TAK-653 (Osavampator) 2 mg – 60 tablets

TAK-653 (Osavampator, NBI-1065845) 2 mg — 60 research tablets. TAK-653 is the most clinically advanced AMPA-receptor positive allosteric modulator (PAM) in development: a non-dissociative, non-psychotomimetic glutamate-system molecule that separated from placebo on the MADRS in a placebo-controlled Phase II study in major depressive disorder, without the hallucinogenic, dissociative or addictive liabilities of NMDA antagonists. It has since entered a Phase III registrational programme under Neurocrine Biosciences, which makes it the reference tool compound for the glutamatergic side of rapid-acting antidepressant pharmacology.

Research Overview

TAK-653 is a selective, non-desensitizing positive allosteric modulator of the AMPA subtype of ionotropic glutamate receptors, the principal mediator of fast excitatory neurotransmission in the mammalian brain [1]. Unlike older AMPA-PAMs, it has been engineered to lack the convulsant liability of high-efficacy ampakines while retaining robust enhancement of synaptic AMPA signaling in physiologically relevant ranges. In the placebo-controlled Phase II SAVITRI study (183 adults with major depressive disorder and an inadequate response to their current antidepressant), a low-dose and a high-dose arm were given once daily for eight weeks alongside ongoing treatment; the low-dose arm (reported as 1 mg) separated significantly from placebo on the MADRS at Day 28 and Day 56, while the high-dose arm (reported as 3 mg) did not [2]. AMPA receptors themselves can now be imaged in the living human brain with the [¹¹C]K-2 PET probe, giving the field a direct translational readout for AMPA-targeted research [3]. The molecule has since advanced under Neurocrine Biosciences as osavampator (NBI-1065845) into a Phase III registrational programme, and represents the first credible non-NMDA, non-dissociative, rapid-acting antidepressant chemotype.

Primary Research Areas

• AMPA-receptor positive allosteric modulation — the most clinically advanced selective AMPA-PAM available as a research tool; the reference compound for non-desensitizing AMPA signaling research [1].
• Rapid-acting antidepressant mechanisms — Phase II evidence as an adjunctive treatment in major depressive disorder with inadequate antidepressant response, with no dissociative effects reported [2].
• Glutamatergic synaptic plasticity — studied for LTP enhancement, BDNF release and synaptogenesis — the proposed mechanism of rapid antidepressant action [1].
• Cognitive and procognitive research — evaluated in working-memory and executive-function paradigms in healthy human and rodent cohorts [1].
• Translational PET pharmacology — studied alongside AMPA-receptor PET imaging ([¹¹C]K-2), which quantifies AMPA receptors in the living human brain [3].

References

1. Hara H, Suzuki A, Kunugi A, Tajima Y, Yamada R, Kimura H. TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats. Pharmacol Biochem Behav. 2021;211:173289.
2. Neurocrine Biosciences. A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of NBI-1065845 (osavampator) in adults with major depressive disorder (SAVITRI). ClinicalTrials.gov: NCT05203341.
3. Miyazaki T, Nakajima W, Hatano M, et al. Visualization of AMPA receptors in living human brain with positron emission tomography. Nat Med. 2020;26(2):281–288.