Does Biogen and Eisai’s Lecanemab Data Validate the Amyloid Hypothesis? (Updated)

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Eisai and Biogen announced positive data Wednesday from a Phase III trial of lecanemab in Alzheimer's disease. Still, questions remain about the drug's implications for the future of Alzheimer's treatment - and the anti-amyloid theory. 

Alzheimer’s is associated with the accumulation of two abnormal proteins in the brain - beta-amyloid and tau. Beta-amyloid typically appears earlier in the disease while abnormal tau generally accumulates later on.

For the last two decades, the bulk of Alzheimer’s drug development has focused on drugs, usually monoclonal antibodies, that target beta-amyloid. However, in that period, more than 200 clinical trials failed to demonstrate clinical benefit, even when they could show evidence of clearance of beta-amyloid.

Headwinds in the Alzheimer's Space

In June 2021, Biogen’s Aduhelm (aducanumab), a drug similar to lecanemab, became the first drug approved for Alzheimer’s in almost 20 years. It has been buried in controversy ever since. Aduhelm demonstrated clearance of beta-amyloid, and at its highest dose, seemed to demonstrate evidence of slowing disease progression.

However, it was approved under an accelerated approval pathway using biomarkers showing evidence of beta-amyloid clearance. Clinical benefit would need to be proven in post-marketing clinical trials.

But payers were reluctant to reimburse for the drug, and in April, the U.S. Center for Medicare and Medicaid Services implemented guidance, restricting reimbursement for Aduhelm to only within the context of a clinical trial.

Further, CMS applied this restriction to the entire class of beta-amyloid-clearing drugs that had yet to be submitted. That would seem to apply to lecanemab.

Unlike Aduhelm, lecanemab demonstrated what Eisai and Biogen said was “highly statistically significant” slowing of the progression of the disease. It reduced the clinical decline by 27% compared to placebo after 18 months based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessment. This trend was first observed after six months.

From a financial and stock point of view, the lecanemab data were tremendous.

“The reported data is pretty much a best-case scenario that not only should lead to approval and reimbursement but could make it challenging for competition (assuming any are successful) to match," wrote Brian Skorney, an analyst with Baird, in a note to clients.

Dr. Michael Irizarry, senior vice president and deputy chief clinical officer for Alzheimer’s disease and brain health at Eisai, told BioSpace lecanemab has a different binding profile than Aduhelm. 

Biogen stock rocketed 40% after the announcement, and Eisai rose 17%.

Hope and Caution

Another underlying issue with Aduhelm was its cost. Biogen initially priced Aduhelm at $56,000 per patient per year. Even after Biogen cut the price in half to about $28,200, reimbursement was still an area of controversy.

In a statement issued Sept. 27, the Alzheimer’s Association noted, “As it stands, this NCD would severely limit Medicare coverage for lecanemab if it is approved.”

So far, the lecanemab data is only known from a press release. The two companies plan to present full data on Nov. 29 at the Clinical Trials on Alzheimer’s Congress. Eisai plans to publish it in a peer-reviewed medical journal. 

Cynthia Carlsson, M.D., senior professor in Alzheimer’s disease and director of the Wisconsin Alzheimer’s Institute at the University of Wisconsin School of Medicine and Public Health told BioSpace the lecanemab data was “encouraging.”

However, “We really need to dig deeper into the data,” she said. “Once [Biogen and Eisai] present it at the Clinical Trials on Alzheimer’s Congress and have some more of the details released, we’ll be able to really evaluate how much of the clinical improvement was from anti-amyloid effects versus other potential effects.”

Alzheimer’s trial design is also a challenge. Although many studies focus on various biomarkers, such as signs beta-amyloid has decreased, clinical efficacy is often determined by measures of how much disease progress has slowed.

“They’ll be measuring amyloid when there’s spinal fluid, and drug absorption and drug bioavailability,” Carlsson said. “They’ll be measuring the perspective of the clinician and family home as well as a patient’s perspective, and how they’re doing with objective positive scores. They’re trying to get a full sense of what the biologic changes are and how that translates into something that’s meaningful life for the family.”

Does Lecanemab Revitalize the Amyloid Theory?

The Aduhelm trials were the first to hint at the slowing of cognitive decline, but those data were complex and were only shown in a high-dose subgroup of patients.

In addition, Aduhelm came with a set of tricky adverse conditions, notably potential brain swelling and brain bleeds. Lecanemab also has the same potential adverse events.

Haruo Naito, chief executive officer of Eisai, said the results of the trial proved the amyloid hypothesis. Biogen CEO Michel Vounatos agreed.

But it may not be that straightforward. A large-scale analysis of tissue samples by National Institute on Aging (NIA)-funded researchers, published Thursday, discovered 44 groups of proteins, dubbed “protein communities” whose levels increased or dropped in “coordinated ways” in the brains of Alzheimer’s patients. The same was not found in the control groups of people without Alzheimer’s. 

The research group directly measured protein levels in more than 1,000 brain tissue samples. In their study, only about half of the protein changes were observed in the corresponding RNA molecules. This suggests something significant is happening after a protein’s coding is sent to the protein-making machinery in the brain.

Neuroinflammation is also a major factor in Alzheimer’s disease. Amyloid, which data suggests accumulates 10 to 20 years before signs of symptoms in Alzheimer’s patients, may exacerbate neuroinflammation and inflammatory pathways, which lead to the development of tau pathology and cell death.

Other research has pointed to common viral infections, such as herpes viruses, that may stimulate neuroinflammation. However, an August study out of NIA seemed to debunk that theory.

The FDA accepted the Biologics License Application for lecanemab under an accelerated approval pathway in July. A decision will likely be made in early 2023.

“For the field of Alzheimer’s disease research, this is a sort of a triumph,” said Marsel Mesulam, M.D., director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern Medicine Feinberg School of Medicine. “The not-so-good news is that this is very cumbersome, it has side effects, it is likely to be very expensive and the clinical effect is very, very small.”