Background

Insufficient activity of the cholinergic system is associated with AD and cognitive decline. Two different strategies have been used to increase cholinergic activity in the AD brain: 1) acetylcholinesterase inhibitors and 2) direct stimulation of cholinergic receptors. NGX267 is a selective agonist at the M1 muscarinic acetylcholine receptor (Fisher et al., 2002). Like other M1 agonists such as AF102B (cevimeline), AF267B has been shown to increase αAPPs, decrease Aβ levels and tau hyperphosphorylation, and block Aβ-induced neurotoxicity in vitro via  M1 receptor-mediated modulation of kinases (e.g. PKC, MAPK and GSK3β; reviewed in Fisher, 2007; Fisher, 2008; Fisher, 2011). AF267B was reported to improve spatial memory in 3xTg-AD mice and was associated with reduced Aβ and tau pathology in the hippocampus and cortex (Caccamo et al., 2006).

NSC001 is a rigid analog of acetylcholine, which is is claimed to have high brain penetration and a better safety margin than other M1 agonists. NSC001 is taken by mouth.

Findings

A first-in-human dose-escalation study, sponsored by TorreyPines, treated 34 healthy men with doses from 1 to 45 mg NGX267, or placebo. The study determined a maximum tolerated dose of 35 mg in this population. Unspecified moderate or severe adverse events occurred after the 35 and 45 mg doses (Ivanova and Murphy 2009).

TorreyPines ran a second Phase 1, enrolling 26 healthy men and women between the ages of 65 and 80. According to a July 2006 press release, the drug was well-tolerated at single doses up to 15 mg, and showed evidence of cholinergic activation. In September 2007, the company announced results of a third Phase 1 study geared toward a schizophrenia indication, where doses up to 30 mg were shown to be safe and well-tolerated in healthy men 55 and younger (press release). 

In September 2008, the company stopped development of NGX267 (press release).

In December 2008, TorreyPines reported positive Phase 2 data on NGX267 to ease dry mouth in 26 people with Sjogren's syndrome. Treatment with 10, 15, or 20 mg increased salivation, with no safety concerns. Gastrointestinal discomfort was seen (press release).

In 2018, Neurimmune and NeuroScios co-founded NSC Therapeutics to develop NGX267 for the treatment of neurodegenerative diseases with cholinergic deficits, such as Alzheimer's and dementia with Lewy bodies. The drug was renamed NSC001/NI004.

In 2019-2020, a Phase 1b trial evaluated the safety of NSC001 in 65 healthy elderly volunteers. Participants took 2.5, 5, 10, or 15 mg, or placebo, daily for four weeks. Exploratory endpoints included CSF and plasma biomarkers, cognition, depression, salivation, and quantitative EEG, among others. According to results presented at the March 2024 AD/PD conference, 62 participants completed the study. Adverse events were mostly mild or moderate. Severe adverse events occurred; they were mainly attributed to lumbar puncture and 24-hour CSF collection on day 1. No typical cholinergic side effects were noted, nor effects on cognition or psychiatric symptoms. The most common adverse event was headache, which was seen equally in the treatment and placebo groups. Brain uptake of the drug was high, with CSF concentrations reaching half that in plasma. NSC001 caused no change in CSF Aβ40 or Aβ42 or NfL, and only a slight reduction in total tau. A significant reduction in pTau181 was attributed to GSK3β inhibition. Four weeks of treatment altered circadian rhythms and normalized alpha waves on EEG; this was interpreted as an indication of target engagement. This study took place in Sweden and Spain, and does not appear in registries.