn=429

A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder (RAP-MD-03)

Started Nov 2016· Primary completion Oct 2018· 📍 40 sites across 1 country (United States)

missedprimaryChange from baseline in MADRS total score at Week 3

Did not differentiate from placebo on primary or key secondary endpoints (announced 2019-03-06 across RAP-MD-01/-02/-03).

NCT02943564RAP-MD-02Phase 3Completedn=658

A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder (RAP-MD-02)

Started Nov 2016· Primary completion Dec 2018· 📍 66 sites across 1 country (United States)

missedprimaryChange from baseline in MADRS total score at Week 3

Did not differentiate from placebo on primary or key secondary endpoints (announced 2019-03-06 across RAP-MD-01/-02/-03).

NCT02932943RAP-MD-01Phase 3Completedn=465

A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder (RAP-MD-01)

Started Oct 2016· Primary completion Sept 2018· 📍 31 sites across 1 country (United States)

missedprimaryChange from baseline in MADRS total score at Week 3

Pivotal acute adjunctive study: rapastinel (weekly IV, added to ongoing antidepressant) did not differentiate from placebo on the primary endpoint or key secondary endpoints (announced 2019-03-06 across RAP-MD-01/-02/-03). Well tolerated; no psychotomimetic side effects. Per-arm MADRS values not disclosed in the announcement and not transcribed from the posted registry results.

NCT02192099GLYX13-C-203Phase 2Discontinuedn=61

Open Label Extension for GLYX13-C-202 (NCT01684163)

Started Sept 2014· Primary completion Nov 2018· 📍 10 sites across 1 country (United States)

NCT01684163GLYX13-C-202Phase 2Completedn=369

Efficacy and Safety of GLYX-13 in Subjects With Inadequate/Partial Response to Antidepressants During the Current Episode of Major Depressive Disorder

Started Nov 2012· Primary completion Apr 2014· 📍 26 sites across 1 country (United States)

NCT01234558GLYX13-C201Phase 2Completedn=115

Single IV Dose of GLYX-13 in Patients With Treatment-Resistant Depression

Started May 2011· Primary completion Jun 2012· 📍 1 site across 1 country (United States)

metprimaryChange from baseline in HDRS-17 (Bech-6 core) after single IV dose

Published proof of concept (Preskorn et al., J Psychiatr Pract 2015, PMID 25782764): single IV doses of 5 and 10 mg/kg produced statistically significant antidepressant effects within 24 hours, sustained for an average of 7 days, without ketamine-like psychotomimetic or dissociative effects; 1 and 30 mg/kg did not separate (inverted-U dose response). Per-arm effect sizes not transcribed; no results posted to ClinicalTrials.gov (hasResults=false).

NCT01014650GLYX13-C-101Phase 1Completedn=53

Single Ascending Dose Safety, Tolerability and Pharmacokinetics Study of GLYX-13 in Normal Volunteers

Started Nov 2009· Primary completion Oct 2015

NCT03855865RAP-MD-31Phase 3Discontinued

Study of Rapastinel as Monotherapy in Major Depressive Disorder (RAP-MD-31; withdrawn before enrollment)

Formulations

FormulationRouteRegimenPharmacokinetics
Rapastinel IV injection (weekly bolus)
Phase 3: 450 mg IV once weekly via pre-filled syringe (RAP-MD-01 registry arms: rapastinel 450 mg vs placebo, weekly IV injections). Contemporary descriptions of the acute adjunctive studies also referenced a 225 mg weekly arm, but the current registry record shows only 450 mg, so 225 mg is not asserted. Phase 2 proof-of-concept (GLYX13-C201): single IV doses of 1, 5, 10 or 30 mg/kg, with the antidepressant signal at 5 and 10 mg/kg. Weekly IV administration was required because of rapid plasma clearance; the IV-only route was a recognized commercial limitation and an oral follow-on (AGN-241751, not this compound) was developed separately.
IntravenousOther—

Mechanism of action (compound-wide)

NMDA-receptor modulator originally characterized as a glycine-site functional partial agonist: at the doses studied it enhances NMDA-receptor-mediated synaptic plasticity (facilitating long-term potentiation and learning) rather than blocking the channel, which is the proposed basis for rapid antidepressant activity without the dissociative/psychotomimetic effects of channel blockers such as ketamine. Preclinical work reported preferential modulation of GluN2B-containing NMDA receptors. Later work on the Naurex chemotype (by the successor companies developing apimostinel and zelquistinel) re-characterized the binding site as a novel allosteric site independent of the glycine co-agonist site; rapastinel's own development-era label — 'NMDA receptor glycine-site functional partial agonist' — is retained here. Derived from the hippocampus-targeting monoclonal antibody B6B21.

