Small Molecule · rapastinel

Rapastinel

DiscontinuedNaurex, Inc.
  • FDA Fast Track (MDD; Granted 2014)
  • FDA Breakthrough Therapy (Adjunctive Treatment Of MDD; Announced 2016-01-29)

Intravenous NMDA-receptor modulator — an amidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) originally characterized as a glycine-site functional partial agonist — developed as a rapid-acting adjunctive treatment for major depressive disorder without ketamine-like psychotomimetic effects. Discovered at Naurex (spun out of Northwestern University; derived from the B6B21 monoclonal antibody program), it showed rapid (within 24 hours) antidepressant signals in Phase 2 after a single IV dose, earning FDA Fast Track (2014) and Breakthrough Therapy designation (January 2016). Allergan acquired Naurex for $560M upfront in 2015 largely on this asset. In March 2019 all three pivotal adjunctive Phase 3 studies (RAP-MD-01/-02/-03) missed their primary and key secondary MADRS endpoints and an interim analysis of the relapse-prevention study (RAP-MD-04) was negative; Allergan terminated the remaining monotherapy and suicidality studies by July 2019, ending development. The founding member of the Naurex NMDAR-modulator chemotype whose successors (apimostinel/GATE-202, zelquistinel/GATE-251) remain in development at Syndeio Biosciences.

Also known as: rapastinel, GLYX-13, GLYX13, GLYX 13, 117928-94-6, L-threonyl-L-prolyl-L-prolyl-L-threoninamide

Data current as of

Key facts

Modality
Small molecule
Chemical class
tetrapeptide, peptide
Chemistry
Single enantiomer
Mechanism
GluN2B Partial agonist
Highest phase
Discontinued
Lead indication
Major depressive disorder
Developer
Naurex, Inc.
Designations
FDA Fast Track (MDD; Granted 2014), FDA Breakthrough Therapy (Adjunctive Treatment Of MDD; Announced 2016-01-29)
Trials
17 tracked · 645 sites

Mechanism of action#

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—ⓘ

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—

Development timeline#

20102012201420162018Phase 11 Nov 2009 — phase change — First-in-human single-ascending-dose study GLYX13-C-101 (NCT01014650) started (registry month precision: November 2009; day is an anchor).Phase 229 Jan 2016 — Breakthrough Therapy — FDA Breakthrough Therapy designation for rapastinel as adjunctive treatment of MDD31 Aug 2015 — Acquisition — Allergan completes acquisition of Naurex, gaining rapastinel (GLYX-13) and NRX-10741 Jan 2014 — Fast Track — FDA grants Fast Track designation to rapastinel (GLYX-13) for major depressive disorder1 May 2011 — phase change — 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 36 Mar 2019 — readout (missed) — 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 endpoints6 Mar 2019 — readout (missed) — RAP-MD-04 adjunctive relapse-prevention Phase 3: interim analysis indicated primary and key secondary endpoints would not be met6 Mar 2019 — readout (missed) — RAP-MD-02 pivotal adjunctive Phase 3: rapastinel did not differentiate from placebo on primary or key secondary endpoints6 Mar 2019 — readout (missed) — RAP-MD-03 pivotal adjunctive Phase 3: rapastinel did not differentiate from placebo on primary or key secondary endpoints15 Oct 2016 — phase change — 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.Discontinued11 Jul 2019 — phase change — 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).11 Jul 2019 — Trial terminated — Allergan terminates all remaining rapastinel studies, ending the program
Phase change Readout Event UpcomingHover a marker for details.
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).

Rapastinel for Major depressive disorder#

DiscontinuedDiscontinuedMajor depressive disorder indication →

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.

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#

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

JapanSlovakiaRussiaHungary

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 StatesJapanSlovakiaPoland

Show all 17 trials

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)

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)
Show all 22 sources
  1. NCT02943577 (RAP-MD-03) — Rapastinel as Adjunctive Therapy in Major Depressive Disorder — ClinicalTrials.gov (U.S. National Library of Medicine)
  2. NCT02951988 (RAP-MD-04) — Rapastinel as Adjunctive Therapy in the Prevention of Relapse in MDD — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT03002077 (RAP-MD-06) — Long-term Safety Study of Rapastinel as Adjunctive Therapy in MDD — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. 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)
  5. 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)
  6. 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)
  7. 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)
  8. 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)
  9. NCT03799900 (RAP-PK-12) — Assessment of Abuse Potential of Rapastinel in Humans — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT03814733 (RAP-PK-18) — Assessment of Effect of Rapastinel on Driving Performance — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. 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)
  12. 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