Aims

To introduce the Neurogenesis Hypothesis for Alzheimer’s Disease as an alternative approach to Amyloid Hypothesis. Phase 2A clinical results of NA-831 will be presented to support this hypothesis.

Methods

Neurogenesis Hypothesis for Alzheimer’s Disease

The hippocampus continues to generate new neurons throughout life, a process is known as adult hippocampal neurogenesis (AHN). There was a marked and progressive decline of DCX+ cell numbers in AD patients as compared with healthy individuals. AHN impairment appears to take place prior to the presence of senile plaques and neurofibrillary tangles. NA-831 has been shown to increase BDNF levels in the hippocampus and exhibit neuroprotection and neurogenesis.

Phase 2 trials of NA-831 was performed in 56 patients with MCI, mild and moderate Alzheimer’s disease. The patients with MCI received 10 mg of NA-831 and patients with mild and moderate AD received 30 mg of NA-831 or placebo orally per day. Subjects with MCI has MMSE score ≥22. Subjects with mild & moderate AD. MMSE: 17-21.

Results

NA-831 showed a significant improvement for MCI patients, with ADAS-Cog-13 score of an average of 3.4 as compared to the placebo after 24 weeks of treatment (p = 0.01; ITT).

NA-831 showed a significant improvement for patients with mild and moderate AD with the ADAS-Cog-13 score change of an average of 4.1 as compared to the placebo after 24 weeks of treatment (p = 0.001; ITT).

NA-831 was well-tolerated at 30 mg/day. There were no serious adverse events observed.

Conclusions

NA-831 has been demonstrated a proof of safety and efficacy as a potential disease-modifying drug for improving cognitive functions for patients with MCI and mild & moderate Alzheimer’s disease.

The Neurogenesis Hypothesis is a viable guidance for research in Alzheimer’s disease

Aims

Background

ALZ-801 (valiltramiprosate) is an oral, brain-penetrant, small molecule inhibitor of amyloid oligomer formation in development for Alzheimer’s disease (AD). ALZ-801 is being evaluated as a disease-modifying treatment in two ongoing Early AD trials: fully enrolled Phase 2 study in APOE4 carriers and APOLLOE4 Phase 3 study in APOE4/4 homozygotes.

Objectives

Evaluate results from pre-specified interim analysis at 52 weeks on plasma biomarkers of AD, hippocampal volume (HV), and clinical outcomes.

Methods

Methods

Open-label Phase 2 biomarker study evaluating ALZ-801 265 mg BID in Early AD subjects (MMSE 22-30) with APOE4/4 or APOE3/4 genotype is conducted at 7 sites in the Czech Republic and Netherlands. Biomarker analyses completed at the Clinical Neurochemistry Laboratory of Gothenburg University, Sweden, were blinded to demographics or genotype. The primary biomarker outcome was p-tau₁₈₁ and HV was the primary imaging outcome. The HV atrophy was compared to matched external control subjects from AD Neuroimaging Initiative cohort (ADNI).

Results

Results

A total of 84 APOE4 carriers enrolled and received ALZ-801, and 80 and 75 subjects completed 26 and 52 weeks, respectively. Plasma p-tau₁₈₁ change from baseline was significant at 13 and 26 weeks and reached -41% at 52 weeks (p=0.016). Bilateral HV atrophy at 1 year was reduced by 25% compared to the matched ADNI subjects. Most common adverse events were mild nausea and COVID infection, with no drug-related serious events and no events of ARIA-E in 75 subjects at 52 weeks.

Conclusions

The significant effects on plasma biomarkers, HV and clinical benefits support the disease modifying potential of ALZ-801 in AD. The favorable safety, low risk of ARIA-E, and convenience of a simple oral regimen, make ALZ-801 an attractive potential treatment with wide access for AD patients.

Aims

Xanamem® is a potent inhibitor of 11-beta hydroxysteroid dehydrogenase type 1, which converts intracellular cortisone to active cortisol. We explored the interaction of p-tau181 and other selected baseline characteristics with clinical outcomes from the Phase 2a randomized trial, XanADu.

Methods

The XanADu trial randomized 185 participants with mild, probable AD to Xanamem 10 mg or placebo for 12 weeks. 72 had stored plasma samples available. Biomarkers included p-tau181 and GFAP (Simoa HD-X assay) and Abeta42/Abeta40 (ELISA assay). The efficacy of Xanamem was explored in 4 prespecified subgroups of p-tau181 > median (> 6.74pg/mL), p-tau181 > 10.2pg/mL, Abeta42/Abeta42 ratio < median and MMSE 20-23. Treatment effects on biomarker levels were assessed. Analysis was by ANCOVA without correction for multiple comparisons.

Results

Clinical characteristics were similar to the original XanADu population: mean (SD) age 71 (8) years, CDR-SB 3.9 (1.6) and MMSE 22 (3). In the p-tau181 > 6.74pg/mL group (n=34), Xanamem showed a clinically significant benefit of 0.6 (mean) or 0.75 (median) CDR-SB points compared to placebo (Cohen’s d=0.41, p=0.09), i.e. a 60-75% relative reduction of disease progression. Similar effect sizes were seen in the p-tau181 > 10.2pg/mL group. A trend was present in the Neurologic Test Battery of executive function (Cohen’s d=0.26, p=0.48) but not on other endpoints such as ADAS-Cog14. Patients with MMSE 20-23 (n=46) had a clinically significant improvement in MMSE of 2 to 3 points compared with placebo (Cohen’s d=0.62, p=0.02). Treatment did not change plasma biomarker levels.

Conclusions

Selecting patients with mild AD by plasma p-tau181 to enrich for risk of disease progression can aid the demonstration of clinical benefit, as seen in this study of Xanamem treatment over 12 weeks.

Aims

AR1001, a small molecule, is being investigated as a polypharmacological therapeutic agent for Alzheimer’s disease (AD). This Phase 2 study aims to evaluate the safety and efficacy of AR1001 in patients with mild to moderate Alzheimer’s disease.

Methods

This double-blind, randomized, placebo-controlled, parallel-group comparison trial of AR1001 investigated its safety and efficacy in mild to moderate AD patients over 52 weeks. MMSE-2 score at the screening visit of ≥ 21 for Mild and ≤ 20 for Moderate was used to divide the participants by AD disease severity.

Plasma samples were collected at week 0, 26, 52 and tested for quantitative determination of biomarkers Neurofilament LightChain (NfL), Glial Fibrillary Acidic Protein (GFAP), Abeta 1-40 (Aβ1-40), Abeta 1-42 (Aβ1-42), and pTau 181 at Quanterix using their Simoa HD-X analyzer using Single Molecule Array (Simoa) technology.

Results

182 participants consented to blood draw for biomarker research at Screening, and 71 participants completed the last visit at week 52. Overall, a clear separation of biomarker levels between the mild and moderate groups are observed at baseline. GFAP and pTau-181 showed statistically significant difference between mild and moderate groups. At week 52, both 10 mg and 30 mg groups demonstrated statistically significant reduction of pTau-181 over baseline. For the mild participants, Nfl and GFAP showed decreasing trend over 52 weeks, whereas the moderate participants showed increasing trend over 52 weeks.

Conclusions

The biomarker results are generally consistent with the analysis of the clinical endpoints, where the mild group outperformed moderate group. Furthermore, the dramatic reduction of pTau-181 is consistent with the expected mechanism of AR1001. A Phase 3 trial to further evaluate the therapeutic potential of AR1001 in early AD population will be conducted this year.