On March 3, 2014, the U.S. FDA granted
Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.[4] As of 2015, the drug had completed
phase II clinical development for this indication and achieved
proof of concept as a rapid-acting antidepressant by demonstrating reduced depressive symptoms at days 1 through 7, as assessed by the
HAM-D, without eliciting psychotomimetic or other significant side effects.[5] On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received
Breakthrough Therapy designation from the U.S. FDA for adjunctive treatment of major depressive disorder.[6]
On March 6, 2019, Allergan announced rapastinel failed to differentiate from placebo during phase III trials.[7] Early successful clinical studies of rapastinel in depression spurred the development of next-generation compounds with similar mechanisms of action including
apimostinel (GATE-202, NRX-1074), a 2nd generation
analog with improved
potency, and
zelquistinel (GATE-251, AGN-241751), a 3rd generation small molecule with improved potency and high oral bioavailability.[8]
Preclinical development
Rapastinel was originally invented by Joseph Moskal, the co-founder of Naurex, via
structural modification of
B6B21, a
monoclonal antibody that similarly binds to and modulates the NMDA receptor.[2][9][10][11] Rapastinel binds to a novel and unique domain on the NMDA receptor complex that is distinct from the
glycine co-agonist binding site.[3][12] Rapastinel exhibits a biphasic dose response in vitro.[3][13] At therapeutically relevant concentrations, rapastinel enhances glutamate-mediated NMDA receptor activity, independent of glycine co-agonism, and enhances the magnitude of NMDAR-mediated synaptic plasticity at
excitatory synapses in the
mPFC.[3][13] Positive modulation of NMDA receptors by rapastinel produces antidepressant effects that are convergent with the
NMDA receptor antagonistketamine, however, rapastinel has no ketamine-like side effects such as cognitive impairment and psychotomimetic symptoms.[14][15]
^Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM (March 2015). "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". Journal of Psychiatric Practice. 21 (2): 140–149.
doi:
10.1097/01.pra.0000462606.17725.93.
PMID25782764.
S2CID36800194.