Drug Development.

Background: Lomecel-B is a novel cell-based therapy with potential to demonstrate clinical benefit on Alzheimer's disease (AD) and its progression. Here we present the results of a phase 2a proof-of-concept trial (n = 49) to further define the potential of Lomecel-B in patients with mild AD dementia.

Methods: This double-blind, randomized, placebo-controlled 45-week trial (ClinicalTrials.gov: NCT05233774) enrolled patients (60-85 yrs.) with mild AD dementia (MMSE score 18-24); with evidence of amyloid on positron-emission tomography (PET) and brain MRI consistent with AD. There were 4 study arms of Lomecel-B intravenous infusion: 25 million (25M) cells once followed by 3 infusions of placebo (N = 13); 25 million (25M) cells (N = 13) or 100 million (100M) cells (N = 11) monthly for 4 months; 4 IV infusions of Placebo (N = 12). The primary endpoint was safety, secondary endpoint was change from baseline to Week 39 in Composite AD Score (CADS) that equally incorporated z-scores of CDR-SB, ADAS-Cog-13, ADCS-ADL, and left hippocampal volume.

Results: The trial achieved its primary endpoint of safety and tolerability (no infusion-related reactions, ARIA or death). One SAE occurred within 30 days post-infusion for each Lomecel-B group with none for placebo. Lomecel-B 25Mx1 demonstrated a trend toward slowing of disease progression relative to placebo on the CADS score (0.38 [-0.06, 0.82], p = 0.091 (pre-specified level of significance for CADS is p = 0.1)). While CADS declined by -0.25 [95% CI, -0.56, 0.07] in placebo, no decline occurred in the individual or pooled Lomecel-B treatment groups. Regarding cognitive function, MoCA improved vs placebo (25Mx1: (4.90 [95% CI, 1.26, 8.55], p = 0.009) and (pooled: 3.74 [95% CI, 0.73, 6.75] p = 0.015). ADRQL and QOL-AD were numerically improved in Lomecel-B treatments; with significant improvement observed in the ADCS-ADL for the 100M×1 (10.74 [95% CI, 0.50, 20.98] p = 0.040) and pooled group at Week 39 p = 0.047). Lomecel-B slowed whole brain volume loss by 49% (100Mx4 (8.31 [95% CI, 0.12, 16.50] p = 0.034) with significant preservation of left hippocampal volume (pooled: 0.0253 [95% CI, 0.0015, 0.0492] p = 0.038), Week 39 compared to placebo.

Conclusion: Together, the study achieved proof-of-concept in a small sample size. Accordingly, these findings support further development of Lomecel-B in a larger dose-finding study.