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

Study:

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.

References:
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.

Drugs in Clinical Pipeline: NRX-107

The orally active  N-methyl-D-aspartate (NMDA) receptor modulator, NRX-1074, is a follow up to Naurex's lead program, Rapastinel (GLYX-13), which recently demonstrated robust and durable antidepressant effects in a Phase 2b study as an intravenous adjunctive therapy in subjects with partial but inadequate response to existing antidepressants.

A single intravenous dose of NRX-1074 resulted in a statistically significant improvement in depression scores within 24 hours in a Phase 2 single-dose study in subjects with major depressive disorder (MDD).

Common Name: -

Synonyms: NRX-1074

IUPAC Name: -

CAS Number: -

Mechanism of Action: NMDA receptor modulator

Indication: Major Depressive Disorder

Development Stage: Phase II

Company: Naurex Pharma

Study Design

The randomized, double-blind, placebo-controlled Phase 2 study evaluated the efficacy and safety of a single intravenous dose of NRX-1074 in subjects with MDD. The study was conducted at 12 clinical centers in the United States. Subjects received one of three dose levels of NRX-1074 or placebo. The primary clinical efficacy measure was the HDRS-17, a standard scale for measuring depression severity, which was administered by off-site independent raters who were blinded to the protocol to ensure the quality and objectivity of the rating data. Safety was also assessed.

In the study, which enrolled approximately 140 subjects, NRX-1074 was well-tolerated with no drug-related serious adverse events reported and no subjects dropping out of the study due to adverse events. This safety profile was also observed in Phase 1 studies with both intravenous and oral NRX-1074 in healthy volunteers.

Findings from the Phase 2 single-dose study, along with oral and intravenous pharmacokinetic findings from Phase 1, will be used to select oral doses for a repeat-dose Phase 2 study. This upcoming randomized, double-blind, placebo-controlled multi-dose study will evaluate the efficacy and safety of repeated oral dosing of NRX-1074 administered as a monotherapy to subjects with MDD.

References:
1. Naurex pipeline: NRX-1074