Blarcamesine Shows Significant Slowing of Alzheimer Disease in Phase 2/3 Trial

Marwan Sabbagh, MD

Newly presented data from a phase 2b/3 study of patients with early-stage Alzheimer disease (AD) showed that treatment with blarcamesine (Anavex Life Sciences) was safe, with no associated neuroimaging adverse events (AEs), and resulted in significant slowed clinical decline on several notable end points. Based on the totality of the data, the company intends a full regulatory submission of blarcamesine in Europe in Q4 of 2024.^1,2

Blarcamesine, a novel, investigational small molecule that activates an upstream compensatory process, also resulted in meaningful treatment effect on predesignated biomarkers within the amyloid, tau, and neurodegeneration (A/T/N) spectrum, further supporting its development as a potential treatment for AD.

Also known as AD-004, the randomized, double-blind, placebo-controlled, parallel group trial randomly assigned patients 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. Presented at the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1, in Philadelphia, Pennsylvania, once daily treatment with the agent 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.

Among blarcamesine-treated patients, treatment-emergent adverse events (AEs) 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 (mild), transient (approximately 7-11 days), and manageable by adjusting titration and dosing time.

"These data are very exciting, particularly in a study that can demonstrate objective slowing of markers of neurodegeneration," lead investigator Marwan Sabbagh, MD, a behavioral neurologist at Barrow Neurological Institute, said in a statement.¹ "The advantage of blarcamesine is that it is a small oral molecule that exerts clinical benefits on cognition and neurodegeneration and could be appealing because of its route of administration and good comparative safety profile. The neuroimaging evaluation performed in the Phase IIb/III study demonstrated no neurological tissue damage such as hemorrhage or Amyloid-related imaging abnormalities (ARIA), as documented with other anti-amyloid targeted therapies."

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 significance 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.

Clinical Dementia Rating-Sum of Boxes score, a key secondary end point, was significant after 48 weeks of treatment. Using mixed model for repeated measures (MMRM) estimates, investigators recorded deltas of –0.502 (P = .020) and –0.465 (P = .045) for the blarcamesine 30 and 50-mg groups, respectively. On Clinical Global Impression-Improvement scale, the 30- and 50-mg blarcamesine groups demonstrated delta values of –0.248 (P = .024) and –0.314 (P = .008), respectively, over the 48-week period.

Sabbagh added, "We believe the scalable and convenient features of blarcamesine could reduce crucial barriers within the currently complex healthcare ecosystem for Alzheimer disease and provide broader access to a diverse population with early Alzheimer disease."

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Blarcamesine is designed to improve upstream autophagy and clearance of misfolded proteins in AD through SIGMAR1 activation. Anavex believes that the agent can be a scalable potential therapeutic solution for AD by countering neurodegeneration and improving autophagy, a key clearance mechanism that removes protein aggregates and misfolded proteins.

Those on active treatment demonstrated significantly reduced brain atrophy after 48 weeks in comparison with placebo (P <.0001). More specifically, it slowed brain atrophy by 37.6% (P =.0019), 63.5% (P = .0035), and 25.1% (P = .0015), in key regions of whole brain, total grey matter, and lateral ventricles, respectively. Investigators did not observe significant changes in total white matter between the treatment groups (P = .8318).

Christopher U. Missling, PhD

On plasma amyloid-ß (Aß)42/40 ratio, pooled blarcamesine groups showed significant increases relative to placebo, with deltas of +0.013 (P = .048). While patients on placebo showed continual increases in relevant biomarkers of neurofilament light (NfL) and plasma phosphorylated tau 181 and 231, those treated with blarcamesine showed significantly less change across the 48-week period. Overall, investigators recorded P values of 0.28, 0.39, and 0.44, respectively, on NfL, p-tau181, and p-tau213, respectively.

"Alzheimer disease is such a devastating disease that affects tens of millions worldwide. The findings from this and previous studies with blarcamesine in Alzheimer’s disease further strengthen our belief in the potential of addressing the complex pathology in Alzheimer’s disease through an upstream precision medicine compensatory process, autophagy through SIGMAR1 activation,” Christopher U. Missling, PhD, president and chief executive officer at Anavex, said in a statement.¹ "We like to thank all the people involved in the study for their invaluable contributions and we look forward to continuing our journey to address the high unmet need for patients with Alzheimer disease with a potential new convenient orally available treatment option for Alzheimer disease."

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REFERENCES
1. 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
2. Sabbagh MN. Blarcamesine in early Alzheimer’s disease: phase 2b/3 randomized clinical trial. Anavex Life Sciences. July 28, 2024. Accessed August 6, 2024. https://www.anavex.com/_files/ugd/79bcf7_79c4b8754b9f4eaca6da3e912e11689b.pdf