Drug Development

Abstract

Background: Alzheimer's disease (AD) is characterized by progressive atrophy of the cerebral cortex and hippocampus, with concomitant increase in ventricular volume. Lomecel-B is a novel cell-based therapeutic approach to AD that targets neuroinflammation, microvascular dysfunction, and has the potential to stimulate endogenous tissue regeneration. We conducted MRI analysis of brain morphology in the CLEAR-MIND study, a 49-patient proof-of-concept study that tested 3 different dosing regimens of Lomecel-B vs placebo in patients with mild AD dementia.

Methods: This double-blind, randomized, placebo-controlled 45-week proof-of-concept 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); 25M cells (N = 13) or 100 million (100M) cells (N = 11) monthly for 4 months; 4 IV infusions of Placebo (N = 12). Lomecel-B treatment groups were evaluated for individual and pooled (25Mx1, 25Mx4, 100Mx4) groups vs placebo, n = 32.

Results: Patients receiving Lomecel-B exhibited slowing of whole brain atrophy (pooled: reduced by 48% vs placebo, p = 0.005). Lomecel-B exhibited reduced left, right and bilateral hippocampal atrophy by 62%, p = 0.021, 53%, p = 0.073 and 59%, p = 0.013, respectively. At Week 39, left, right and bilateral ventricular enlargement were reduced in Lomecel-B pooled group by up to 34%, p = 0.097, 40%, p = 0.044 and 37%, p = 0.066 respectively, compared to placebo. Moreover, diffuse tensor imaging (DTI) used to index neuroinflammation indicated increased inflammation in AD placebo but substantial reduction in the Lomecel-B pooled group, particularly the cingulate cortex (100% reduction, p = 0.002).

Conclusion: Brain MRI in this proof-of-concept study with small sample size reveals that Lomecel-B was associated with measurable neuroanatomical and neuroinflammatory improvements compared with progressive AD pathology observed in placebo. Accordingly, these findings support further development of Lomecel-B in a larger dose-finding study.