A group of prominent researchers and clinicians is calling on the FDA to revise its approval process for Alzheimer's disease drugs, advocating for a focus on amyloid removal as the key indicator of efficacy. Published in Alzheimer's and Dementia, their perspective suggests that drugs demonstrating significant and safe amyloid clearance, along with changes in downstream biomarkers, should be granted traditional approval, even if immediate cognitive benefits are not fully evident. This proposal arrives in the wake of encouraging Phase 3 trial results for lecanemab and donanemab, both of which effectively target and remove amyloid plaques in the brain.
The core argument centers on the extensive evidence accumulated over four decades, which implicates cerebral amyloid-beta (Aβ) aggregation as a primary cause of Alzheimer's disease. The authors contend that the field's understanding of the pathogenic cascade following amyloid deposition has advanced to the point where changes in imaging and blood-based biomarkers can accurately reflect disease progression. They highlight that the three FDA-approved immunotherapies, along with gantenerumab, all remove brain amyloid, and the extent of amyloid reduction correlates with slower biomarker and cognitive decline.
Shifting the Regulatory Paradigm
The researchers propose a shift from the current regulatory requirement of demonstrating cognitive or clinical change for drug approval. Instead, they suggest that the FDA could grant standard approval to anti-amyloid antibodies that substantially remove aggregated Aβ from the brain, particularly when accompanied by positive changes in downstream biomarkers. Cognitive, clinical, and quality-of-life data could then be gathered during the drug's post-approval clinical use.
Drawing parallels with the approval of lovastatin in 1987 based on LDL-cholesterol reduction, the authors argue that amyloid removal can serve as a surrogate marker for regulatory considerations. They emphasize that the lecanemab and donanemab Phase 3 trials have provided strong evidence that robust amyloid reduction can impact the disease process. Specifically, they suggest the FDA should consider evidence of amyloid lowering below 15 to 20 centiloids, supported by improvements in tau, microglial inflammation, astrocytosis, or neurodegeneration biomarkers, as grounds for traditional approval.
Implications for Future Treatments
The authors express hope that their argument will stimulate discussion among regulators, clinicians, scientists, and the public regarding access to disease-modifying treatments for Alzheimer's disease. They note that ongoing secondary prevention trials of approved amyloid immunotherapies are likely to further support this proposed regulatory change. As self-injected, more potent second-generation immunotherapies and DNA-based anti-amyloid drugs enter clinical trials, the need for a streamlined approval process becomes increasingly critical to address the growing burden of Alzheimer's disease, which affects an estimated 60 million people worldwide.
