medwireNews: The mesenchymal stem cell therapy laromestrocel has met its primary safety endpoint in the CLEAR MIND trial of patients with mild Alzheimer disease (AD), while also showing potential efficacy in slowing whole brain and hippocampal volume loss.
“Overall, laromestrocel was safe and well tolerated in the study population, in both single and multiple dosing regimens,” state the authors, which “coupled with signals of potential efficacy, support ongoing clinical development of this novel class of therapeutics for AD.”
For the phase 2a study, Brian Rash (Longeveron, Miami, Florida, USA) and colleagues enrolled 50 patients with clinically diagnosed mild AD from 10 US centers. At baseline, the patients (mean age 74.1 years, 55.1% women) had mean Mini–Mental State Examination and Montreal Cognitive Assessment scores of 21.2 and 18.1, respectively, both of which are scored out of 30 points with higher values indicating better cognitive performance.
The patients, the majority of whom were White (95.9%) and Hispanic/Latino (75.5%), were randomly assigned to receive monthly infusions of placebo for 4 months (Group 1, n=12) or laromestrocel according to one of three infusion regimens: 25 million cells in the first month followed by monthly placebo infusions for 3 months (Group 2, n=13); monthly infusions of 25 million cells for 4 months (Group 3, n=13); or monthly infusions of 100 million cells for 4 months (Group 4, n=12). One patient in the high dose group did not receive treatment, leaving 49 participants in the intention-to-treat population.
In all, three patients treated with laromestrocel – one in each group – experienced the primary endpoint of at least one treatment-emergent serious adverse event (TESAE) within 4 weeks of an infusion, compared with none of the patients taking placebo, with the difference not reaching statistical significance.
The SAEs were grade 3 anemia, grade 4 lumbar radiculopathy, and grade 4 acute respiratory failure. All the events were “related to pre-existing conditions, none of these events was assessed as related to study product, and all resolved,” note the authors.
In addition, the total number of TESAEs and TEAEs were comparable for the laromestrocel and placebo groups, occurring in 21–24 versus 18 patients and 1–3 versus 0 patients, respectively, and “there were no deaths on the study and no TE-AEs leading to study or treatment discontinuation,” state Rash et al.
They also highlight that “[t]here were no hypersensitivities or infusion-related reactions observed during the study” and “no events of ARIAs [amyloid-related imaging abnormalities] […] including clinically asymptomatic microhemorrhages [were] detected in any study patient.”
The researchers comment: “Because we found no evidence for ARIAs, infusion with laromestrocel could indicate a potentially new class of treatment with a favorable safety profile compared to existing anti-amyloid antibody treatments, potentially complimentary to other therapeutic strategies.
“Moreover, we speculate that laromestrocel expresses protective neurovascular and anti-inflammatory effectors that have the potential to help offset ARIAs in a combination treatment.”
Clinical assessments carried out at 39 weeks showed “provisional support for a slowing of disease progression,” with laromestrocel, notes the team, with disease progression observed in the placebo group significantly attenuated among patients in group 2 and for the three laromestrocel groups combined. Disease progression was measured using a Composite Alzheimer’s Disease Score (CADS) calculated by averaging equally weighted z-scores for the Alzheimer’s Disease Cooperative Study Activities of Daily Living, Clinical Dementia Rating scale sum of boxes, Alzheimer’s Disease Assessment Scale-cognitive subscale 13, and left hippocampal volume on magnetic resonance imaging (MRI).
Moreover, among the exploratory outcomes, whole brain atrophy measured at week 39 using volumetric MRI was significantly slowed by 48% among 32 patients in the combined laromestrocel group compared with the progression observed among 10 patients in the placebo group, while left, right, and bilateral hippocampal atrophy was significantly lessened by 62%, 53%, and 59%, respectively, compared with placebo.
The investigators note that “[n]ot all clinical and imaging biomarker results showed clear dose responses, but repeated dosing produced better responses than single dosing in 27 of 35 total clinical and [volumetric] MRI measures.”
They acknowledge the small sample size of the study, the high proportion of patients of Hispanic ethnicity, and the short 39-week study duration, and therefore welcome further studies that will examine extended treatment durations and follow-up periods.
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