Alzheimer Agent Lomecel-B Meets Primary End Point in Phase 2a CLEAR MIND Study

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Investigators observed no new safety concerns, no cases of Alzheimer-related imaging abnormalities, and no notable changes in laboratory evaluations and EKG.

Wa’el Hashad, chief executive officer, Longeveron

Wa’el Hashad

Longeveron recently announced positive topline data from its phase 2a CLEAR MIND study (NCT05233774) of Lomecel-B, with results showing that the agent met its primary end point of safety, with slowing of disease worsening in patients with mild Alzheimer disease (AD). The company is planning to report additional exploratory end points of brain volumetry by MRI, biomarkers relevant to inflammation and endothelial/vascular system, and measures of cognitive function.1

The trial was comprised of 50 patients aged 60-85 years old with a diagnosis of mild AD in accordance with National Institutes of Health-Alzheimer’s Association criteria, a Mini-Mental State Exam (MMSE) score of 18-24, and a brain MRI and PET scan consistent with AD. At the conclusion of the 39-week treatment period, the agent met its primary end point of safety, with no new concerns. Investigators reported no incidences of hypersensitivity, no cases of amyloid-related imaging abnormalities (ARIA), no clinically asymptomatic microhemorrhages on MRI, and no notable changes in laboratory evaluations and electrocardiogram.

"We believe these results provide important validation of both the safety and therapeutic potential of Lomecel-B™ in the treatment of Alzheimer’s disease and provide a robust foundation for additional clinical trials in this and other indications," Wa’el Hashad, chief executive officer, Longeveron, said in a statement. “We believe these results provide important validation of both the safety and therapeutic potential of Lomecel-B™ in the treatment of Alzheimer’s disease and provide a robust foundation for additional clinical trials in this and other indications."

Lomecel-B is a living cell product made from specialized cells isolated from the bone marrow of young healthy adult donors. These specialized cells, known as medicinal signaling cells (MSCs), have been shown to perform a number of complex functions in the body, including the formulation of new tissue. In the trial, patients were randomly assigned 1:1:1:1 to either Lomecel-B at a dose of 25 x 106 cells (25M) on day 0, followed by placebo infusions at weeks 4, 8 and 12; Lomecel-B at a dose of 25M administered on day 0, week 4, week 8, and week 12 for a total of 4 doses; and at a dose of 100 x 106 cells (100M) administered on day 0, week 4, week 8, and week 12, for a total of 4 doses.

In total, 49 of the 50 randomized patients were treated in the study, which spanned 10 centers in the US. Within the first 30 days of treatment, there was 1 serious adverse event (AE) reported in each Lomecel-B treatment group and none on placebo. Each serious AE was reviewed and assessed by the Data and Safety Monitoring Board with no safety issues raised.

Investigators assessed the therapy on other secondary measures, including the Composite Alzheimer’s Disease Score (CADS), which combines the Alzheimer’s Disease Assessment Scale- Cognitive subscale 13, Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Clinical Dementia Rating-Sum of Boxes, and left hippocampal volume. For efficacy analysis, testing of the secondary endpoint proceeded using a pre-specified, 2-sided alpha of 0.1. Individual components of the CADs were evaluated at 2-sided alpha of 0.05.

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After 39 weeks of treatment, investigators reported statistically significant improvement in CADS for the Lomecel-B 25 x 106 cells (25M) x 1 dose (P = .091) vs placebo and for the pooled Lomecel-B groups (25M x 1 dose, 25M x 4 doses, 100 x 106 cells [100M] x 4 doses; P = .099). On specific CAD components, Lomecel-B (25M x 1 dose) demonstrated statistically significant slowing of disease progression in left hippocampal volume (P = .015) relative to placebo. ADCS-ADL and left hippocampal volume at week 39 were statistically significant for the pooled Lomecel-B treatment groups (25M x 1 dose; 25M x 4 doses; 100M x 4 doses) relative to placebo (P = .047) and (P = .038), respectively.

"These study results with Lomecel-B™ are encouraging,” Jeffrey Cummings, MD, vice chair of research, UNLV Department of Brain Health, said in a statement.1 "The study met its primary safety endpoint and is supported by lack of deterioration in cognitive or atrophy signals. The efficacy observations are encouraging, and these results should be used as a foundation for further studies."

Prior to CLEAR MIND, Longeveron conducted a phase 1, first-in-human trial of 33 patients with mild AD to assess the safety of Lomecel-B. Patients in the trial were randomized to receive a single intravenous infusion of a low-dose (2 x 107 cells) or high-dose (1 x 108 cells) of Lomecel-B, or placebo. After 30 days of treatment, the agent met its primary end point of safety, with only one observed treatment-emergent serious AE found in the high-dose Lomecel-B arm. The patient reported back pain which resulted in 24-hour hospitalization; however, it was deemed unrelated to the active treatment.2

Additional data from the phase 1 study showed significantly higher post-treatment anti-inflammatory serum biomarkers in treated patients. These included soluble interleukin-2 receptor α (sIL-2Rα), IL-10, IL-12, and IL-4. sIL-2Rα significantly increased in the high-dose Lomecel-B arm vs placebo (P <.0049) while the low-dose arm significantly increased IL-10 (P <.0349) and IL-12 (P <.0015) vs placebo. The low-dose Lomecel-B arm showed no significant changes in MMSE, and was significantly better than placebo at week 13 by 2.69 (±1.39) points (P = .0182; 2-sided 95% CI, 0.51-4.97).

REFERENCES
1. Longeveron announces positive top-line results for Lomecel-B in its CLEAR MIND phase 2a clinical trial in the treatment of mild Alzheimer’s disease. News release. Longeveron. October 5, 2023. Accessed December 22, 2023. https://investors.longeveron.com/news/News/news-details/2023/Longeveron-Announces-Positive-Top-Line-Results-for-Lomecel-B-in-its-CLEAR-MIND-Phase-2a-Clinical-Trial-in-the-Treatment-of-Mild-Alzheimers-Disease/default.aspx
2. Brody M, Agronin M, Herskowitz BJ, et al. Results and insights from a phase 1 clinical trial of Lomecel-B for Alzheimer’s disease. Alzheim & Dement. 2023;19(1):261-273. doi:10.1002/alz.12651
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