Monday, March 30, 2015

Drugs in Clinical Pipeline: Rapastinel

Rapastinel [L-threonyl-L-prolyl-L-prolyl-L-threoninamide] is a novel modulator of the  N-methyl-D-aspartate receptor (NMDA) receptor currently in clinical development as a potential first-in-class adjunctive therapy for Major Depressive Disorder (MDD) for patients who have only had a partial response to other anti-depressants. Rapastinel is an intravenous therapy administered through a fixed-dose, pre-filled syringe in a bolus injection that lasts less than one minute.
In studies to date, Rapastinel has been shown to have rapid, robust, and sustained effects on depression symptoms and has been very well-tolerated. This profile of efficacy and tolerability represents a potential major breakthrough for patients suffering from depression.

On March 3, 2014 the FDA granted Fast Track designation to the development of Rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder. In addition to its antidepressant effects, Rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models [2].

Common Name: Rapastinel
Synonyms: GLYX-13; Glyx-13
IUPAC Name: (S)-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-1-[(S)-1-((2S,3R)-2-amino-3-hydroxybutanoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carboxamide
CAS Number: 117928-94-6
Mechanism of Action: NMDA receptor modulator
Indication: Depression; Major Depression Disorder
Development Stage: Phase II/III
Company: Naurex Inc


In an initial Phase 2 study, a single intravenous administration of Rapastinel (GLYX-13) produced significant reductions in depression scores in subjects with MDD who had failed treatment with one or more antidepressants. The effects on depression symptoms were evident within a few hours and persisted for several days, with some subjects experiencing relief that lasted multiple weeks. The size of the antidepressant effect observed after just a single administration of Rapastinel (GLYX-13) was nearly double that typically observed with most existing antidepressant drugs after weeks of repeated dosing.

In a subsequent Phase 2 study as an adjunctive therapy in subjects with difficult-to-treat depression, repeat dosing of Rapastinel (GLYX-13) over 6 weeks resulted a robust anti-depressant effect-with patients improving from moderate / severe depression to mild depression or remission. In addition, the benefit was maintained for at over 10 weeks following removal of the drug.

In both Phase 2 studies, as well as previous Phase 1 studies in healthy subjects, Rapastinel (GLYX-13) was well tolerated, with no serious adverse events related to treatment. Importantly, Rapastinel (GLYX-13) did not cause the schizophrenia-like psychotomimetic effects associated with drugs that block the NMDA receptor, such as ketamine.

Phase III studies are underway.

1. Naurex pipeline: GLYX-13
2. Burgdorf, J.; et. al. The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats. Neurobiol Aging 2011, 32(4), 698-706.