Blarcamesine (ANAVEX2-73) is an orally available drug candidate under development by Anavex Life Sciences for neurodegenerative aging of the Alzheimer’s (AD) and Parkinson’s dementia (PDD) types and several other CNS disorders.. It is designed to restore cellular homeostasis by targeting the sigma-1 (σ1/SIGMAR1) and muscarinic receptors. It is in late-stage development for AD, having apparently succeeded in a Phase III clinical trial and an open-label extension (OLE), and was submitted to the European Medicines Agency (EMA) for approval in December 2024.
Target: the Sigma-1 Receptor
Blarcamesine’s main target, the sigma-1 receptor, is expressed in many different tissue types, but is especially enriched in the cerebellum, nucleus accumbens, and cerebral cortex. Variants of the sigma-1 receptor have been associated with increased risk of AD, and several sigma-1 receptor agonists have been found to ameliorate learning impairments in several animal models, including transgenic models of AD, in which they are also neuroprotective.
Localized at the endoplasmic reticulum (ER), the sigma-1 receptor regulates calcium signaling between it and the mitochondria. More recently, it has been identified as a key regulator of autophagy, particularly in autophagosome biogenesis and autophagosome-lysosome fusion. In September 2025, a new paper delineated blarcamesine’s specific biochemical mechanism in restoring autophagy via sigma-1 receptor activation.
Consistent with these mechanistic findings, blarcamesine enhances the complete autophagy process in human cells and in C. elegans and ameliorates beta-amyloid-induced muscle paralysis in C. elegans. In cell models, blarcamesine counteracts beta-amyloid-induced impairments in mitochondrial function. Blarcamesine protects mice against spatial working and contextual long-term memories induced by injecting beta-amyloid 25-35 into their brain ventricles and ameliorates the increase in hippocampal lipid peroxidation.
Additionally, Anavex asserts that sigma-1 receptor agonism “protects healthy gene expression through Chromatin Remodeling” and “prevents toxic RNA from translating into proteins (post-transcription).”
Clinical Research
In August 2014, Anavex registered a Phase IIa crossover trial (NCT02244541) on Clinicaltrials.gov whose purpose was to compare oral and intravenous doses of blarcamesine in subjects with biomarker- and clinically-diagnosed AD, followed by a six-month extension in which all subjects received oral treatment. The company made a rapid series of changes to the original study design. When the trial met its primary safety endpoint. In one of these changes, Anavex extended the extension period for an additional 208 weeks (NCT02756858).
In April 2020, Anavex-affiliated scientists published an exploratory analysis of this trial, finding favorable associations between patients’ changes in MMSE over the first 57 weeks and their mean plasma concentration of blarcamesine; the absence of the genetic risk variants of SIGMAR1 and COMT (in 21 sequenced patients); and baseline Mini-Mental State Examination (MMSE) score. They also identified a favorable correlation between the lack of risk variants in SIGMAR1 and subjects’ change in the Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL) at the same time point. The favorable associations between plasma drug concentration and changes in MMSE and ADCS-ADL were sustained at week 148, as assessed by linear mixed-effect models.
In July 2022, Anavex initiated a randomized, double-blind, placebo-controlled 48-week Phase IIb/III safety and efficacy trial of blarcamesine in people 60-85 years old with a clinical- and biomarker-based diagnosis of so-called “mild” cognitive impairment (MCI) or early-stage mild dementia due to AD (ANAVEX2-73-AD-004, registered as NCT03790709). The trial was completed in June 2022 and was rolled into the open-label extension (OLE) study ATTENTION-AD (NCT04314934), which ended in June 2024.
In January 2025, Anavex-affiliated researchers published the results of the ANAVEX2-73-AD-004 trial. The 508 subjects were randomized 1:1:1 to receive either medium- or high-dose blarcamesine or placebo once daily for 48 weeks. The co-primary outcomes were participants’ change in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) and ADCS-ADL from baseline to the end of the trial, at which point subjects were invited to enroll in the ATTENTION-AD OLE.
In the first of several oddities, the report states that 508 subjects were randomized and 503 dosed, and that “Primary and secondary analyses were carried out in the protocol-specified analysis populations, the ‘intent to treat’ (ITT) population, which corresponds to the what is typically termed “modified intent to treat” (mITT) and was defined as all randomized patients who received at least one study dose.” This is already an unorthodox construction, but the paper then gives 462 randomized participants as the intent-to-treat population, of whom 338 completed the trial.
