Leqembi, Kisunla and Beyond: The Next Wave of Alzheimer’s at CTAD 2024

Thanks to the momentum created by the approvals and launches of Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla, Alzheimer’s researchers gathered in Madrid last month for the 2024 Clinical Trials of Alzheimer’s Disease (CTAD) conference the question of how these anti-amyloid antibodies are used throughout the treatment regimen.

“This is a breakthrough as disease-modifying agents for Alzheimer’s disease begin to mature,” said Howard Fillit, co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation BioSpace. “I saw several sessions on some new ideas about using these medications as maintenance therapy. . . and how we will use it [in] Combination therapy.”

The conference also presented ongoing efforts to improve safety and effectiveness, the potential of combination treatments and promising data on novel therapies. With 500,000 people diagnosed with Alzheimer’s disease each year in the United States alone, the global therapeutics market is expected to grow in importance $9.2 billion until 2030. After that decades of failure, space advances at a speed never seen in the past.

“After years and years of investment, it feels like a lot of things are coming to a positive conclusion,” said Lisa Ricciardi, CEO of Cognition Therapeutics.

A key role for anti-amyloid antibodies

Fillit believes the future of Alzheimer’s treatment lies in combination therapies – a topic on which he chaired a roundtable discussion at CTAD. While the currently approved anti-amyloid antibodies Leqembi and Kisunla are expected to become the standard of care for the disease, removing amyloid plaques isn’t everything.

“The monoclonal antibodies show a 30 percent slowing of the progression of Alzheimer’s disease, but the goal is to reach 100 percent,” Fillit said. “Combination therapies could be a step towards this.”

For example, he continued, future treatment pathways could combine anti-amyloid antibodies with anti-tau and anti-inflammatory therapies. About a quarter of novel drugs currently in development address the neuroinflammatory aspect of Alzheimer’s disease, he noted.

Another interesting topic, Fillit said, is the adjustment of protocols for Leqembi and Kisunla for therapeutic maintenance. Kisunla is currently dosed until the amyloid is removed from the brain. Leqembi can be dosed indefinitely, but most data currently only covers 18 months.

“Although the PET scans are negative and the amyloid plaques are gone, the disease appears to be progressing,” Fillit said. Continuous treatment, such as once a month at a reduced dosage, could potentially maintain the equivalent of disease remission to prevent beta-amyloid accumulation again, according to Fillit.

Reducing ARIA risk

R. Nolan Townsend, CEO of Lexeo Therapeutics, said BioSpace that finding ways to reduce the incidence of amyloid-related imaging abnormalities (ARIA) – brain swelling associated with amyloid-targeting therapies – has been a major focus at CTAD.

Lilly presented Results from the TRAILBLAZER-ALZ 6 study, which aimed to examine how different doses of Kisunla might affect the incidence of ARIA. The company found that a modified titration arm significantly reduced ARIA-E, swelling caused by fluid leakage.

In particular, Leqembi and Kisunla are contraindicated in patients carrying two copies of them APOE4 Gene, a genetic variation that leads to a high risk of developing Alzheimer’s disease and approx 15% of all cases of the disease, as these people are at increased risk of ARIA.

At CTAD, Lexeo presented data from the first clinical trial to address the underlying genetic cause APOE4-associated Alzheimer’s disease. LX1001 is a unique gene therapy that provides protection APOE2 Allele to the central nervous system of patients carrying two copies of it APOE4. APOE2 is associated with a significantly lower risk of developing Alzheimer’s disease and a slower progression of the disease.

Lexeo’s Phase I/II study 15 homozygous enrolled APOE4 Patients with mild cognitive impairment or mild to moderate Alzheimer’s disease. After a single dose of gene therapy, all participants experienced symptoms APOE2 According to Lexeo, after 12 months, there was stabilization of amyloid pathology in cerebrospinal fluid (CSF) protein expression, and more than two-thirds experienced consistent reductions in all CSF tau biomarkers. To date, no signs of ARIA have been observed with Lexeo’s gene therapy and are not expected to occur.

“Every step forward for [Alzheimer’s] Patients is helpful,” Townsend said. “It is all the more helpful to be able to offer complete therapy without ARIA.”

Lexeo plans to work with the FDA and sees a possible path to accelerated approval using surrogate endpoints such as: APOE2 expression and tau PET imaging, said Chief Development Officer Sandi See Tai BioSpace. The company is considering initially focusing on moderate patients, an area of ​​unmet need where gene therapy has shown better signaling data, she added.

A daily oral option

While Lexeo is pushing forward with its one-off gene therapy, Cognition Therapeutics is taking a different approach with CT1812, a daily pill. CT1812 is an oligomer antagonist that penetrates the blood-brain barrier and binds to the sigma-2 receptor complex to displace toxic amyloid beta oligomers. This approach targets the disease earlier in the Alzheimer’s cascade, before the oligomers have a chance to bind to synapses and cause nerve damage.

If approved, “we think this would be a great drug to start with.” [treatment] with,” Ricciardi said, citing the small molecule’s accessibility, clean safety profile and “low overhead.”

In CTAD, cognition presented a pre-specified analysis from the Phase II SHINE study testing CT1812 in patients with mild to moderate Alzheimer’s disease. Participants with lower baseline levels of the P-tau217 protein – an established blood-based biomarker for Alzheimer’s disease – saw a 95 percent slowing of cognitive decline as measured by the ADAS-Cog 11 and a 108 percent slowing of decline using the MMSE, two different ones Tests Used to measure cognitive impairment.

P-tau217 is the key, Ricciardi said BioSpaceBecause patients who can benefit most from it can now be easily identified with a simple blood test. “It’s a game-changer,” she said.

Cognition looks forward to meeting with the FDA following completion of the Phase II trial, where the company will develop a Phase III trial approach, Ricciardi said.

Could Stem Cells Treat Alzheimer’s?

At Regeneration Biomedical (RBI), founder and president Christopher Duma is trying something completely extraordinary: he is bringing stem cells directly into the brains of Alzheimer’s patients. RBI presented Data at CTAD from three patients treated in a phase I trial with adipose tissue-derived stem cells administered into the lateral ventricles of the brain. After 12 weeks, p-tau and beta-amyloid levels were reduced and MMSE scores trended towards cognitive improvements in two out of three subjects, the company reported. No safety signals were observed in the first cohort.

“Alzheimer’s disease is a disease of the whole brain,” Duma said BioSpace. “You can’t just target one area of ​​the brain and fix it [it].” Duma wanted an approach that would have a bathing effect on the brain, that could bypass the blood-brain barrier while targeting the spinal cord. “Everything is connected by one thing: the ventricular system in the brain.”

RBI’s therapeutic approach begins with the removal of stem cells from a patient’s fatty tissue using liposuction. The stem cells are then taken to a laboratory where the cells expressing Wnt, a signaling protein known to stimulate other stem cells, are propagated. These expanded stem cells are then given back to the patient through an opening just under the scalp, which delivers the stem cells directly to the brain. The Wnt-expressing cells administered may “wake up” the existing stem cells in the brain to trigger brain tissue regrowth, stop inflammation and repair the waste disposal system, Duma explained.

Duma compared the stem cells to a vaccine. “You will need boosters to remind the stem cells to get going again,” he said.

He also sees potential for combining stem cell therapy with an anti-amyloid, which would remove the plaques and thus increase the effectiveness of the stem cells. “Maybe the synergy of these two would be very exciting. This means we are open to a clinical study.”