Rapastinel

Also known as: GLYX-13
Tetrapeptide with the amino acid sequence Thr-Pro-Pro-Thr-NH2.
Rapastinel failed to demonstrate efficacy in phase III clinical trials for MDD, as announced by Allergan on March 6, 2019.
Positive allosteric modulator of N-methyl-D-aspartate receptors (NMDARs), which are critical for synaptic plasticity and neurotransmission.
Unlike ketamine, which blocks NMDARs, Rapastinel enhances NMDAR activity through a novel binding domain independent of the glycine coagonist site.
Acts as a weak coagonist with glutamate, facilitating NMDAR-mediated signal transduction. This mechanism is believed to underlie its potential antidepressant effects by promoting long-term potentiation (LTP) and enhancing synaptic plasticity, particularly in the hippocampus and medial prefrontal cortex (mPFC).
Detailed pharmacological studies indicate that Rapastinel does not bind to the NMDAR glycine site, with 0% displacement observed at 30 μM, suggesting a high-affinity site near the amino terminal-ligand binding interface. Critical amino acids, such as R392E in NR2A and R393E in NR2B, are essential for its effects, and their mutation abolishes Rapastinel’s activity.
In preclinical models, Rapastinel’s brain concentrations associated with antidepressant-like efficacy range from 30 to 100 nM.
A dose of 10 mg/kg results in approximately 30 nM, while 30 mg/kg achieves about 100 nM.
Pharmacokinetic data show a Tmax of approximately 20 minutes and a half-life of about 20 minutes in the extracellular fluid, indicating rapid distribution and clearance.
Pharmacodynamics

NMDAR Subtype Modulation: Rapastinel enhances [3H] MK-801 binding in HEK cells expressing NR2A-D subtypes with the following EC50 values:

NR2A: 9.8 pM
NR2B: 9.9 nM
NR2C: 2.2 pM
NR2D: 1.7 pM

In comparison, glycine has EC50 values ranging from 100 to 350 nM for these subtypes, highlighting Rapastinel’s higher potency at certain NMDAR subtypes.

Calcium Mobilization: At concentrations of 10 to 300 nM, Rapastinel enhances NMDA-induced calcium influx by approximately 30%. At concentrations ≥1 μM, it inhibits calcium influx by about 25%. The EC50 for NMDA is 2.8 μM, and for D-serine, it is 290 nM, indicating its modulatory effects on calcium signaling pathways.
Electrophysiological Effects: In rat mPFC slices, 100 nM Rapastinel increases NMDAR-mediated excitatory postsynaptic currents (EPSCs) and enhances the magnitude of LTP, with the effect being maximal at 100 nM and reduced at 1 μM. It does not affect paired-pulse facilitation or miniature EPSCs, suggesting a postsynaptic action. This enhancement is linked to increased synaptic plasticity, potentially contributing to its antidepressant effects.
Comparison to Ketamine: Unlike ketamine, which inhibits NMDARs with an IC50 of approximately 1.0 μM and 98% displacement at the MK-801 site, Rapastinel enhances NMDAR activity. Additionally, Rapastinel does not affect presynaptic glutamate release, a mechanism observed with ketamine, further distinguishing its pharmacological profile.

Clinical Trials

Phase II Trial: A randomized, double-blind, placebo-controlled proof-of-concept study involved 116 patients with MDD who had not responded to at least one biogenic amine antidepressant. Patients received a single intravenous (IV) dose of Rapastinel at 1, 5, 10, or 30 mg/kg or placebo. The results, published by Preskorn et al. in 2015, showed that doses of 5 and 10 mg/kg significantly reduced depressive symptoms as measured by the Hamilton Depression Rating Scale (Ham-D17) from day 1 to day 7, with an onset of action within 2 hours as assessed by the Bech-6 subscale (source). No psychotomimetic or significant side effects were reported, and the effect was maintained for an average of 7 days.
Phase III Trials: Despite the promising phase II results, multiple phase III studies failed to demonstrate efficacy. Three trials involving a total of 1,510 patients with MDD who had a partial response to antidepressant therapy were conducted. In two studies totaling 872 patients, participants received weekly IV injections of 450 mg Rapastinel or placebo in addition to their oral antidepressants. A third study with 638 participants included a third treatment arm of 225 mg Rapastinel weekly. The primary endpoint was the change in scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline at the end of three weeks. In all three trials, Rapastinel did not significantly differ from placebo, as reported in March 2019 (source). This failure raised questions about its clinical utility, despite earlier promise.

Safety and Tolerability
In the phase II trial, Rapastinel was well tolerated, with no reports of psychotomimetic effects or other significant side effects, distinguishing it from ketamine, which is known for such side effects. In phase III trials, Rapastinel was also found to be well tolerated, but its lack of efficacy over placebo limited its clinical advancement. Additional studies, such as a randomized trial assessing effects on driving performance, showed that single doses of 900 or 1800 mg did not impair driving compared to placebo, further supporting its safety profile (source).
Preclinical studies provided insights into Rapastinel’s effects on synaptic plasticity. It increases dendritic spines 24 hours post-treatment in the rat dentate gyrus and layer V of the mPFC, enhances LTP, and reduces long-term depression (LTD) at Schaffer collateral-CA1 synapses in the hippocampus. It also facilitates metaplasticity processes, differing from NMDA receptor antagonists. The BDNF-TrkB-mTOR signaling pathway in the midbrain ventrolateral periaqueductal gray is required for its antidepressant effects, and genetic deletion of GluN2B from excitatory neurons in the mPFC blocks these effects, highlighting cell-type specificity (source).