When scientists describe Alzheimer?s disease (AD) in general terms, they can be surprisingly metaphorical. That is certainly the case with Tommaso Croese, MD, PhD, medical director of ImmunoBrain Checkpoint (IBC), a clinical-stage biotechnology company. He says that the AD-afflicted brain is like a garden that has become choked with weeds (which represent amyloid-beta plaques), overrun by destructive pests (abnormal tau proteins), and worn down by severe weather (brain inflammation). Such metaphors are valuable because they convey that AD-driven processes are complex?so complex, in fact, that AD remains incredibly challenging to treat.
Although the complexities of AD are still being unraveled, the population trends are all too clear. According to the Alzheimer?s Association, more than 6 million people in the United States live with AD, and that number will rise to nearly 13 million by 2050. According to the World Health Organization, there are over 55 million cases of AD and other dementias worldwide. Despite these daunting statistics, there are reasons to be hopeful. The most encouraging development may be the emergence of antibody-based therapies that promise to stave off cognitive decline.
Several companies have programs for developing antibodies that target the fundamental pathophysiology of AD and other neurodegenerative diseases. For example, Eisai and Biogen have been collaborating on antibodies that target amyloid-beta protein. (Indeed, two of these antibodies have already received regulatory approval.) Aprinoia Therapeutics is working on APNmAb005, an antibody that is designed to bind pathological tau and prevent its spread to neurons through the synapses. And IBC is working on IBC-Ab002, an antibody that targets the immune activity responsible for AD-associated inflammation in the brain.
Alzheimer?s therapies go to market
Cambridge, MA?based Biogen has worked on drugs for brain diseases for more than 40 years. The company has poured resources into developing six drugs for multiple sclerosis and was the first to develop a drug (Spinraza) for spinal muscular atrophy.
In the context of AD, Biogen has developed two drugs in collaboration with Tokyo, Japan?based Eisai. One of these drugs is aducanumab (Aduhelm), a monoclonal antibody that, after some initial issues with its supporting evidence, was approved in 2021 for patients with mild cognitive impairment or dementia. It is the first AD treatment to receive accelerated approval from the U.S. Food and Drug Administration (FDA).
Biogen and Eisai also collaborated on lecanemab-irmb (Leqembi), a monoclonal antibody that targets aggregated soluble and insoluble forms of amyloid-beta protein. Leqembi was approved in July 2023 for patients with mild cognitive impairment or dementia, based on Phase II data that demonstrated its ability to reduce plaque accumulation in the brain.
Leqembi was pivotal for two reasons, according to Ivana Rubino, PhD, Biogen?s head of global medical for neuropsychiatry and Alzheimer?s disease. First, Lequembi was the first AD drug to receive full approval from the FDA. Second, on the day the FDA approved the drug, another agency, the U.S. Centers for Medicare and Medicaid Services, delivered encouraging news. ?[It] made the historic decision to provide full reimbursement for people with Alzheimer?s seeking treatment,? Rubino recalls. ?That really created a new era for Alzheimer?s disease.?
Lequembi is administered as an infusion twice a month. In the future, patients could have the option to receive the treatment via subcutaneous injection.
However, amyloid-beta is not the only issue for AD cases. Misfolded tau proteins also have an outsize role in the condition. ?We need to most likely address both pathways to really start to see more and more of the clinical efficacy,? Rubino suggests. Besides collaborating with Eisai, Biogen is working independently to develop an AD drug candidate that targets tau protein. The company has shared data from a Phase Ib study of the new drug, dubbed BIIB080, which targets microtubule-associated protein tau mRNA and reduces production of abnormal protein. Initial results are considered encouraging.
Targeting checkpoints for Alzheimer?s disease
While Biogen and Eisai bask in the success of having developed the most recent AD drug to enter the market, other companies are working on new therapies. What?s more, some of these companies are focused on targets other than amyloid-beta plaques and abnormal tau. For example, Rehovot, Israel?based IBC is prioritizing immune mechanisms in the brain that play a role in AD.
Founded in 2015, IBC is leveraging research from the laboratory of Michal Schwartz, PhD, a professor at the Weizmann Institute of Science in Israel. (Schwartz is also IBC?s co-founder and chief scientific officer.) IBC?s approach relies on the understanding that AD is not simply a disease of neurons in the brain; immune activity also plays a role in its manifestation and progression.
