Oral blarcamesine delivers long-term benefit in early AD

Findings from the phase IIb/III ATTENTION-AD study reflect the continued benefit of oral blarcamesine in individuals with early Alzheimer’s disease (AD) after receiving the drug continuously for up to 4 years.

“The critical element is long-term safety,” noted Dr Marwan Sabbagh from the Barrow Neurological Institute, Phoenix, Arizona, US, at AAIC 2025. “After 4 years, there were no new emergent events … There were no amyloid-related imaging abnormalities events, no deaths relative to the drug, no adverse toxicities on vital signs, and no liver toxicities.”

Moreover, treatment-emergent adverse events (TEAEs) tended to be mild, and most were transient and resolved with dose reduction, Sabbagh added. “Titration adjustment demonstrated the manageable nature of the most frequent TEAE (eg, dizziness) … Adherence was also excellent over the long term.”

A delayed-start analysis was conducted to evaluate the effect of early treatment initiation up to 192 weeks in 508 participants with confirmed early AD pathology. They were randomized 1:1:1 to once-daily oral blarcamesine 30 mg, blarcamesine 50 mg, or placebo for 48 weeks. After which, all participants rolled over to blarcamesine at their best tolerated dose (up to 50 mg) in the open-label extension phase (OLE). [Sabbagh, et al, AAIC 2025]

Of note, there was variability in the dosing restart primarily due to COVID. Hence, some participants had continuous treatment while others had a treatment interruption or a washout for a certain period during the OLE.

Key efficacy findings

Blarcamesine significantly reduced clinical decline, as reflected by the continued improvement in clinical functional outcomes up to week 192. Sabbagh noted that the differences were robust and did not wash out regardless of the delayed restart.

When looking at ADAS-Cog₁₃*, the week-48 treatment difference in estimated mean change between early (ie, those who received blarcamesine throughout the trial) and delayed (ie, those who transitioned from placebo to blarcamesine) starters was -2.027. By week 192, this increased to -3.83 (p=0.0165) among participants who had a washout period and to -4.20 (p=0.0083) among those who did not.

A similar trend was observed for ADCS-ADL**. At week 48, the difference in estimated mean change between early and delayed starters was +0.775. This increased at the end of the OLE among participants who had a washout (+4.30; p=0.0206), more so among those who did not (+5.75; p=0.0015).

Drug interruption led to a loss of drug effect and was associated with slightly worse efficacy results. The more pronounced effect among those who had no drug interruption highlights the benefit of continued long-term treatment, Sabbagh noted. “There was no substantial loss of drug effect … [Hence,] continued blarcamesine treatment – without interruption – is encouraged for a more favourable outcome.”

Novel mechanism of action

“There are no approved oral disease-modifying small molecule therapies for the treatment of early AD … Blarcamesine has a new mechanism of action. This is not an amyloid-dominated or a tau-dominated mechanism, but a SIGMAR1 activation,” noted Sabbagh.

He further explained that impaired autophagy, which leads to lysosomal and somatic dysfunction, could be a triggering event for the accumulation of amyloid and the downstream pathology.

“[The idea is to] restore autophagy through SIGMAR1 activation … [By administering] an oral SIGMAR1 activator, autophagy would be restored by normalizing lysosomal function, which, in turn, leads to docking, auto-degradation, neuroprotection, and homeostasis,” Sabbagh continued.

Taken together, the findings underline the potential disease-modifying effect of oral blarcamesine and that early treatment initiation and continued long-term treatment yield a sustained therapeutic benefit in early AD patients, Sabbagh said. “Altogether, these results indicate that blarcamesine may be an effective, safe, and novel scalable oral treatment for early AD.”