Background

This small molecule is claimed to activate AMPA receptors and increase the production of brain-derived neurotrophic factor in neurons. According to company information, it promotes neurogenesis and cognitive function. It is given orally, and is said to cross into the brain. It is being developed to treat Alzheimer’s disease, and also for the treatment and prevention of COVID19.

The NA-831 structure has not been disclosed. A patent application suggests it may be a cyclic prolyl glycine peptide or related structure. These molecules are naturally present in the brain, and positively modulate AMPA receptors (e.g. see Gudasheva et al., 2016).

No preclinical work is published on NA-831.

Findings

In Phase 1, 32 healthy volunteers in four cohorts received multiple doses of NA-831 ranging from 5 to 50 mg daily over one week. At AAIC 2018, the compound was shown having had dose-linear pharmacokinetics, low variability between people, and no adverse effects up to the highest dose tested (abstract). Additional Phase 1 results presented at CTAD 2021 established that doses up to 100 mg/day were well tolerated in healthy volunteers.

According to information on clinicaltrials.gov, a Phase 2 study began in September 2018, enrolling 126 participants with mild cognitive impairment due to AD, defined as an MMSE of 23 or greater. Treatment was to be 10, 20, or 40 mg per day or placebo for 24 weeks, against a primary outcome of change from baseline on the CDR-SB. Other outcomes were ADCS-ADL MCI version and the CIBIC-Plus. The trial took place in New Zealand, and is listed as having been completed in September 2019.

At the 2019 CTAD meeting, the company presented results of a Phase 2 trial that differed in its details from the registered trial (LB14 in CTAD abstracts). This study enrolled 112 people for six months treatment. Sixty-four were classified as having MCI, with an MMSE of 20 or greater, and received 10 mg NA-831 or placebo daily. The remaining 48 were defined as early onset AD with mild to moderate dementia, with MMSE scores greater than 17. They took 30 mg/day or placebo. The primary outcomes were the ADAS-Cog13, the brief cognitive rating scale (BCRS) and the CIBIC-plus. The company reported that NA-831 improved several domains on the BCRS starting at 12 weeks, including fatigue, anxiety, irritability, affective lability, disturbance to waking, daytime drowsiness, headache, and nocturnal sleep. ADAS-Cog scores declined 4.1 points less than on placebo in the mild to moderate group, and 3.4 points less in MCI group after treatment. More patients were reported to have improved on the CIBIC-Plus in the drug group versus placebo. No adverse events were reported.

At the October 2023 CTAD conference, the company presented protocols for a Phase 2 trial testing NA-831 in combination with aducanumab, and a Phase 3 with lecanemab. Neither trial is registered yet.

NA-831 is also in trials for depression and COVID-19 disease. In August 2023, the company announced positive top-line results for a small study in people with major depressive disorder (press release). A Phase 3 for the treatment of COVID-19 disease in combination with dexamethasone or the antiviral atazanavir is ongoing. A Phase 2 trial testing a combination with the polio vaccine for COVID was completed.

No peer-reviewed papers are available for this compound.

For details on NA-831 trials, see clinicaltrials.gov.