An open letter to the Alzheimer’s disease community from Biogen Head of Research and Development, Alfred Sandrock, M.D., Ph.D

Statement from Head of Research and Development, Alfred Sandrock, M.D., Ph.D.:Biogen Inc. – On June 7, 2021, Aduhelm became the first approved treatment to address a defining pathology of Alzheimer’s disease: targeting the reduction of amyloid plaques in the brain. We believe patients, family members and physicians deserve the facts about the therapy and the process by which it was approved so they may make informed decisions. The approval of Aduhelm by the FDA came after an extensive development, testing and review process. Over more than a decade, we at Biogen engaged in rigorous and science-driven research and development that assessed whether Aduhelm could help patients worldwide who suffer from Alzheimer’s disease. We are proud of the work our dedicated team has done to develop Aduhelm and of the potential it brings to Alzheimer’s patients. We are equally proud of the professionalism both our team and the FDA demonstrated during a thorough review process.

Unfortunately, Aduhelm’s approval has been the subject of extensive misinformation and misunderstanding. It is normal for scientists and clinicians to discuss data from experiments and clinical trials, to debate, and to disagree, on the interpretation of data. That is how science advances and we welcome these discussions. Recently, however, there has been a turn outside the boundaries of legitimate scientific deliberation. We welcome a formal review into the interactions between the FDA and Biogen on the path to the approval of aducanumab. A better understanding of the facts is good for everyone involved to assure confidence in both the therapy and the process by which it was approved as we prioritize the issues that affect patients.

A step toward such transparency is to correct some of the misinformation we have seen: More than 250 drugs have been granted Accelerated Approval by the FDA. The FDA instituted its Accelerated Approval Program in 1992 to allow for earlier approval of drugs that treat serious conditions, and to fill an unmet medical need based on a surrogate endpoint that is reasonably likely to predict a clinical outcome. Since 1992, 253 accelerated approvals have been granted to drugs to treat HIV/AIDS, sickle cell anemia, Duchenne muscular dystrophy (DMD), multiple sclerosis (MS) and particularly in the oncology therapeutic area. In oncology, for example, the surrogate may be tumor shrinkage, as this is likely to predict increased survival. Many cancer patients have benefitted from novel immunotherapy treatments that have received accelerated approval, and death rates from cancer have declined dramatically. The accelerated approval of Aduhelm has been granted based on data from clinical trials showing the effect of Aduhelm on reducing amyloid beta plaques, a surrogate biomarker that is reasonably likely to predict clinical benefit, in this case a reduction in the rate of clinical decline. We believe that this will be further established as we collect more data from the ongoing EMBARK study and the post-marketing confirmatory trial.

Several people have stated that all previously studied anti-amyloid antibodies clear amyloid from the brain but have failed as a class to demonstrate benefit. This is factually incorrect. First generation anti-amyloid antibodies were not specific for aggregated forms of amyloid beta, or targeted soluble monomeric amyloid beta, or were deficient in effector function. As a result, these antibodies do not clear amyloid from the brain. As such, there is no basis for using the failure of these antibodies as a reason to question the approval of Aduhelm. The review process that led to accelerated approval was extensive and thorough, during which we responded to numerous questions and requests from the FDA. The approval is supported by data of more than 3,000 patients and 2.2 million pages of clinical data and analyses.

Separately, we have seen statements that all of ADuhelm’s results are “post hoc” – in other words, that a filter was applied after the fact to interpret the data in a certain way. That is also factually incorrect. The primary and secondary endpoints had been pre-specified in the Phase III trial protocols, before the first patient was enrolled into the trials. The Aduhelm label shows the results on these pre-specified endpoints, based on data that had already been collected at the sites by the time the trials were prematurely terminated on March 21, 2019. Safety data were also extensively reviewed and are well documented in the label, so that physicians can make informed benefit-risk decisions and take appropriate actions as they monitor their patients under treatment. It is important to recognize that collaboration between industry and regulatory agencies is common, appropriate and beneficial. That was exemplified at its best with the COVID-19 vaccine development. As a doctor, a scientist and the Head of Research and Development at Biogen, I believe scientists at regulatory agencies and drug manufacturers must work together in an effort to defeat other devastating public health threats.

The FDA’s decision to approve ADuhelm to treat patients with Alzheimer’s disease was based on thorough analysis of the data. As stated by Dr. Patrizia Cavazzoni, Director, the FDA Center for Drug Evaluation and Research, in discussing the agency’s decision to approve the treatment: “In all studies in which it was evaluated… Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion.” At the time of approval of Aduhelm, the FDA further stated: “The clinical trials for Aduhelm were the first to show that a reduction in these plaques—a hallmark finding in the brain of patients with Alzheimer’s—is expected to lead to a reduction in the clinical decline of this devastating form of dementia.”

The FDA also stated: “Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients.” The FDA also shared that it “is requiring Biogen to conduct a post-approval clinical trial to verify the drug’s clinical benefit.”

In the announcement of its decision to approve Aduhelm through its Accelerated Approval pathway, the FDA explained the rigor underlying its analysis: “We examined the clinical trial findings with a fine-tooth comb, we solicited input from the Peripheral and Central Nervous System Drugs Advisory Committee, we listened to the perspectives of the patient community, and we reviewed all relevant data. We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit. In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy.”

Aduhelm is the first Alzheimer’s treatment approved since 2003. An important question is being overlooked by many: what would be the impact of deferring access to this treatment, despite the clinical data underlying its approval? Based on our current estimates of the progression rates of the disease, every day over 1,000 Americans will advance from early stages of disease to moderate and severe stages of disease, and thus may progress beyond the stages during which Aduhelm should be initiated. We feel a strong obligation to be able to offer new options to patients with this devastating disease.