New 3-Year Data Highlight Continued Treatment Effects of Blarcamesine in Slowing Alzheimer Disease

Timo Grimmer, MD

Newly announced data from an open-label extension (OLE) of the phase 2/3 AD-004 trial showed that treatment with investigational blarcamesine (Anavex Life Sciences) resulted in continued treatment benefits through up to 4 years in patients with early-stage Alzheimer disease (AD). In addition, a delayed-start analysis of treatment with oral blarcamesine was significant reflecting importance of early treatment initiation.¹

Anavex plans to share the trial results from the OLE, otherwise known as ATTENTION-AD, at the upcoming AD/PDTM 2025 Conference, held April 1-5, in Vienna, Austria. In the study, a delayed-start analysis was performed using the prespecified Mixed effect Model Repeat Measure (MMRM) model, to evaluate the effect of early treatment with blarcamesine on all data collected in the double-blind and OLE phases of the program.

Results from the delayed-start analysis revealed a significant difference on Alzheimer’s Disease Assessment Scale-Cognitive Subcale-13 (ADAS-Cog13) between those who started blarcamesine treatment early and late (least square [LS] mean difference, –2.70; P = .0348) after 144 weeks, favoring the early start group. Notably, the treatment difference with blarcamesine continued to increase up to Week 192 (LS mean difference -3.83, P = 0.0165), suggesting that earlier initiation of treatment led to greater cognitive stability compared to delayed initiation by ~1 year.

"Long-term clinical ATTENTION-AD study results support the importance of continued long-term blarcamesine treatment,” coordinating investigator Timo Grimmer, MD, head of the Center for Cognitive Disorders at the Technical University of Munich, said in a statement.¹ "Blarcamesine is easily scalable and might be a potential therapeutic solution for patients with Alzheimer disease to potentially offer hope and relief and equitable and accessible for diverse populations and maintaining sustainability within the global healthcare systems."

Studied in other diseases like Parkinson and Rett syndrome, Blarcamesine acts primarily as an agonist of the sigma-1 receptor. This agent is designed to inhibit mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. It also has exhibited anti-apoptotic and anti-oxidant activity. In December 2024, Anavex submitted a marketing authorization application for blarcamesine as a potential treatment for AD, using findings from the double-blind portion of AD-004 as the basis for the submission.²

Additional findings from the delayed-start analysis showed that those exposed to blarcamesine earlier had numerically favorable data on Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale at week 144 (LS mean difference, +2.32; P = .125). Notably, the treatment difference continued to increase up to week 192 and reached statistical significance (LS mean difference, +4.30; P = .0206). Currently, 74 participants in the Compassionate Use Program are receiving blarcamesine, with some continuing treatment for over 9 years after completing OLEs in early and mild-to-moderate AD, and no severe or life-threatening adverse events (AEs) attributed to the therapy.³

Christopher U. Missling, PhD

"Alzheimer disease, like other chronic progressive diseases, requires a long-term therapeutic strategy. Blarcamesine mechanism of action with its convenient once daily oral dosing supports long-term therapy," Christopher U. Missling, PhD, president and chief executive officer at Anavex, said in a statement.¹ "We remain excited about the scalable and convenient features of oral blarcamesine, which could be appealing because of its route of administration and good comparative safety profile. This could reduce crucial barriers within the currently complex healthcare ecosystem for Alzheimer disease and potentially provide broader access to a diverse population with early Alzheimer disease."

READ MORE: Phase 1b PRECISE-AD Trial of Oligomer-Targeting Agent PMN310 Gets Underway

Overall, blarcamesine exhibited a favorable safety profile, with most AEs being mild to moderate, primarily occurring during the initial titration phase, and manageable with adjusted schedules. Importantly, no severe or life-threatening AEs or deaths were attributed to blarcamesine. In the ATTENTION-AD trial, dizziness—the most frequent treatment-emergent AE from the ANAVEX®2-73-AD-004 trial—was reduced significantly (25.2% to 9.6%) with an extended titration period (10 weeks vs. 2-3 weeks), showing its transient and manageable nature.

In the original AD-004 trial, which was recently published in the Journal of Prevention of Alzheimer's Disease, patients 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. In the trial, treatment with the investigational age 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 ADAS-Cog13, the coprimary end point. The functional co-primary end point, change in ADCS-ADL, was trending positive but did not reach statistical significance at week 48.^3,4

Additional data from the double-blind portion showed that 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.

A subgroup analysis presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference had clinical efficacy end points analyzed based on prespecified genetic SIGMAR1 variants (wild-type [WT] genotype and rs1800866 genotype [RS variant]) for all participants. All told, those with 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.⁵

REFERENCES
1. New Phase IIb/III Clinical Data Demonstrates Over Three Years of Continuous Treatment with Oral Blarcamesine to Significantly Benefit Early Alzheimer’s Disease Patients. News release. Anavex Life Sciences. January 13, 2025. Accessed January 13, 2025. https://www.anavex.com/post/new-phase-iib-iii-clinical-data-demonstrates-over-three-years-of-continuous-treatment-with-oral-blar
2. Anavex Life Sciences announces submission of blarcamesine MAA for treatment of Alzheimer’s disease to EMA. News release. November 26, 2024. Accessed January 13, 2025. https://www.anavex.com/post/anavex-life-sciences-announces-submission-of-blarcamesine-maa-for-treatment-of-alzheimer-s-disease-t#viewer-gn1s4909
3. 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 January 13, 2025. https://www.anavex.com/post/results-from-anavex-life-sciences-landmark-phase-iib-iii-trial-of-blarcamesine-presented-at-alzheime
4. Sabbagh MN, Chezem WR, Jin K, Missling CU. Blarcamesine in Early Alzheimer Disease Phase 2b/3 Randomized Clinical Trial. Alzheimers Dement. 2025;9(20):e090729. doi:10.1002/alz.090729
5. 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 January 13, 2025. https://finance.yahoo.com/news/anavex-blarcamesine-achieves-pre-specified-080000308.html