FDA Grants Historic Approval for Alzheimer's Disease Therapy in Permissive Decision

Wilson Sonsini Goodrich & Rosati

On June 7, 2021, the U.S. Food and Drug Administration (FDA) approved Biogen, Inc.'s Aduhelm (aducanumab) to treat Alzheimer's disease through the FDA Accelerated Approval Program in a landmark decision. The FDA's approval has received mixed reactions, in part because two phase III clinical trials for Aduhelm were suspended in 2019. The FDA's decision has significant policy implications, as discussed below, and future litigation regarding reimbursement and coverage of Aduhelm is expected given the uncertainty surrounding the drug's efficacy and exorbitant price. Still, the decision is viewed as opening a new opportunity for commercializing therapies with less data than previously anticipated.

Understanding Alzheimer's Disease Pathology

Prior to Aduhelm, the FDA had not approved a therapy for Alzheimer's disease since 2003. Alzheimer's disease is an irreversible neurodegenerative disorder associated with progressive memory loss, neuropsychiatric symptoms, and cognitive decline. It affected an estimated 5.8 million Americans in 2020, is the most common form of dementia and the sixth leading cause of death among American adults. The disease is characterized by two types of pathological lesions in the brain related to the death of neurons and loss of their synaptic connections: amyloid plaques and neurofibrillary tangles. Amyloid plaques form in the space between the neurons and consist of aggregates of the amyloid beta (Aβ) protein. Neurofibrillary tangles, on the other hand, are composed of misfolded tau protein and form within the neurons.

Over the past decade, the National Institute of Health (NIH) has significantly increased its investment in Alzheimer's disease and dementia research. However, despite advances in diagnostic tools for Alzheimer's disease, much remains unknown about the disease's pathophysiology and efforts to treat Alzheimer's disease have historically targeted the symptoms rather than the root causes of the disease.

The absence of marketable therapeutics targeting disease causation is not for lack of trying. Since the 1999 publication of a study demonstrating the potential for Aβ immunization to reverse deficits in mice brains, there have been repeated attempts to develop anti-Aβ immunization therapeutics to address this primary disease pathology. But even though certain promising anti-Aβ immunization therapeutics advanced to phase III clinical trials, efforts to develop such drugs eventually failed. Hence, Aduhelm is prima facie unique in that it has gained regulatory approval for reducing Aβ plaques in the brain.

Biogen's Aduhelm

Aduhelm is Biogen's human monoclonal antibody administered to patients via a monthly intravenous infusion. The drug crosses the blood-brain barrier and binds to Aβ aggregates, or fibrils, which form the core of Aβ plaques. Once bound to these Aβ aggregates, Aduhelm activates microglia—immune defense cells located within the brain and spinal cord—to enhance the destruction of amyloid plaques. In the clinical trials, magnetic resonance imaging detected side effects related to minor hemorrhaging or fluid accumulation in 41 percent of treated patients; however, in many of the patients, no symptoms other than headaches were reported from the side effects.

Biogen encountered numerous obstacles while seeking regulatory approval for Aduhelm. For example, in 2019, Biogen and Eisai suspended late-stage phase III clinical trials for Aduhelm because of a lack of evidence demonstrating efficacy. These phase III trials were a major sticking point in the drug's approval.

Aduhelm FDA Approval Pathway

On June 7, 2021, the FDA granted Aduhelm Accelerated Approval for the treatment of Alzheimer's disease. Under the traditional FDA approval process, the FDA's Center for Drug Evaluation and Research extensively analyzes the target condition, evaluates risks and benefits from the drug's clinical data, and assesses risk mitigation strategies. Accelerated Approval, however, presents drug manufacturers the opportunity for expedited review for eligible drugs that (1) treat serious or life-threatening conditions and (2) offer significant benefits over available therapies.

Drugs approved under the FDA's Accelerated Approval pathway must exhibit a therapeutic effect on a "surrogate endpoint," which reasonably predicts the clinical benefit in relation to the "standard endpoint" in cases of diseases with lengthy courses of treatment. In other words, one or more clinical data points serve as indicators of a drug's therapeutic benefit in treating a disease which would otherwise require a much more extensive treatment period to determine efficacy. Aduhelm received Accelerated Approval after reducing Aβ pathology in trials on Alzheimer's patients, a result that supports a therapeutic benefit.

However, Aduhelm's Accelerated Approval has generated controversy due to residual uncertainties surrounding the drug's clinical benefit for Alzheimer's patients. In November 2020, upon reviewing Aduhelm's two late-stage development, phase III clinical trials—only one of which indicated a reduction in clinical decline—the FDA's Peripheral and Central Nervous System Drugs Advisory Committee opined that one successful trial should not reasonably be used as the primary evidence supporting FDA approval. Although the committee did not discuss Accelerated Approval, the FDA found studies showing a substantial reduction in Aβ levels sufficient to approve Aduhelm under the Accelerated Approval pathway despite the committee's recommendation.

Obtaining FDA Approval through the Accelerated Approval pathway means that Biogen is required to conduct post-approval, phase IV confirmatory trials for Aduhelm. If the phase IV clinical trials do not confirm Aduhelm's expected clinical benefit in relation to current surrogate endpoint projections, the FDA may remove the drug from the market. Biogen and the FDA have not yet determined the timing of the phase IV clinical trials.

Industry Reactions and Policy Implications

In November 2020, Cigna estimated that approximately 1.4 million Americans may be eligible for Aduhelm. It is anticipated that Aduhelm's approval, though controversial, may spur the emergence of additional novel therapeutics directed toward Alzheimer's disease pathology, a phenomenon that has previously occurred with regard to the development of drugs for multiple sclerosis. However, pricing and coverage issues may limit the drug's accessibility.

For an Alzheimer's patient with a mild form of the disease receiving an infusion once every four weeks, Biogen estimates the annual cost of the drug at $56,000, a "bewildering" price that has provoked criticism. It is unclear how the costs associated with Aduhelm will be allocated. Costs are expected to fall within Medicare's Part B program, since most Alzheimer's patients experience symptoms in their sixties. However, FDA approval is not a guarantee of Medicare Part B coverage, and Medicare has not yet announced how it will proceed with respect to the drug.

In light of Aduhelm's costs, healthcare experts are urging the Centers for Medicare & Medicaid Services (CMS) to instigate a national coverage determination (NCD) process for the drug, which would include an independent assessment and evidentiary review. CMS generally utilizes NCDs to stipulate specific patient coverage criteria that safely and efficiently limits coverage of expensive drug therapies with contested efficacies.

Looking forward, the decision to approve the drug begs the question of how in particular the FDA analyzed Aduhelm's data differently than its Peripheral and Central Nervous System Drug Advisory Committee and landed at the favorable conclusion. Indeed, this approval may provide insights regarding the level of uncertainty that the FDA is willing to accept when permitting the commercialization of innovative therapeutics, including for other high-value indications, such as cancer.

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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