Longeveron and Lexeo Therapeutics are working on CGT therapies to treat Alzheimer’s disease, but it’s not clear whether they have a better chance of success than traditional approaches.
Alzheimer’s is a difficult neurological disease to manage and treat. Despite its prevalence—nearly 7 million people in the United States are affected—and several approaches ranging from small molecules to behavioral therapies to immunotherapies, a vast majority of clinical trials have failed in this disease state.
With Alzheimer’s disease trial failure rates ranging from 98% to 99.6% depending on context, a few companies are aiming to upend traditional approaches with investigational cell and gene therapies. Of these, Longeveron and Lexeo Therapeutics have the most advanced pipelines.
Longeveron is developing Lomecel-B for Alzheimer’s, as well as for aging-related frailty and hypoplastic left heart syndrome. In Alzheimer’s, Lomecel-B completed Phase IIa trials in Q4 2023 and received Regenerative Medicine Advanced Therapy designation from the FDA in July 2024.
Consisting of allogeneic medicinal signaling cells extracted from the fresh bone marrow tissue of younger adult donors and cultured, Lomecel-B is pro-vascular, pro-regenerative and anti-inflammatory. Longeveron’s approach is novel because the MSCs can cross the blood-brain barrier to provide therapeutic effect within the brain and reduce inflammation. By contrast, the blood-brain barrier can present an additional challenge to small molecule drug development, as small molecules do not easily cross it unless they meet specific criteria.
In the Phase IIa CLEAR MIND trial, patients were split into four cohorts with three cohorts receiving different dosing regimens and one cohort receiving only placebo. All cohorts were given a total of four infusions spaced four weeks apart.
The trial’s primary and secondary endpoints were reached, Longeveron stated in an October 2023 press release. Despite the occurrence of one serious adverse event in one of the experimental treatment arms and none in the placebo group, Lomecel-B was determined to be safe. In terms of efficacy, the therapy slowed down progression and prevented disease worsening in multiple assessments such as the Composite Alzheimer’s Disease Score, the company said. Full Phase IIa results were presented at the 2024 Alzheimer’s Association International Conference in July.
Meanwhile, Lexeo Therapeutics is taking a different tack, working on three different investigational gene therapies for Alzheimer’s. All of them use AAV-based vectors to target products of the APOE gene, which has three alleles associated with varying levels of risk for Alzheimer’s. While LX1001 works by expressing the protective APOE2 protein in the central nervous system of patients who are homozygous for the higher-risk APOE4 allele, LX1021 expresses the protective Christchurch form of the APOE2 protein in the CNS of APOE4-homozygous patients and LX1020 both expresses the APOE2 protein in the CNS of APOE4-homozygous patients and suppresses APOE4 protein with miRNA.
While LX1001 is currently in Phase I/II trials with results expected in November 2024, LX1021 is in preclinical studies and LX1020 is in the discovery phase.
Since Lexeo is only targeting APOE4-associated Alzheimer’s disease, its products are aimed at a patient subpopulation that comprises 40% to 50% of the total Alzheimer’s population. By contrast, Longeveron’s approach with its flagship product is broader and does not necessarily take genetic mutations into account.
The CGT-for-Alzheimer’s Space
In addition to Longeveron and Lexeo, some earlier-stage companies are cropping up in the CGT-for-Alzheimer’s space. Regeneration Biomedical, for example, presented results on July 28 for the first two patients in a Phase I trial of its stem cell therapy. The company claims its therapy induces notable improvements in the cognitive scores of patients with late-stage Alzheimer’s disease. This will be a significant development if borne out by large-scale trials, as most therapies that have shown efficacy have done so only for patients with mild cognitive impairment.
If proven to be efficacious in trials, CGT for Alzheimer’s disease could provide a new treatment option in a disease state where even currently approved Alzheimer’s treatments may have significant shortcomings. For instance, even though Biogen’s anti-amyloid drug Aduhelm (aducanumab) was greenlit in 2021, its approval was controversial and the manufacturer discontinued development and commercialization in January 2024 to focus on Leqembi (lecanemab), which, like Aduhelm, is associated with adverse events such as amyloid-related imaging abnormalities and infusion reactions. By contrast, Lomecel-B showed no incidence of hypersensitivity, infusion-related reactions or amyloid-related imaging abnormalities in its safety profile. If CGT can continue to avoid or even lessen the occurrence and/or severity of adverse events, it would gain a notable advantage in the field.
Nonetheless, given the relatively high historical failure rate of Alzheimer’s trials, one complication for this space is scalability toward larger patient cohorts in Phase III trials stemming in part from stringent inclusion criteria. In addition, Alzheimer’s disease clinical trial complications such as high screening failure rates compared to other disease states continue to be a challenge.
With the rise of investigational CGTs coming to the Alzheimer’s space, do keep an eye on progress on these fronts within the next two to three years.
