Anavex Submits Marketing Authorization Application for Blarcamesine in Alzheimer Disease in the EU

Christopher U. Missling, PhD

According to a new announcement, Anavex Life Sciences has submitted its marketing authorization application (MAA) for blarcamesine, a small molecule activator of the sigma-1 receptor (SIGMAR1), as a potential treatment for patients with Alzheimer disease (AD). Thus far, the European Union (EU) has not set a specific prescription drug user fee act date to decide the drug’s fate.¹

The application is based on data from the phase 2/3 AD-004 trial, a randomized, double-blind, placebo-controlled, 48-week study of 508 individuals with a confirmed diagnosis of early-stage AD. In the trial, treatment with blarcamesine resulted in significant slowing of clinical decline by 38.5% in the 50 mg group and by 34.6% in the 30-mg group, relative to placebo, on Alzheimer’s Disease Assessment Scale-cognitive subscale 13 (ADAS-Cog13), the coprimary end point.²

Patients in the study were randomly assigned 1:1:1 to either blarcamesine at 30 mg (n = 170) or 50 mg (n = 168) doses, or placebo (n = 170), for a 48-week period. The functional co-primary end point, change in AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL), was trending positive but did not reach significant at week 48. In the blarcamesine 30- and 50-mg groups, investigators observed deltas of 0.890 (P = .354) and 0.652 (P = .527), respectively, at the week 48 time point.

"It’s a remarkable milestone accomplishment and this regulatory submission in the EU represents an important step in our efforts to potentially bring the first oral novel treatment Alzheimer disease to the Alzheimer disease community," Christopher U. Missling, PhD, president and chief executive officer at Anavex, said in a statement.¹ "I would like to thank all involved and especially the participating families within our clinical development program, were we have seen that oral blarcamesine has the potential to slow the progression of this relentless and ultimately fatal disease."

In terms of safety, treatment-emergent adverse events (TEAEs) from blarcamesine tended to occur within the first 24 weeks after starting treatment and were primarily related to titration schedule. Across both dosed groups, the most common treatment titration AEs were dizziness, confusional state, balance disorder, and fatigue, among others. All AEs, including dizziness, were mostly grade 1 or 2, transient, and manageable by adjusting titration and dosing time.

After 48 weeks, blarcamesine significantly reduced brain atrophy compared to placebo (P < .001), slowing atrophy by 37.6% in whole brain volume (P = .0019), 63.5% in total gray matter (P = .0035), and 25.1% in lateral ventricles (P = .0015), with no significant difference observed in total white matter (P = .8318). After 48 weeks of treatment, the Clinical Dementia Rating-Sum of Boxes score, a key secondary endpoint, showed significant improvement with MMRM-estimated deltas of –0.502 (P = .020) and –0.465 (P = .045) for the blarcamesine 30 mg and 50 mg groups, respectively.

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At the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, a subgroup analysis of the study confirmed blarcamesine’s mechanism of action as a potential therapy for AD. The analysis, led by Marwan Sabbagh, MD, a professor of neurology at Barrow Neurological Institute, had clinical efficacy end points analyzed based on prespecified genetic SIGMAR1 variants (wild-type [WT] genotype and rs1800866 genotype [RS variant]) for all participants.³

Participants with the SIGMAR1 WT gene demonstrated greater clinical benefit with blarcamesine compared to the full intent-to-treat population, showing slowed clinical progression by 49.3% vs. 36.3% on the ADAS-Cog13 and by 33.7% vs. 27.6% on the CDR-SB. This group, which excludes individuals with the SIGMAR1 rs1800866 variant, highlighted the consistency of SIGMAR1 activation with blarcamesine. Among SIGMAR1 WT participants, blarcamesine significantly slowed clinical decline compared to placebo.

On the ADAS-Cog13, WT participants in the blarcamesine group demonstrated a difference of –2.317 points (95% CI, –4.182 to –0.453) compared to placebo, reflecting a 49.8% reduction in decline at 48 weeks (P = .015). In contrast, participants with the rs1800866 variant showed a smaller, non-significant difference of –1.593 points (95% CI, –4.174 to 0.989; P = .2254). On the CDR-SB scale, WT participants receiving blarcamesine had 33.7% less decline compared to placebo (difference of –0.601, 95% CI, –1.070 to –0.133; P = .012), while those with the variant exhibited a non-significant difference of –0.230 (95% CI, –0.826 to 0.367; P = .4485).

"This MAA submission is the first for oral blarcamesine as we are requesting a review of the Marketing Authorization Application with the aim to move closer to bringing this therapy to patients with Alzheimer’s disease worldwide," Juan Carlos Lopez-Talavera, MD, PhD, head of research and development at Anavex, said in a statement.¹ "Blarcamesine’s safety and efficacy profile could represent a novel treatment that could be complementary or an alternative to anti-beta amyloid monoclonal antibody drugs."

REFERENCES
1. Anavex Life Sciences announces submission of blarcamesine MAA for treatment of Alzheimer’s disease to EMA. News release. November 26, 2024. Accessed November 26, 2024. https://www.anavex.com/post/anavex-life-sciences-announces-submission-of-blarcamesine-maa-for-treatment-of-alzheimer-s-disease-t#viewer-gn1s4909
2. Results from Anavex Life Sciences landmark phase 2b/3 trial of blarcamesine presented at Alzheimer’s Association Conference. News release. Anavex Life Sciences. July 28, 2024. Accessed August 6, 2024. https://www.anavex.com/post/results-from-anavex-life-sciences-landmark-phase-iib-iii-trial-of-blarcamesine-presented-at-alzheime
3. Anavex’s Blarcamesine Achieves Pre-specified Efficacy in Phase IIb/III Alzheimer’s Trial: Data Presented at CTAD Conference 2024. News release. Anavex Life Sciences. October 31, 2024. Accessed November 26, 2024. https://finance.yahoo.com/news/anavex-blarcamesine-achieves-pre-specified-080000308.html