The investigators combined the two blarcamesine dosage groups in their analysis. Blarcamesine-treated subjects exhibited significantly less worsening on ADAS-Cog13 (a co-primary outcome) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB — the secondary outcome), but the other co-primary outcome (ADCS-ADL) showed only a favorable trend. Additionally, blarcamesine-treated subjects’ plasma Aβ42/40 ratio increased significantly, and their whole-brain volume loss was attenuated relative to placebo. One or more serious treatment-emergent adverse events occurred in 16.7% of blarcamesine-treated and 10.1% of placebo-treated subjects.
Additionally, the authors made numerical comparisons between the effect size in the blarcamesine arm of ANAVEX2-73-AD-004 and the effect sizes for lecanemab and donanemab in their Phase III trials, suggesting that blarcamesine’s effects are superior.
This report was subjected to incisive criticism in a Letter to the Editor and a series of PubPeer critiques by Jesse Brodkin of Behavioral Instruments, who disclosed a prior short stock position in Anavex, and by a pseudonymous reviewer. The investigators’ rebuttal is not entirely responsive or satisfactory.
Later in January, Anavex announced the topline results of the ATTENTION-AD OLE (ANAVEX®2-73-AD-EP-004). Anavex-affiliated scientists presented the results in more detail at the 2025 Alzheimer’s Disease and Parkinson’s Disease (AD/PD) Conference in Vienna, Austria in April 2025. The extension data are for 96 weeks after the trial onset at most trial sites, but for 144 weeks after the beginning of OLE in Australia (192 weeks after the trial onset), where they had a longer followup time because the original ANAVEX2-73-AD-004 trial began and was completed prior to expanding it to other sites. During the OLE, all subjects received blarcamesine, though blinding to their original assignment during the trial proper was maintained.
The trialists used a delayed-start analysis using the prespecified mixed model for repeated measures (MMRM) to compare the cognitive and functional trajectories of subjects who had been on blarcamesine from the beginning of the trial to those who had initially been on placebo. Complicating this analysis, some subjects experienced delays in (re)starting blarcamesine between the trial proper and the initiation of the OLE due to the COVID pandemic. Hence, the trialists performed subgroup analyses on subjects who had experienced few or no days of interrupted treatment, compared with the entire ITT population (see questions regarding the “ITT population” above).
Subjects who had been assigned to blarcamesine throughout the randomized period and the OLE enjoyed significantly less worsening of ADAS-Cog13 and ADCS-ADL than did those originally assigned to placebo, and those with few or no interrupted treatment days benefited even more. Notably, the ADAS-Cog13 difference in the continuous-treatment subgroup (3.83 points) well exceeds the 2-point difference generally considered clinically meaningful.
However, the blarcamesine-start and placebo-start subjects appeared to converge on ADAS-Cog13 between weeks 48 and 96; for a true disease-modifying drug, one might expect the two groups to decline in parallel but preserve their difference during a medication interruption.
In September 2025, Anavex-affiliated scientists deposited a preprint of a prespecified pharmacogenetic analysis of the ANAVEX2-73-AD-004 trial. Similar to the Phase IIa crossover trial (NCT02244541), this analysis found that subjects lacking SIGMAR1 and COMT risk variants responded more positively to blarcamesine from baseline to 48 weeks on the co-primary cognitive and functional outcomes ADAS-Cog 13 and ADCS-ADL. The authors suggest that the slower decline in the genetically favorable cohort treated with blarcamesine is comparable to the “barely detectable” changes in prodromal AD (i.e., subjects with detectable beta-amyloid in their brains, but who are not yet clinically in MCI).
Regulatory Status
In November 2025, Anavex issued an update on their discussions with regulators regarding blarcamesine for early AD. They stated that the EMA’s Committee for Medicinal Products for Human Use (CHMP) had come to “a negative trend vote on the Marketing Authorisation Application (MAA) for blarcamesine following its CHMP oral explanation” and that they expected the CHMP to come to a formal opinion in its December meeting. Anavex stated that “based on feedback and continued guidance from the CHMP, EMA and the Alzheimer’s disease community” and in accordance with EMA procedures, it intended to request a new, independent CHMP review by a different set of reviewers, supplying them with relevant biomarker data.
In the same update, Anavex stated that following preliminary discussions, FDA’s Center for Drug Evaluation and Research (CDER) had advised them to request a meeting to discuss their blarcamesine AD clinical trial results.
In addition to AD, PDD, and PD, blarcamesine is in development for Rett syndrome, infantile spasms, Fragile X Syndrome, Angelman syndrome, and an undisclosed rare disease.