Alzheimer's disease, affecting nearly 7 million people in the United States, has seen limited success in clinical trials, with failure rates ranging from 98% to 99.6%. Several companies are now exploring cell and gene therapies (CGTs) as alternative approaches, with Longeveron and Lexeo Therapeutics leading the way. These therapies aim to address the unmet need for effective treatments in this challenging disease landscape.
Longeveron's Lomecel-B
Longeveron is developing Lomecel-B for Alzheimer's, aging-related frailty, and hypoplastic left heart syndrome. Lomecel-B completed Phase IIa trials in Q4 2023 and received Regenerative Medicine Advanced Therapy designation from the FDA in July 2024. Lomecel-B consists of allogeneic medicinal signaling cells extracted from the bone marrow of younger adult donors. These cells are pro-vascular, pro-regenerative, and anti-inflammatory. The therapy can cross the blood-brain barrier, providing therapeutic effects within the brain and reducing inflammation.
In the Phase IIa CLEAR MIND trial, patients were divided into four cohorts, with three receiving different dosing regimens of Lomecel-B and one receiving a placebo. All cohorts received four infusions spaced four weeks apart. The trial met its primary and secondary endpoints. Longeveron reported that Lomecel-B was safe, despite one serious adverse event in an experimental arm and none in the placebo group. Efficacy assessments showed that the therapy slowed disease progression and prevented worsening, as measured by the Composite Alzheimer's Disease Score. Full Phase IIa results were presented at the 2024 Alzheimer's Association International Conference in July.
Lexeo Therapeutics' Gene Therapies
Lexeo Therapeutics is pursuing a different strategy, developing three gene therapies for Alzheimer's, all using AAV-based vectors to target products of the APOE gene. The APOE gene has three alleles associated with varying Alzheimer's risk levels. LX1001 expresses the protective APOE2 protein in the central nervous system of patients homozygous for the high-risk APOE4 allele. LX1021 expresses the protective Christchurch form of APOE2 in the CNS of APOE4-homozygous patients, while LX1020 expresses APOE2 and suppresses APOE4 using miRNA. LX1001 is in Phase I/II trials with results expected in November 2024, LX1021 is in preclinical studies, and LX1020 is in the discovery phase. Lexeo's therapies target the 40% to 50% of Alzheimer's patients with APOE4, while Longeveron's approach is broader and not dependent on genetic mutations.
Emerging CGT Approaches
Regeneration Biomedical is also exploring stem cell therapies for Alzheimer's. The company presented results on July 28 from the first two patients in a Phase I trial, claiming notable improvements in cognitive scores in patients with late-stage Alzheimer's. If confirmed in larger trials, this could be a significant advancement, as most effective therapies have only shown efficacy in patients with mild cognitive impairment.
Potential and Challenges of CGTs in Alzheimer's
If proven efficacious, CGTs could offer a new treatment option for Alzheimer's, where current treatments have limitations. For example, Biogen's Aduhelm (aducanumab) faced controversy and was discontinued, while Leqembi (lecanemab) is associated with adverse events like amyloid-related imaging abnormalities and infusion reactions. Lomecel-B, in contrast, showed no hypersensitivity, infusion-related reactions, or amyloid-related imaging abnormalities in its safety profile. However, the high failure rate of Alzheimer's trials and challenges in scaling up to larger patient cohorts in Phase III trials, due to stringent inclusion criteria and high screening failure rates, remain significant hurdles.
