Promising Data on Lomecel-B for Alzheimer Disease

Joshua M. Hare, MD, FACC, FAHA

Longeveron's Lomecel-B is an allogeneic bone marrow-derived medicinal signaling cell (MSC) formulation. At the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 2nd in Philadelphia, Pennsylvania, the company reported data from the phase 2a CLEAR MIND trial (NCT05233774), which evaluated Lomecel-B for the treatment of Alzheimer disease (AD).

At the conference, CGTLive® interviewed Joshua M. Hare, MD, FACC, FAHA, cofounder, chief science officer, and chairman, Longeveron, and professor of medicine, Miller School of Medicine, University of Miami, about the presentation to learn more. Hare gave an overview of the data presented and explained why it is promising for the field.

CGTLive: Can you tell us about the data from the CLEAR MIND trial presented at AAIC 2024?

Joshua M. Hare, MD, FACC, FAHA: Longeveron had conducted a phase 1 trial several years ago. It was the first attempt to do lomecel-B in patients with mild AD. In that phase 1 study, we elected to do a single dose intravenously with 2 dosing regimens, low and high dose, and include a placebo group. Even though it was phase 1, we wanted to get some early information as to whether or not there was any efficacy signals. We first and foremost found that it was safe—very safe—and importantly, there are no instances of amyloid related imaging abnormalities (ARIA) or other serious side effects attributable to the lomecel-B. We did also have a hint of efficacy. It was a very small study and so we didn't want to make too much of that.

We decided that the next best thing to do was conduct a larger trial that had as 1 of its objectives getting a better handle on an efficacy signal. The 3 objectives of the CLEAR MIND study were to test repeat dosing regimens (we hadn't done that before); get a handle on the target engagement (we wanted some clearer, supportive evidence of reducing neuroinflammation); and then finally, we wanted to further delineate clinical outcome effects. We were very, very pleased. The trial, I think, exceeded our expectation. We hit on all 3 of those objectives. The safety data was excellent—a very acceptable safety profile, even with repeat dosing. We did find evidence of reduction in neuroinflammation using MRI imaging. We used a protocol called diffusion tensor imaging (DTI), which has a protocol that has been developed to look at neuroinflammation. We found a remarkable decline in neuroinflammation using the DTI, both in white matter and gray matter areas. That was very exciting.

As secondary end points, we had designed some clinical outcomes—particularly the prespecified secondary end point was a composite Alzheimer's disease (CAD) score, and that CAD score was made up of the outcomes of 4 measures. One was the sum of boxes. Another was the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). The third was the hippocampal volume; we had seen improvements in hippocampal volume in the phase 1, and we wanted to further explore that. The fourth component of the CAD score was an activities of daily living metric. According to the prespecified P value of .1, we did see an improvement in at least 1 of the groups treated with lomecel-B versus placebo. Also, there was evidence of disease progression in the placebo group. So the placebo group got a little bit worse, and one of the doses had a statistically significant improvement. All of the doses had a trend towards improvement relative to the placebo.

So in this relatively small study proof-of-concept, we saw a signal on the prespecified secondary end points. We went on to look at other components of clinical outcome. We looked at different metrics of cognitive function, like the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), and we found statistically significant improvement in the MoCA score relative to placebo. That was very exciting.

Then one of the final aspects of the trial which is also novel—we had done very careful cardiac MRI imaging—I already told you about the DTI, but we also did volumetric imaging, and we showed a statistically significant slowing of brain atrophy in multiple areas of the brain, particularly the hippocampus. The hippocampus is a region that's heavily implicated in AD outcomes. It undergoes atrophy as part of the disease, and we slowed that atrophy rather substantially. This was a very exciting finding, and furthermore, we could show that the slowing of the atrophy correlated with clinical improvements in the cognitive scores. So, in summary, we definitely exceeded our expectations with the outcomes of the small study, and our conclusion is that we will go on and do a much larger, more clinically powered study now as our next step.

We did get regenerative medicine advanced therapy designation from the FDA in the last 2 weeks, which is also a nice feature that allows us greater access to the FDA, and we feel will allow us to accelerate the conduct of our next trial in consultation with the FDA, which will hopefully also accelerate the approval of the drug should the should the next set of trials meet their endpoints.

This transcript has been edited for clarity.

REFERENCES
1. Rash BG, Ramdas KN, Agafanova N, et al. The CLEAR MIND Study: Results from a Phase 2a Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Lomecel-BTM in Mild Alzheimer’s Disease Dementia. Presented at: 2024 AAIC, July 28-August 2; Philadelphia, Pennsylvania.