Schwartz?s laboratory, which has long studied the interactions between the immune system and the brain, published its first results in 1998, when little was known about how the brain benefits from the immune system. In 2006, the laboratory showed that the brain?s cognitive ability depends on immune system integrity. The deeper the laboratory?s scientists looked, the more evidence they found suggesting that aging-related neurodegenerative diseases could be linked to the failure of an aging immune system, and that activating or inhibiting the immune system could be a viable treatment approach.
?Based on the data from mice and human [studies], we believe that the major contributor to disease progression is the local brain inflammation,? Schwartz says. By targeting brain immune activity, IBC has developed a treatment for AD that could potentially be applicable to other forms of dementia.
IBC?s treatment harnesses the immune system to fight against the local brain inflammation, which is distinct from the inflammation associated with autoimmune disease. IBC?s antibody specifically targets the checkpoint pathway PD-1/PD-L1, one of the mechanisms of immune activity control in aging and disease progression.
?It stops disease progression mainly by reducing the local brain inflammation,? Schwartz explains.
Preclinical data showed improved cognitive performance, lower levels of brain inflammation, and better overall neuronal survival. IBC is testing its antibody in five different clinical trial cohorts in the United Kingdom, the Netherlands, and Israel. Patients at any stage of the disease can receive treatment, not just those in the early stages.
Participants receive doses by injection every three months. According to IBC?s Croese, one task for the trial is to establish the safety of the drug in a fragile population. Another task is identifying the most effective therapeutic regimen for AD patients by testing different drug doses with each cohort. In total, IBC plans to test its drug in 40 patients (8 per cohort). The company hopes to have Phase I data by early 2025.
As the drug is focused on reducing brain inflammation, it does not necessarily get rid of existing plaques or tau tangles in the brain. Combination therapies are one way to address this issue?something IBC is considering.
The National Institute on Aging is also considering the potential of combination therapies. The agency has awarded $150 million in grants to evaluate the effects of two anti-tau therapies and an anti-amyloid-beta therapy on 900 patients with early AD. The so-called Alzheimer?s Tau Platform trial, which has sites across the United States, will likely recruit participants aged 60 or older with asymptomatic AD or mild cognitive impairment (as confirmed by tau blood test, PET scans, and cognitive testing). Random participants will receive a combination of anti-amyloid-beta medication with or without one or both tau medications for 24 months, but more drugs could be added to the trial that target other disease drivers such as metabolic dysfunction or inflammation.
The long road to diagnosis and treatment
Perhaps the biggest challenge for drug developers is AD?s complexity and the daunting collection of pathological pathways and possible environmental factors that contribute to disease development. Even now, experts have many questions that need answers.
Early diagnosis matters for preserving brain function before extensive neuronal damage takes place. Unfortunately, in most cases, abnormal protein activity in the brain starts long before patients have any physical symptoms, making it difficult to determine the exact onset of cognitive loss. ?That?s why the only thing that was historically available to patients in the later stages of the disease were symptomatic treatments,? Rubino says. ?Such treatments can alleviate symptoms but cannot really change what?s happening in the brain.?
Moreover, patients don?t present with symptoms in the same way, and this is something that scientists have to consider during testing. Depending on the day and disease stage, patients can have different symptoms, making it harder to assess the effects of new treatments. Some AD symptoms may have nothing to do with the disease at all. People can have those same symptoms due to stress or a lack of sleep.
Rubino notes that at present, the only way to confirm that someone is in the early stages of the disease is to use biomarkers that are assessed by imaging and lumbar puncture?expensive, invasive technologies that are not widely available. This is why there is significant interest in identifying reliable blood biomarkers as an objective measure for screening more patients and gaining insights into what?s going on in the brain much sooner.
Another concern for drug developers is the difficulty of getting drugs to cross the blood-brain barrier, which tightly regulates the movement of substances into the brain?s internal environment. This has historically limited the effectiveness of drugs for treating neurological disorders. To provide a sense of the difficulty the blood-brain barrier poses, Croese notes that only about 0.1% of injected antibodies for neurological diseases get into the brain. Such a low percentage means that patients often have to get high doses of antibody to ensure that enough gets into the brain to have an effect.
Concerns about safety and the risk of adverse events are also important, especially given the fragility of the target population. Because amyloid is a structural component of blood vessels, anti-amyloid-beta antibodies can cause bleeding in the brain. This possibility emphasizes a requirement that must be met by AD therapies that would stimulate the immune system to bind to pathological proteins: These therapies must hit their targets without inflaming or damaging healthy brain tissue.