Therapeutics

NYX-458

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Overview

Name: NYX-458
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): PD-MCI
U.S. FDA Status: PD-MCI (Discontinued)
Company: Aptinyx Inc.

Background

NYX-458 is an oral NMDA receptor modulator with pro-cognitive and antidepressant actions. It was being developed to treat cognitive impairment in people with Parkinson’s disease, where it was intended to mitigate NMDA receptor dysregulation caused by a lack of dopamine.

With a novel spiro-β-lactam-based chemical structure, NYX-458 differs from other NMDA agonists such as ketamine and MK-801. It was designed to mimic the activity of rapastinel, a peptide drug and NMDA partial agonist given by intravenous infusion. In Phase 2 trials, rapastinel elicited rapid and long-lasting improvements in people with treatment-resistant depression, but failed to replicate that result in large, pivotal Phase 3 studies (Moskal et al., 2017; 2019 Allergan press release). 

In a nonhuman primate model of Parkinson’s disease, NYX-458 caused rapid cognitive improvements that persisted for three months across domains of attention, working memory, and executive function. It did not change motor symptoms, levodopa efficacy, or the occurrence of dyskinesias (Barth et al., 2020). The related NMDA modulator NYX-2925 showed little off-target activity, and enhanced NMDA receptor currents and long-term synaptic potentiation in rat hippocampus. This compound entered the CSF and enhanced cognitive performance in rodent models of learning and memory (Khan et al., 2018).

Findings

In November 2019, Aptinyx began a Phase 2 study in people with Parkinson’s disease or Lewy body disease with mild cognitive impairment or mild dementia. The 99 participants took 30 mg NYX-458 or placebo daily for 12 weeks. Primary outcomes were safety including adverse events, changes in vital signs or lab results, and neuropsychiatric or motor symptoms. Secondary outcomes assessed efficacy on scales of daily function and cognitive symptoms, and a battery of computerized cognitive tests.

On February 27, 2023, Aptinyx announced negative top-line results (press release). NYX-458 did not demonstrate clinically meaningful improvements over placebo on any efficacy endpoints. The company stopped development.

In March 2023, the company submitted trial results to clinicaltrials.gov. In June the company was liquidated.

Last Updated: 04 Jan 2024

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References

Paper Citations

  1. Moskal JR, Burgdorf JS, Stanton PK, Kroes RA, Disterhoft JF, Burch RM, Khan MA. The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant. Curr Neuropharmacol. 2017;15(1):47-56. PubMed.
  2. Barth AL, Schneider JS, Johnston TH, Hill MP, Brotchie JM, Moskal JR, Cearley CN. NYX-458 Improves Cognitive Performance in a Primate Parkinson's Disease Model. Mov Disord. 2020 Apr;35(4):640-649. Epub 2020 Jan 22 PubMed.
  3. Khan MA, Houck DR, Gross AL, Zhang XL, Cearley C, Madsen TM, Kroes RA, Stanton PK, Burgdorf J, Moskal JR. NYX-2925 Is a Novel NMDA Receptor-Specific Spirocyclic-β-Lactam That Modulates Synaptic Plasticity Processes Associated with Learning and Memory. Int J Neuropsychopharmacol. 2018 Mar 1;21(3):242-254. PubMed.

External Citations

  1. press release
  2. clinicaltrials.gov
  3. press release

Further Reading

Papers

  1. Degirmenci Y, Angelopoulou E, Georgakopoulou VE, Bougea A. Cognitive Impairment in Parkinson's Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches. Medicina (Kaunas). 2023 Oct 1;59(10) PubMed.
  2. Skylar-Scott IA, Sha SJ. Lewy Body Dementia: An Overview of Promising Therapeutics. Curr Neurol Neurosci Rep. 2023 Oct;23(10):581-592. Epub 2023 Aug 12 PubMed.
  3. Kwan C, Huot P. An overview of the active clinical trials for Parkinson's disease psychosis. Neurodegener Dis Manag. 2022 Aug;12(4):165-170. Epub 2022 May 20 PubMed.