Although there is yet no cure for Alzheimer’s, the field is at a critical crossroads, which is prompting further study. A single, magical “cure” for this complicated disease is unlikely to emerge. The recent historic approval of a drug to delay the progression of Alzheimer’s, together with a deeper understanding of the disease, is strengthening this notion of the scientific community.
A few medications aimed at removing the beta-amyloid protein, the hallmark of Alzheimer’s, have received approval from the FDA. However, the complexity of the disease demands the exploration of other possible treatment pathways as well.
Why is it challenging to treat Alzheimer’s?
The most prevalent type of dementia, Alzheimer’s disease (AD), causes severe cognitive and functional impairment that significantly affects everyday living. It becomes incapacitating and ultimately fatal as brain damage mounts.
The fact that the damage starts decades before the first symptoms arise is one of the disease’s most concerning characteristics. Studying it becomes exceedingly difficult as a result. Even when symptoms do manifest, each patient may experience them quite differently.
While many aspects of the disease onset are still unknown, the accumulation of specific proteins in the brain has been connected to the degeneration of neurons, the nerve cells that control memory, language, and behavior. Beta-amyloid proteins build up as plaques around neurons as the disease worsens, while tau proteins manifest as tangles inside neurons.
Team Amyloid faces a challenging path!
A good 30 years of research has concentrated on medications to eliminate beta-amyloid. However, even with a very promising drug, success requires the almost perfect execution of a clinical study. Nine beta-amyloid-targeting medicines have failed phase 3 trials in the past five years.
According to Dr. Sara Imarisio, Head of Strategic Initiatives at Alzheimer’s Research UK, many companies have been reluctant to invest in Alzheimer’s drugs because of the disease’s characteristic intricacies, which include a heterogeneous population (different rates of disease advancement and symptoms), challenges getting medications to cross the blood-brain barrier (BBB), and testing a drug in an elderly population with other concurrent illnesses.
In 2021, Biogen’s monoclonal antibody (mAb) Aduhelm, which works to remove beta-amyloid plaques, got accelerated approval from FDA. However, the medicine received criticism for its high price and disputed efficacy. It went underutilized since Medicare refused to pay for it outside of clinical studies.
However, early this year, Leqembi (lecanemab), another amyloid-targeting antibody by the Japanese company Eisai in collaboration with Biogen, received accelerated approval by the FDA. In a clinical investigation, it decreased the loss of cognitive function by 27% over 18 months compared to a placebo. A full-fledged approval, allowing broader coverage by health insurance providers, is expected in July.
Getting the drug’s levels sufficiently elevated in the brain and across the BBB without sacrificing safety is the primary challenge for current beta-amyloid targeting medicines.
These medications cause the infiltration of disease-fighting cells, but that has the potential side effect of cerebral edema (ARIA-E), which can result in brain swelling. Drugs frequently struggle to attain adequate potency levels that offset the potentially harmful side effects because only a tiny portion of the initial dose of the injectable mAb can penetrate the BBB.
Companies like Roche and Voyager are developing “shuttle” technology to enhance drug distribution across the BBB. Conversely, oral small-molecule medications have a higher chance of crossing the BBB. Alzheon, a private US biotech company, is now conducting phase 3 studies for ALZ-801, an amyloid-targeting drug, that is expected to complete in mid-2024.
Alternative treatment options
While removing beta-amyloid has already demonstrated some significant (albeit minor) advantages, inhibiting some mechanisms that cause neuronal damage may be the optimal strategy for patients.
Let’s explore some of the alternative strategies attracting the most interest.
The topic receiving the most attention these days is improving the brain’s immune system, particularly microglia, immune cells that remove trash from around neurons.
Numerous companies are now investing in medications that target TREM2 to promote the proliferation of microglia since the increase in studies that have improved our understanding of the microglial receptor TREM2.
The mid-stage (phase 2) human trial for the injectable mAb AL002 from Alector/Abbvie will end in late 2023 or early 2024. DNL919, a mAb from Denali/Takeda, is undergoing a preliminary (phase 1) human trial expected to end in July 2023. Likewise, Vigil Neuroscience is developing a TREM2 targeting pill currently in the pre-clinical laboratory phases.
Clearing Tau Tangles
Although the attention on beta-amyloid has cast a shadow over the clearing of tau, the strategy is still sound. The scientific understanding of this strategy is developing, particularly concerning optimum binding domains, which may result in more efficacy in removing tau tangles.
Even though early tau-based strategies were unsuccessful, a few pharmaceutical companies are still developing medications that try to reduce and remove the proteins that accumulate in the brain.
Among the companies conducting phase 2 trials are Eli Lilly, whose oral LY3372689 trial will reach the end in June 2024, Janssen Research & Development, LLC, whose injectable mAb JNJ-63733657 will reach the end of the trial in late 2025, and Roche/UCB, whose injectable mAb bepranemab is due in 2025.
According to some experts, neurodegeneration can result from poor metabolism and abnormal lipid metabolism in the brain, and AD is best described as a neuro-metabolic illness.
T3D-959, an oral medication in a phase 2 trial, is the leading candidate from T3D Therapeutics. The once-daily pills try to control the transcription of genes linked to glucose energy and lipid metabolism to combat neurodegeneration.
Some other possible treatment alternatives
Reducing neuroInflammation (NLRP3)
Although research on the NLRP3 inflammasome target is still in its early phases, experts have developed an interest in it. Beta-amyloid and tau can activate inflammasomes, a multiprotein complex essential for triggering inflammatory reactions. It may contribute to persistent neuroinflammation development, which may cause neuronal degeneration and cognitive impairment. Although pre-clinical testing constitutes the majority of NLRP3 inhibitor research in AD, NLRP3 can lead to several other inflammatory illnesses, and some major pharmaceutical companies, including Roche, Novartis, and Novo Nordisk, have invested in NLRP3 inhibitors.
Although it is still in the early preclinical stages, experts believe that gene-editing technology CRISPR has a potential miracle treatment for complex disorders.
Martin Kampmann’s lab at the University of California, San Francisco, is investigating how CRISPR-Cas9 can reprogram immune cells in the brain, a concept comparable to immunomodulation targeting TREM2.
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- A study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of DNL919 in healthy participants. https://clinicaltrials.gov/ct2/show/NCT05450549. Last Update Posted: 16th September, 2022. Accessed: 8th May, 2023.
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- A study of JNJ-63733657 in participants with early Alzheimer’s disease (Autonomy). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04619420. Last Update Posted: 13th April, 2023. Accessed: 9th May, 2023.
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