The FDA authorized the first novel Alzheimer’s treatment in 2021. Biogen and Eisai’s Aduhelm (aducanumab) help eliminate beta-amyloid from the brain.
Beta-amyloid aggregation into brain plaques has dominated Alzheimer’s research for years, yet beta-amyloid-targeting medications have failed to show benefits.
Alzheimer’s is a complex disease whose cause is currently unknown. When Alzheimer’s symptoms appear, it may be too late for treatments, say some.
Biogen discontinued two phase III trials of Aduhelm in early-stage Alzheimer’s patients in 2019 because they were unlikely to fulfill their primary aim. Later that year, Biogen reported that one of the trials reduced cognitive deterioration in patients. Patients in this trial received a high medication dose.
An FDA advisory panel doubted Aduhelm’s efficacy after studying its marketing application. Ten of 11 panelists voted against the drug’s approval, and the eleventh wasn’t sure. Despite the panel’s suggestion, the FDA authorized the medicine under the fast approval pathway, which allows clearance based on a “surrogate endpoint that reasonably predicts a clinical benefit to patients.”
Aduhelm was approved because it decreases brain amyloid plaques. Director of the FDA’s Center for Drug Evaluation and Research Patrizia Cavazzoni called the treatment “the first to tackle Alzheimer’s disease’s fundamental process.”
Why? Little data suggests Aduhelm will benefit Alzheimer’s patients. Other experimental mAbs that reduce brain amyloid have not shown clinical advantages. Consider bapineuzumab, which failed phase III studies when developed by Elan and Wyeth (and then J&J and Pfizer). The medicine reduced amyloid plaques but didn’t enhance Alzheimer’s patient outcomes. In 2012, medication development was halted.
Joel Perlmutter, David Knopman, and Aaron Kesselheim resigned when the medicine was approved. Kesselheim remarked, “This may be the FDA’s worst approval decision I can remember” and “there’s no good evidence the medicine works.”
The HHS Inspector General is also investigating the drug’s approval. The FDA’s clearance of Aduhelm raised concerns because of claimed scientific issues, the advisory committee’s vote against approval, and suspicions of an improperly close relationship between the FDA and industry. We’ll review how the FDA applies the accelerated approval procedure to address these issues.
In December 2021, the EMA denied the drug’s EU marketing license. “ Although Aduhelm lowers amyloid beta in the brain, the link between this effect and clinical improvement has not been proven. The primary studies showed mixed results on Aduhelm’s effectiveness in treating early-stage Alzheimer’s.
“Studies did not establish that the treatment was safe because brain scans of some individuals indicated anomalies that could cause harm. The anomalies can’t be appropriately evaluated and handled in clinical practice.
The Agency believed Aduhelm’s benefits didn’t exceed its hazards.
Aduhelm cost $56,000 a year in the US until being dropped to $28,000 in December 2021. In January 2022, CMS indicated it will cover mAbs that target amyloid plaques, but only for individuals enrolled in “qualified” clinical studies. Aduhelm is the only licensed medicine in this category, but Eli Lilly’s donanemab is in development.
CMS doesn’t know the drug’s risk-benefit ratio. CMS Chief Medical Officer and Director of the Center for Clinical Standards and Quality Lee Fleisher said, “This proposed National Coverage Determination is the result of a robust evidence analysis conducted through a thorough review process that found while this treatment may have promise, it may also harm patients. This injury ranges from headaches, dizziness, and falls to brain hemorrhage.”
Mid-February was the deadline for CMS’s proposal comments. Over 9900 comments were sent, although many are “copy and paste” statements criticizing the FDA’s approval of the medicine.
Pharmaceutical corporations, doctors, and patient groups also commented. Some appreciate CMS’s move; Doctors for America said, “Given the paucity of data surrounding aducanumab’s safety and persistent safety concerns, we applaud CMS’s planned decision to restrict coverage of this medicine and others with similar mechanisms of action under Coverage for Evidence Development.”
Some disagree. The Alzheimer’s Association disagrees with CMS’ planned NCD for monoclonal antibodies aimed against amyloid for Alzheimer’s disease (anti-amyloid mAbs).
CMS should continue to apply its long-standing precedent to each medication in this class: If FDA-approved, CMS should cover treatment in this class when delivered according to its FDA label, including tests and procedures required for treatment delivery and maintenance.
BIO opposed CMS’s decision. BIO concerns CMS’s power to apply CED to restrict coverage for on-label uses of FDA-approved pharmaceuticals, notably for a currently approved treatment and an entire class of drugs in the pipeline for approval soon.
Since the comment period closed, UsAgainstAlzheimer’s has launched a campaign calling for Medicare to cover Alzheimer’s therapies. The campaign apparently costs millions.
The CMS will decide on coverage in April 2022, but the issue will likely last longer.