Lomecel-B Becomes First Agent to Gain Regenerative Medicine Advanced Therapy Designation for Alzheimer Disease

Author(s):

In a phase 2 trial, the agent met its primary end point of safety, with slowing of disease worsening in patients with mild AD.

Joshua Hare

According to a recent announcement, the FDA has granted regenerative medicine advanced therapy (RMAT) designation to Longeveron’s allogeneic cellular investigational therapy Lomecel-B. With the decision, it becomes the first such agent to receive RMAT designation for the treatment of Alzheimer disease (AD).¹

Established under the 21st Century Cures Act, RMAT designation is a dedicated program designed to expedite the drug development and review processes for promising pipeline regenerative medicine products, including cell therapies. Lomecel-B, a proprietary, scalable, “off-the-shell” cellular therapy, is made from living cells called medicinal signaling cells, or MSCs, that are isolated from fresh bone marrow tissue that has been donated by adult donors aged 18 to 45.

Lomecel-B, which also remains in development for other conditions such as aging-related frailty and hypoplastic left heart syndrome, first showed promise in the phase 2a CLEAR MIND study (NCT05233774). Topline results announced earlier this year showed that the agent met its primary end point of safety, with slowing of disease worsening in patients with mild AD. At the end of the 39-week treatment period, investigators reported no new safety concerns, in addition to no cases of amyloid-related imaging abnormalities, no clinically asymptomatic microhemorrhages on MRI, and no notable changes in laboratory evaluations and electrocardiogram.²

"The RMAT designation is an important milestone for Longeveron and the Lomecel-B™ program that recognizes the potential of our cellular therapy to have a positive impact on patients afflicted with this devastating disease," Joshua Hare, co-founder, chief science officer, and chairman of the board at Longeveron, said in a statement.¹ "Alzheimer’s Disease is a neurodegenerative disorder that leads to progressive memory loss and death and currently has very limited therapeutic options. In the CLEAR MIND Phase 2a clinical trial, Lomecel-B™ demonstrated an overall slowing/prevention of disease worsening compared to placebo. The trial achieved the primary safety and secondary efficacy endpoints and showed statistically significant improvements in pre-specified clinical and biomarker endpoints in specific Lomecel-B™ groups compared to placebo."

CLEAR MIND was a trial that 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. 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 terms of efficacy, statistically significant improvements in the Composite Alzheimer’s Disease Score (CADS) were observed after 39 weeks in 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). CAD 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 the Lomecel-B 25M x 1 dose group, treated patients saw a statistically significant slowing of disease progression in left hippocampal volume (P = .015) relative to placebo.

Additional clinical data and imaging biomarker results, announced in 2023, further highlighted Lomecel-B’s impact on AD. All told, Lomecel-B™ (25M x 1 dose, P =0.009) and the pooled treatment group (25M x 1 dose, 25M x 4 doses, 100M x 4 doses, P =0.015) demonstrated statistically significant improvements in the Montreal Cognitive Assessment (MOCA), relative to placebo. In addition, investigators observed a dose-dependent response improvement in MMSE for Lomecel-B-treated patients (mean increase at highest dose: 3.0 [±3.6]; P = .028). Furthermore, quality of life, measured by the Alzheimer’s Disease Related Quality of Life scale, revealed higher level of improvement in patients on active therapy (100M x 4 doses).³

"We are thrilled to receive the RMAT designation for Lomecel-B™ for the treatment of mild Alzheimer’s disease and we look forward to meeting with the FDA to discuss the path forward and the development plans for Alzheimer disease in the very near future," Nataliya Agafonova, MD, chief medical officer at Longeveron, said in a statement.¹

Supplementary data from CLEAR MIND also showed that Lomecel-B (100M x 4 doses) reduced whole brain volume loss by 49% (P = .034). Additionally, Lomecel-B™ (25M x 1 dose, p=0.015) and the pooled treatment group (25M x 1 dose, 25M x 4 doses, 100M x 4 doses, p=0.038) demonstrated statistically significant reductions in left hippocampal volume loss at Week 39 relative to placebo (25M x 1 dose degree of reduction: 84%). Lastly, brain volume preservation in the Lomecel-B (100M x 4 dose) dose group was accompanied by 20% and 33% reduction in left and right ventricular enlargement, respectively, at week 39 compared with placebo.¹

REFERENCES
1. Longeveron® Announces U.S. FDA Grants Lomecel-B™ Regenerative Medicine Advanced Therapy (RMAT) Designation for the Treatment of Mild Alzheimer’s Disease. News release. Longeveron. July 10, 2024. Accessed July 11, 2024. https://www.biospace.com/article/releases/longeveron-announces-u-s-fda-grants-lomecel-b-regenerative-medicine-advanced-therapy-rmat-designation-for-the-treatment-of-mild-alzheimer-s-disease/
2. 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 July 11, 2024. 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
3. Longeveron announces additional positive clinical data and imaging biomarker results from the CLEAR MIND phase 2a trial of Lomecel-B in the treatment of mild Alzheimer disease. December 20, 2023. Accessed July 11, 2024. https://investors.longeveron.com/news/News/news-details/2023/Longeveron-Announces-Additional-Positive-Clinical-Data-and-Imaging-Biomarker-Results-from-the-CLEAR-MIND-Phase-2a-Trial-of-Lomecel-Bin-the-Treatment-of-Mild-Alzheimers-Disease/default.aspx