On 15 April at the American Academy of Neurology (AAN) 2024 Annual Meeting, during a scientific platform session titled ‘Emerging Science’, Alzheon presented results from its Phase II Biomarker Trial and reviewed its APOLLOE4 Phase III Trial both evaluating its oral, brain-penetrant, amyloid-oligomer inhibitor ALZ-801 in apolipoprotein E 4 (APOE4) carrier patients with early Alzheimer’s disease (AD).

Given the complex pathophysiology of AD, key opinion leaders previously interviewed by leading data and analytics company GlobalData highlight that there is no consensus on the disease-modifying therapies (DMTs) with the greatest curative potential.

However, amyloid beta (Aβ)-targeting therapies hold promise, with this mechanism of action (MOA) recently seeing some success with the US Food and Drug Administration’s (FDA) approval of Biogen’s anti-Aβ monoclonal antibody (mAb) Aduhelm in 2021, followed by the FDA approval of Eisai/Biogen’s anti-Aβ mAb Leqembi in January 2023.

ALZ-801 has the potential to be the first oral Aβ-targeting therapy to be approved in the US and EU in early AD patients who are homozygous for the APOE4 allele, a subgroup that has a strong unmet need for disease-modifying approaches.

GlobalData forecasts that the anti-Aβ therapies will reach approximately $7.1bn in the mild cognitive impairment (MCI) and mild AD patient populations by 2030 globally (US, France, Germany, Italy, Spain, UK, Japan, and China), with ALZ-801 accounting for approximately 10% of this market as the only oral asset to be available outside of China in an MOA dominated by mAbs.

Interim two-year data presented at AAN 2024 from a four-year open-label biomarker Phase II study evaluated the DMT effects of ALZ-801 in 84 APOE4 carrier patients with early AD (n=31 APOE4/4 homozygotes and n=53 APOE3/4 heterozygotes).

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A total of 70 patients of the 84 enrolled completed the 104-week treatment period and were included in the outcomes evaluation.

Overall, ALZ-801 treatment demonstrated sustained improvement over two years in plasma biomarkers, hippocampal volume, and cognitive effects in the target population.

In its primary endpoint of plasma phosphorylated-tau 181, a statistically significant early and sustained reduction was observed at all timepoints, reaching 31-43% over 52-104 weeks (p=0.045).

On secondary endpoints, plasma Aβ42 decreased ~4% over 104 weeks (p=0.042).

The primary imaging outcome of magnetic resonance imaging hippocampal volume showed hippocampus atrophy (3.6%) that was approximately 28% less than matched external controls (Alzheimer’s Disease Neuroimaging Initiative, ADNI-1 study; NCT00106899), demonstrating a strong correlation with ALZ-801’s cognitive benefits.

These cognitive benefits were seen in Rey Auditory Verbal Learning Test total memory scores and Digit Symbol Substitution Test scores, which remained above/at baseline at 104 weeks having improved at 26 weeks, as well as 50% and 33% of MCI and mild AD subjects, respectively, maintaining their AD stage at 104 weeks as measured by their Clinical Dementia Rating score.

Further, ALZ-801 demonstrated a benign safety profile over the two years, with no observed cases of amyloid-related imaging abnormalities related to underlying vasogenic oedema, a known side effect of the anti-Aβ mAbs, to date.

The presented biomarker results support the disease-modifying effects of ALZ-801 in APOE4 carriers with early AD with promising clinical efficacy and favourable safety.

Alzheon is planning to announce topline results for its pivotal APOLLOE4 Phase III trial in the third quarter (Q3) of 2024.

Should Phase III outcomes follow the positive outcomes from the two-year Phase II biomarker data and support the hypotheses that by acting upstream of anti-Aβ mAbs, ALZ-801 could provide significantly improved amyloid clearance, it will pave the way for Alzheon’s potential NDA submission later this year and subsequent launch in 2025 as the first oral anti-Aβ DMT in the US.