Background

NX210c is a cyclized 12-amino-acid peptide derived from a protein involved in embryonic neuronal development. It is delivered by intravenous injection.

This peptide was designed from the most conserved sequence of the thrombospondin repeats from the SCO-spondin protein. SCO-spondin, a large, multifunctional glycoprotein specific to the CNS extracellular matrix, is produced by the subcommissural organ during embryogenesis, and is essential for neural development. SCO-spondin has also been proposed to function in adult neurogenesis (Inada et al., 2023).

Both linear and cyclic forms of this peptide have been evaluated preclinically. The linear NX210 is converted in vivo to NX210c by formation of an intrachain disulfide bridge between two cysteines. In a mouse amyloidosis model, NX210 and NX210c reduced pathologic markers of Aβ42, p-Tau, and inflammation, after intraventricular injection of Aβ oligomers (Le Douce et al., 2021). In this study, conducted by Axoltis researchers, the peptides improved behaviors related to cognition and memory in the Y maze, passive avoidance test, and Morris water maze.

In other Axoltis-sponsored preclinical work, NX210 protected against oxidative stress and stimulated axonal regrowth and functional recovery in a spinal cord injury model (Sakka et al., 2014). NX201 and NX201c both protected neurons from glutamate excitotoxicity by disrupting the apoptotic signaling cascade; NX210c was more effective (Deletage et al., 2021). NX210c increased synaptic transmission in brain slices, and improved memory in mice treated with the NMDAR agonist phencyclidine (Lemarchant et al., 2022). The company also claims that NX210c reduces blood-brain barrier permeability, but that data is not public. In the only published study independent of Axoltis, NX210 protected against cell loss in ischemic stroke models (Yang et al., 2022).

Findings

From June to November 2020, the company conducted a Phase 1 safety trial of NX210. It enrolled 39 healthy adults in five cohorts, to receive single intravenous doses of 0.4, 1.25, 2.5, 5, or 10 mg/kg, or placebo. According to published results, one-third of participants reported mild adverse events. The most common were dizziness, headache, and sleepiness. NX210 cyclized to NX210c in blood. The peptide was widely distributed and rapidly cleared, with a half-life in plasma of 20 minutes or less. Potential pharmacodynamic effects were reported on EEG, and on plasma tryptophan and homocysteine (Bourdes et al., 2022).

In October 2022, the FDA granted NX210c Orphan Drug Designation for ALS.

In December 2022, a multiple-dose Phase 1 trial began enrolling 29 healthy aged volunteers. Thirty participants are to receive 5 or 10 mg/kg NX210c or placebo by 10-minute intravenous infusion three times a week for four weeks. The primary outcome is adverse events; blood and CSF pharmacokinetic measures serve as secondary outcomes. The study assesses neurologic safety using the Neurocart Battery, as well as 34 blood and 16 CSF biomarkers. Conducted in the Netherlands, the trial is set to finish in December 2024.

In December 2023, the company announced initial results (press release). The treatment remained safe and well-tolerated, with mild adverse events and no evidence of neurologic harm. Data presented at the 2024 AD/PD conference in Lisbon claimed decreases in blood homocysteine and the tight junction protein claudin 5, which were interpreted as evidence of blood-brain barrier repair. Blood levels of neurofilament light chain were said to decrease, although no numbers were shown. Changes in blood and CNS biomarkers were sustained for 40 days of follow-up, despite the drug’s short plasma half-life. The company plans to expand this trial to enroll people with Parkinson’s disease.

In April 2024, the company registered a Phase 2 trial  in ALS. To begin in September 2024, it will recruit 80 adult patients. The trial will compare four weeks of thrice-weekly 5 or 10 mg/kg doses to placebo, with a three-month follow-up. The sole outcome listed on clinicaltrials.gov is blood neurofilament light, or the CSF/serum albumin ratio, an indicator of blood-brain barrier integrity. Completion is expected in February 2026.

For details on NX210c trials, see clinicaltrials.gov and the WHO Trial Registry.