TargetActionAffinity
GluN2BprimaryGRIN2BPartial agonist—ⓘ

← Full rapastinel compound page (identity, identifiers, all indications)

Sources

  1. Allergan Announces Phase 3 Results for Rapastinel as an Adjunctive Treatment of Major Depressive Disorder (MDD) (2019-03-06) — Allergan plc (archived on the AbbVie newsroom)
  2. Allergan Successfully Completes Naurex Acquisition (2015-08-31) — Allergan plc (via PR Newswire)
  3. Allergan's Rapastinel Receives FDA Breakthrough Therapy Designation for Adjunctive Treatment of Major Depressive Disorder (MDD) (2016-01-29; also states Fast Track granted 2014) — Allergan plc (via PR Newswire)
  4. Moskal JR, et al. The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant. Curr Neuropharmacol. 2017;15(1):47-56 — Current Neuropharmacology / PubMed
  5. NCT01014650 (GLYX13-C-101) — Single Ascending Dose Study of GLYX-13 in Normal Volunteers — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT01234558 (GLYX13-C201) — Single IV Dose of GLYX-13 in Patients With Treatment-Resistant Depression — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT01684163 (GLYX13-C-202) — Efficacy and Safety of GLYX-13 in Subjects With Inadequate/Partial Response to Antidepressants — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT02192099 (GLYX13-C-203) — Open Label Extension for GLYX13-C-202 — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT02932943 (RAP-MD-01) — Rapastinel as Adjunctive Therapy in Major Depressive Disorder — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT02943564 (RAP-MD-02) — Rapastinel as Adjunctive Therapy in Major Depressive Disorder — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. NCT02943577 (RAP-MD-03) — Rapastinel as Adjunctive Therapy in Major Depressive Disorder — ClinicalTrials.gov (U.S. National Library of Medicine)
  12. NCT02951988 (RAP-MD-04) — Rapastinel as Adjunctive Therapy in the Prevention of Relapse in MDD — ClinicalTrials.gov (U.S. National Library of Medicine)
  13. NCT03002077 (RAP-MD-06) — Long-term Safety Study of Rapastinel as Adjunctive Therapy in MDD — ClinicalTrials.gov (U.S. National Library of Medicine)
  14. NCT03352453 (RAP-MD-20) — Rapastinel for Rapid Treatment of Symptoms of Depression and Suicidality in MDD (terminated: business reasons) — ClinicalTrials.gov (U.S. National Library of Medicine)
  15. NCT03560518 (RAP-MD-32) — Rapastinel as Monotherapy in Patients With MDD (terminated: business decision to stop the program) — ClinicalTrials.gov (U.S. National Library of Medicine)
  16. NCT03614156 (RAP-MD-33) — Monotherapy Rapastinel in the Prevention of Relapse in MDD (terminated: business decision to stop the program) — ClinicalTrials.gov (U.S. National Library of Medicine)
  17. NCT03668600 (RAP-MD-99) — Adjunctive or Monotherapy Rapastinel Open-Label Extension (terminated: business decision to stop the program) — ClinicalTrials.gov (U.S. National Library of Medicine)
  18. NCT03675776 (RAP-MD-30) — Rapastinel as Monotherapy in Patients With MDD (terminated: business decision to stop the program) — ClinicalTrials.gov (U.S. National Library of Medicine)
  19. NCT03799900 (RAP-PK-12) — Assessment of Abuse Potential of Rapastinel in Humans — ClinicalTrials.gov (U.S. National Library of Medicine)
  20. NCT03814733 (RAP-PK-18) — Assessment of Effect of Rapastinel on Driving Performance — ClinicalTrials.gov (U.S. National Library of Medicine)
  21. NCT03855865 (RAP-MD-31) — Rapastinel as Monotherapy in MDD (withdrawn before enrollment: business decision to stop the program) — ClinicalTrials.gov (U.S. National Library of Medicine)
  22. Preskorn S, et al. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract. 2015;21(2):140-9 — Journal of Psychiatric Practice / PubMed