A study recently published in the journal Nature indicates that aducanumab shows promise, in both preclinical and clinical settings, in prevention and reduction of amyloid-β (Aβ) plaques in patients with Alzheimer’s.
Aducanumab (marketed as Aduhelm) is an amyloid beta-directed antibody indicated to treat Alzheimer’s disease. Aduhelm is approved under the accelerated approval pathway, which provides patients with a serious disease earlier access to drugs when there is an expectation of clinical benefit despite some uncertainty about the clinical benefit.
Accelerated approval is based upon the drug’s effect on a surrogate endpoint— an endpoint that reflects the effect of the drug on an important aspect of the disease — where the drug’s effect on the surrogate endpoint is expected, but not established, to predict clinical benefit. In the case of Aduhelm, the surrogate endpoint is the reduction of amyloid beta plaque. The accelerated approval pathway requires the company to verify clinical benefit in a post-approval trial.
Previous studies using antibody-based immunotherapy against Aβ deposits failed to show promising results. The authors of the Nature study tested the amyloid hypothesis assuming that this previous work had issues with antibodies’ efficacy and specificity.
In this study, Jeff Sevigny and colleagues from Biogen, Cambridge, Massachusetts, USA and Neurimmune, Schlieren-Zurich, Switzerland report that in preclinical settings, in a transgenic mouse model of Alzheimer’s disease, the antibody was able to penetrate the brain, and specifically accumulated and bound to parenchymal, but not vascular Aβ deposits.
In clinical settings, the research team studied the effects of aducanumab in a double blind placebo controlled phase 1b randomized trial. 165 people with early-stage Alzheimer’s disease were given a monthly injection of the antibody for one year, at 33 sites in the US.
The main result from this trial indicates that the treatment with aducanumab contributed to a significant reduction of beta-amyloid plaques in patients with early-stage Alzheimer’s disease, in a time- and dose-dependent way. Moreover, cognitive decline could be significantly slowed in antibody-treated patients as opposed to the placebo group.
As per the mechanism(s) of action of aducanumab, the authors believe that the clearance of amyloid-β deposits was most likely related to the enhanced recruitment of microglia. They argue that an Fc gamma R-mediated microglial recruitment and phagocytosis appeared to contribute to the aducanumab’s effects.
According to telegraph.co.uk, Dr. Roger Nitsch, one of the senior authors of this study, stated that “In the high dose group the amyloid has almost completely disappeared. The effect size of this drug is unprecedented”. Of note, and as per this online article, there are now two large phase-three clinical studies taking place to further evaluate safety and efficacy of aducanumab.
However,as per The New York Times this was “a decision that has been met with scathing rebuke from many Alzheimer’s experts and other scientists and calls for investigations into how the agency approved a treatment that has little evidence it helps patients”.
Moreover, and as CNN reported, Courtney Rhodes, an FDA spokeswoman, said, “Given the unmet needs for patients with Alzheimer’s disease — a serious, progressive and ultimately fatal disease — the agency chose to use the accelerated approval pathway to allow earlier access to patients while we continue to acquire data on the drug’s benefit.”
According to Steven Woloshin, MD, MS and Aaron S. Kesselheim, MD, JD, MPH as stated in their June 6, 2022, JAMA article the FDA recently approved aducanumab (Aduhelm) for people with mild symptoms of Alzheimer disease, which reduced brain amyloid plaque (protein deposits), a main feature of Alzheimer disease. But, as per these authors, plaque reduction, has not been a reliable marker for cognitive function in past trials, and not everyone with plaques has or will get Alzheimer disease.
Furthermore, two clinical trials tested aducanumab. When analyzed together, they showed no change in remembering, learning, reasoning, or functioning vs placebo.
The authors discuss that adverse effects were common. “In the trials, 41% of patients experienced brain swelling or bleeding. While most cases were mild and managed with dose reduction, 1% to 2% of patients required hospitalization”.
The authors’ conclusion was clear: “In 2 clinical trials, after 18 months it reduced amyloid plaque levels, but that did not translate to any clinical effect in 1 trial or a noticeable effect in the other. Potentially serious harms are common. The FDA has required that another trial be completed by 2030 to decide whether aducanumab has a meaningful patient benefit.”
Moreover, according to the authors, the approval followed the unproven concept of amyloid hypothesis that was introduced 3 decades ago. It stated that Alzheimer disease (AD) is due to deposition of the protein amyloid-β (“amyloid”) in the brain, and therefore, removing or reducing its load should be anticipated to benefit patients with AD. This concept has been an appealing, but precariously simple-minded and speculative mindset for an immensely complicated disease without any proven mechanism for validating the underlying biochemical process.
The authors concluded that the approval of Biogen’s drug, aducanumab, with reference to reduced amyloid plaque after treatment is most likely based on misinterpretation and thus unjustified.