Background

This compound is an agonist of the intracellular sigma-1 chaperone protein. Specifically, it is a mixed ligand for sigma1/muscarinic receptors. Expressed in most tissues and located at focal contacts between mitochondria and the endoplasmic reticulum, the sigma-1 receptor forms heterodimers with many other membrane receptors, and as such influences multiple cellular pathways and physiological processes. Blarcamesine reportedly binds the sigma-1 receptor in the high nanomolar and the muscarinic receptor in the low micromolar range.

The compound has been reported to have memory-preserving and neuroprotective effects in mice treated with the muscarinic receptor antagonist scopolamine, with synthetic Aβ oligomer injection, or with the NMDA receptor agonist dizocilpine (Villard et al., 2011). Other studies in the Aβ oligomer injection model suggest that blarcamesine may block tau hyperphosphorylation and protect mitochondria (Jan 2013 conference news; Lahmy et al., 2013; Lahmy et al., 2014). Activation of the sigma receptor promotes autophagy, which may contribute to blarcamesine’s neuroprotective actions by facilitating clearance of pathogenic proteins (Christ et al., 2019; Yang et al., 2019).

Findings

According to information previously on its website, Anavex conducted an initial Phase 1 study in healthy men in Germany that claimed to determine a maximal tolerated dose of 55 mg.

In August 2014, the company listed a Phase 2a study that was to compare oral and intravenous doses in a two-phase, 36-day crossover design followed by a six-month extension. The study design was originally registered as double-blind, though the treatment descriptions were open-label. It was to enroll 32 people with mild to moderate AD whose clinical diagnosis was consistent with findings on a CT or MRI scan. Intervention was to consist of a five-week period of either daily oral doses or daily infusions, which cross over to the other delivery mode at midpoint, followed by six months of once-daily oral dosing. The stated primary outcome was to determine the maximum tolerated dose. Secondary outcomes included pharmacokinetic blood tests as well as various efficacy measures such as MMSE, ADCS-ADLs, and EEG. This trial was conducted in Melbourne, Australia. It used no placebo control.

According to the clinicaltrials.gov changes record, in October 2014 Anavex entered changes switching study design to open-label, reducing the number of arms from eight to four, and reducing the number of exclusion criteria from 23 to four, with investigator discretion added. The study started recruiting in December 2014. In September 2015 the follow-up period of daily dosing was lengthened from six to 12 months (see clinicaltrials.gov changes record). In October 2019, the company added a four-year open-label extension, to run through November 2020.

According to a presentation at AAIC 2016, after 31 weeks of dosing in 28 patients, the drug met safety endpoints. Most adverse events were mild or moderate, with headache and dizziness the most frequent. Most people took 20 or 30 mg daily; the maximum tolerated dose was 48 mg. Scores on MMSE and ADCS-ADL remained steady. A subsequent paper showed safety to have been maintained out to 148 weeks. Statistical modeling of complete trial data linked changes in MMSE and ACDS-ADL scores over 57 weeks with blood blarcamesine levels, baseline MMSE, and genetic variants in the sigma receptor gene and catechol-O-methyltransferase genes (Hampel et al., 2020).

In July 2018, a Phase 2b/3 trial at 16 sites in Australia began enrolling 450 people with mild cognitive impairment or early dementia, plus PET or CSF confirmation of AD pathology. Participants are randomized to 50 or 30 mg blarcamesine or placebo, taken as capsules once daily for 48 weeks. The primary outcomes are change in ADAS-Cog and ADCS-ADL, safety, and tolerability. Secondary measures include CDR- SB, structural and functional MRI, and sleep score. The trial assesses blood and CSF concentrations of Aβ40, Aβ42, total and phosphorylated tau, NfL, YKL-40, neurogranin, and BACE1. A subgroup analysis is planned based on participants’ sigma receptors and COMT genotype. In October 2019, Anavex added a two-year, open-label safety extension and, in June 2020, it announced the trial would expand to sites in the United Kingdom and Canada (see press release).

The main trial was completed in June 2022, with a final enrollment of 509. According to top-line results presented at the 2022 CTAD conference in San Francisco, both dose groups were combined and compared to placebo. Analyzed in this way, the drug was reported to slow decline on the ADAS-Cog by 45 percent and on the secondary CDR-SB by 27 percent. Graphs plotting the treatment and placebo group's values on outcome measures over time were not shown. Data was not presented for the co-primary, the ADCS-ADL. In the safety analysis, dizziness and confusion occurred in 25 and 13 percent of patients taking blarcamesine, respectively, compared to 5.6 and 2.5 percent in the placebo group (see slides).

At the August 2024 AAIC, the company showed additional data, reporting that treatment with either dose was associated with an approximately 2-point difference in the ADAS-Cog13 and 0.5-point difference in CDR-SB after 48 weeks, which were statistically significant. This was presented to translate to 35 percent less decline in the ADAS-Cog and 25 percent less on the CDR-SB in the treated group. The ADCS-ADL did not differ between treatment and placebo groups. The Clinical Global Impression declined less on drug, as did measures of brain volume, gray matter volume, and ventricular enlargement. The Aβ42/40 ratio in plasma was increased. Other biomarkers showed numerical improvement, but changes were not statistically significant. The company plans to apply for European marketing approval in 2024, based on the cognitive endpoint results (press release). The open-label extension finished in June 2024.

This compound is also in development for Parkinson’s disease dementia and Rett Syndrome (Ette et al., 2023). Top-line results from a placebo-controlled, Phase 2 PDD study were presented at the 2020 CTAD conference. It enrolled 132 participants, and treatment with 30 or 50 mg daily for 14 weeks was reported to result in improvements in memory and attention measures compared to placebo. An open-label extension ran until June 2022. Anavex in February 2021 received Michael J. Fox Foundation funding for a pharmacokinetics/CNS exposure study in 24 people with Parkinson's disease.

For Rett Syndrome (Kaufmann et al., 2019), Anavex announced symptomatic improvements for a 31-patient Phase 2 study (Dec 2020 press release). A Phase 3 trial of 31 adult patients was completed in September 2021, and the company announced positive top-line results in February 2022 (press release), though the trial is mired in controversy (BusinessWire, BioSpace). A Phase 2/3 trial in 92 pediatric patients began in July 2020 and ran until June 2023.

In November 2022, blarcamesine received Orphan Drug Designation from the U.S. FDA for Fragile X syndrome. The company has published positive preclinical results in mouse models of this disease (Cogram et al., 2022; Reyes et al., 2021).

In May 2024, two related class-action lawsuits were filed against Anavex Life Sciences Corporation (8 May PR Newswire, 8 May PR Newswire).

For trial details, see clinicaltrials.gov.

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