Historically, drugs for Alzheimer’s disease have been little more than a salve, addressing symptoms of this devastating neurological condition, but not the underlying cause. Times have changed.

Scientific advances have spurred researchers to set their sights on targeting the disease itself, giving new hope to the idea that it may not only be possible to slow Alzheimer’s progression but to prevent it entirely, says Dr. Michael Irizarry, senior vice president of clinical research and deputy chief clinical officer of the neurology business group for Tokyo-based Eisai Co.

Eisai is now using these advances to drive the development of Alzheimer’s therapeutics and diagnostics, including a promising drug candidate called lecanemab. An anti-amyloid beta protofibril antibody, lecanemab is still in phase 3 trials, but Eisai has already initiated a rolling submission for the drug to the FDA.

Of course, if it’s approved, it won’t be the first amyloid-targeting drug to enter the market — Biogen’s Aduhelm won that honor last June. Yet, harsh skepticism has followed Aduhelm since it hit the scene, creating a new question for Eisai: Can the company shake off the shadows of doubt hanging over amyloid drugs and usher lecanemab across the finish line?

Scientific advances driving progress

Before the early 2000s, an Alzheimer’s diagnosis was solely based on clinical factors, such as progressive short-term memory impairment.

“It’s a pretty exciting time in Alzheimer’s research right now because we’re seeing a lot of the science and the technical ability to create medicines converge,” Irizarry says. “What has really helped to enable better clinical trials is the development of biomarkers for Alzheimer’s disease.”

Just as high blood sugar is used as a biomarker for diabetes, similar measurable physical changes can indicate Alzheimer’s. Amyloid PET scans are used to detect one such biomarker in the brain — abnormal deposits of beta amyloid, a type of protein. Other Alzheimer’s biomarkers can be detected in the cerebrospinal fluid. These biomarkers and others not only help doctors diagnose Alzheimer’s, but allow researchers to refine their recruiting processes and choose optimal therapeutic doses.

“Once we could measure amyloid in the brain, we realized that maybe 20% of patients that we were enrolling for early Alzheimer’s disease trials were amyloid-negative, so they had dementia that may be due to other causes and wouldn’t necessarily respond to the [amyloid-targeting] treatments we were trying,” Irizarry says. “It also allowed us to select the right doses that we were testing.”

Tracking biomarkers allowed Eisai to quickly determine the optimal dose of lecanemab in its phase 2 trial. In that study, which included some 800 people with Alzheimer’s disease, more than 80% of participants given the highest dose switched from being amyloid-positive to amyloid-negative, based on an Amyloid PET scan, Irizarry says. The trial also found some evidence that lecanemab could slow clinical decline in participants.

Largely based on those findings, Eisai asked the FDA to start the review process for lecanemab in September, applying for a Biologics License Application under the accelerated approval pathway.

Controversy and promise

Irizarry says Eisai hopes to complete its FDA submission in the first half of 2022. In the meantime, lecanemab is currently being tested in two phase 3 studies. The first trial, Clarity AD, has already enrolled 1,795 patients with early Alzheimer’s disease to test lecanemab against a placebo treatment. Results are anticipated in September or October. A second phase 3 study is currently enrolling patients with abnormal amyloid PET scans, but no Alzheimer’s symptoms.

It might be possible to win an accelerated approval based on phase 2 data and then soon after, have confirmatory results from the phase 3 study, which could lead to full FDA approval, Irizarry says.

However, securing FDA approval might not be the only hurdle that lecanemab needs to navigate. A similar FDA approach was used by Biogen for its amyloid-targeting treatment, Aduhelm, which was approved in June. It was the first new Alzheimer’s drug approved since 2003, and the first potentially disease-modifying treatment for Alzheimer’s. Both lecanemab and Aduhelm stem from a partnership between Eisai and Biogen, but Biogen took the lead on Aduhelm, while Eisai has focused on lecanemab.

The FDA approval of Aduhelm also ignited controversy that could haunt lecanemab as it moves forward. Aduhelm gained approval based on data demonstrating a reduction in the amount of amyloid plaque in the brain — and a modest improvement in clinical symptoms — despite the fact that one of its two phase 3 trials failed to meet its primary endpoint. This has led many to question whether Aduhelm — and amyloid-targeting therapies — will provide enough clinical benefit to patients. Even if they do, are those improvements enough to justify the costs of the drug?

In addition, the Centers for Medicare and Medicaid Services (CMS) is now mulling a National Coverage Determination (NCD) that Eisai officials say could deny many patients access to amyloid-targeting therapies, including lecanemab. The proposed NCD would limit Medicare coverage for monoclonal antibody drugs that target amyloid to people participating in CMS-approved randomized clinical trials and trials supported by the National Institutes of Health. Under the proposal, the drugs would not be reimbursed outside of those trials.

But Irizarry says that while there are challenges, Aduhelm’s approval has also helped to clear a path forward.

“We’re really trying to build on what Aduhelm has accomplished so far. There have been challenges, but we’re trying to build on the science of Aduhelm,” he says.

Irizarry also points out that although Aduhelm and lecanemab are both amyloid-targeting drugs, there are key differences between how they work. For example, lecanemab has shown in early trials that it could lead to fewer incidences of a brain swelling side effect called ARIA than Aduhelm — making it a potentially safer option.

But even if lecanemab is approved, Eisai also knows that amyloid-drugs might be more effective in combination with other treatments instead.

Taking a multi-pronged approach

While some of Eisai’s focus is on lecanemab, it isn’t the only Alzheimer’s therapeutic Eisai is exploring. In January the company also enrolled its first subject in a trial involving an antibody targeting a specific form of tau, another protein implicated in Alzheimer’s-related brain changes. Tau is thought to prompt the formation of neurofibrillary tangles, Irizarry says. The tau-targeting antibody will be tested in combination with lecanemab. 

“We think that similar to oncology, combination approaches may be more effective,” Irizarry says.

Other Alzheimer’s research is also ongoing at Eisai.

“We, and other groups, are working on blood-based biomarkers that can confirm amyloid in the brain, or confirm tau in the brain,” he says. “The hope is to really simplify the whole patient journey from diagnosis, to treatment, and care, and conversely understanding whether we can prevent Alzheimer’s disease altogether by treating it earlier in the pre-symptomatic phases.”

Ultimately, new approaches, treatments and diagnostic techniques may lead to better outcomes.

“My hope is that over the next five to 10 years, we’ll have several treatments for Alzheimer’s disease that can be used in combination,” Irizarry says.