Alzheimer’s disease is a progressive neurodegenerative disorder that slowly destroys memory and thinking skills, eventually impacting the ability to carry out simple tasks. Biotechnology company Biogen has been a major player in this field, developing therapies that target the underlying disease pathology rather than just its symptoms. This effort led to the development of two high-profile treatments that have profoundly shaped the landscape of Alzheimer’s research and patient care.
Targeting Amyloid Beta
The scientific foundation for Biogen’s approach is the Amyloid Hypothesis, the theory that the disease is triggered by the accumulation of amyloid-beta (Aβ) protein fragments in the brain. These fragments aggregate into sticky clumps known as amyloid plaques, which are toxic to surrounding neurons. The hypothesis suggests that an imbalance between the production and clearance of these Aβ peptides is an early factor in the disease process.
Biogen’s drugs are monoclonal antibodies, laboratory-made proteins designed to mimic the immune system. These antibodies are engineered to bind to the amyloid-beta protein, tagging it for removal by the brain’s immune cells. By reducing amyloid plaques, the treatments aim to slow the underlying progression of the disease, lessening the effects that lead to neurodegeneration and cognitive decline.
The Aduhelm Controversy and Legacy
Biogen’s first anti-amyloid treatment was aducanumab, marketed as Aduhelm, which received accelerated approval from the U.S. Food and Drug Administration (FDA) in June 2021. This approval was controversial because two large-scale clinical trials yielded conflicting results regarding the drug’s ability to slow cognitive decline. One study suggested a small benefit, while the other did not show a statistically significant effect, leading experts to question the clinical benefit.
The FDA based its decision on the drug’s proven ability to reduce amyloid plaques, using this as a surrogate endpoint under the Accelerated Approval Pathway. However, the approval faced scrutiny due to uncertain efficacy, safety risks, and its initial annual price of $56,000. The Centers for Medicare & Medicaid Services (CMS) severely restricted coverage, limiting it only to patients in CMS-approved clinical trials. This prevented broad patient access and led to minimal sales, resulting in Biogen discontinuing the drug’s development and commercialization in early 2024. The Aduhelm saga proved that anti-amyloid antibodies could clear plaques and forced a re-evaluation of the regulatory process for Alzheimer’s therapies.
Leqembi: Current Treatment Landscape
The successor drug, lecanemab, developed by Biogen in partnership with Eisai and marketed as Leqembi, presented a clearer clinical profile and regulatory outcome. Leqembi targets the soluble, toxic forms of amyloid-beta, known as protofibrils, which are damaging to neurons. Clinical trial data demonstrated a statistically significant reduction in the rate of cognitive and functional decline in patients with early-stage Alzheimer’s.
The Phase 3 Clarity AD trial showed that Leqembi slowed disease progression by 27% over 18 months compared to a placebo, providing clear evidence that removing amyloid could translate to a measurable clinical benefit. This data led to the drug receiving traditional FDA approval in July 2023, converting it from its initial accelerated status. Leqembi is indicated for patients with mild cognitive impairment or the mild dementia stage of Alzheimer’s disease who have confirmed amyloid pathology in the brain, typically through a PET scan or spinal fluid analysis.
Safety Concerns and Monitoring
The class of anti-amyloid monoclonal antibodies, including Aduhelm and Leqembi, shares a common safety concern known as Amyloid-Related Imaging Abnormalities (ARIA). ARIA manifests as either temporary swelling in the brain (ARIA-E, for edema) or small spots of bleeding (ARIA-H, for hemorrhage). While ARIA is often asymptomatic and detected only on MRI, it can occasionally cause symptoms such as headache, confusion, dizziness, or visual disturbances.
The risk of developing ARIA is higher for individuals who carry the ApoE \(epsilon\)4 gene, a common genetic risk factor for Alzheimer’s disease. Regular magnetic resonance imaging (MRI) monitoring is mandatory for patients receiving these treatments, especially during the first year of therapy. This monitoring allows clinicians to detect ARIA early and manage it by temporarily or permanently discontinuing the medication depending on the severity of the findings.