What’s With the New Alzheimer’s Drug?

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Issue 3, Volume 112

By Andy Chen 

Over the past few decades, billions of dollars have been invested into treating Alzheimer's disease with no promising results. That was the case until the Food and Drug Administration (FDA) approved aducanumab, marketed as Aduhelm, ending the nearly two-decade-long absence of approval for Alzheimer's drugs. More than simply improving symptoms, aducanumab promises to slow the progression of Alzheimer’s. Can it really do what it promises, though?

Alzheimer's disease, first discovered in 1906, is a progressive disorder that causes memory loss and destruction of mental functions. The disease affects an estimated 6.2 million Americans and is the sixth leading cause of death in the United States. Scientists suspect amyloid plaques, abnormal protein structures formed by the aggregation of beta-amyloid between neurons, to be a root cause of Alzheimer’s. Misfoldings and mutations in the amyloid precursor protein (APP) creates beta-amyloid, a longer and stickier version of the APP. Beta-amyloid is also produced at a higher rate than APP, leading to the formation of amyloid clumps—clumps are associated with disruption in cell communications, death of neurons, and symptoms of Alzheimer’s.

Aducanumab, classified as a monoclonal antibody, is the first therapy to target plaques, reducing amyloid aggregates and preventing their buildup in the first place. The drug functions by recognizing and binding to beta-amyloid, effectively lowering the amount of protein that could combine to form the plaques. In fact, aducanumab clinical trials in all phases consistently reported significant reduction in amyloid plaques. However, it is still uncertain whether reducing plaques will improve the conditions of patients with Alzheimer's.

Aducanumab, created by the biotechnology company Biogen in Cambridge, Massachusetts, did not walk a smooth path to approval. In March 2019, the drug was almost discontinued after two large late-stage clinical trials failed an interim analysis. While both trials showed decreased beta amyloid plaques, one trial called ENGAGE indicated negative results in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), implying that aducanumab was ineffective. In a later reevaluation of the data, however, Biogen found that participants in the high dosage subset in the other trial, dubbed EMERGE, experienced a slight improvement in their cognitive functions. Following this event, the firm pursued an FDA approval for aducanumab.

In June, the FDA disregarded the concerns from its advisory committee and approved aducanumab, basing their decision mostly on the drug’s ability to lower levels of amyloid plaques rather than its clinical benefits. Unsurprisingly, the FDA received backlash for approving the controversial drug. Many scientists, including members of the advisory committee, expressed that there was not enough conclusive evidence that the drug provided any benefits. Three members of the committee even resigned in protest after the approval was announced.

The FDA finally recognized the problem of inadequate evidence only after approval and took a different approach. They moved aducanumab onto an accelerated approval program, an alternative pathway that permits drugs treating serious diseases to be used without definite signs of benefits. In aducanumab’s case, it targeted the biological causes of the disease, and Biogen needed to produce a post-marketing analysis by 2030 to prove the effectiveness of the drug.

Despite the FDA’s second chance for aducanumab, its situation remains a topic of great controversy. Aside from the lack of concrete evidence supporting its efficacy, aducanumab has serious side effects. In clinical trials, 40 percent of the high dosage groups experienced brain swelling or bleeding. Nausea, dizziness, and diarrhea also occurred more frequently in these groups. In fact, prominent hospitals, private insurers, and the Department of Veterans Affairs all deemed the drug risky and prohibited its use.

Meanwhile, some like Eric Siemers, a drug-development consultant in Zionsville, Indiana, believe that aducanumab’s approval could lead the way to the revival of neuroscience research, especially with neurodegenerative disease. Many groups such as the Amyotrophic Lateral Sclerosis Association welcome the new flexibility shown by the FDA and hope that the same flexibility would be directed towards other serious neurological diseases.

However, the drug tominersen, created by Roche and Ionis Pharmaceuticals, is an example of why flexibility in regulation could backfire. Tominersen was developed to treat Huntington’s disease, another neurodegenerative disease like Alzheimer’s, and targeted the toxic version of the huntingtin protein responsible for symptoms, similar to aducanumab. While Tominersen demonstrated potential for treating Huntington’s at first, it was eventually discontinued in its phase III clinical trials when studies showed that the drug worsened patients’ conditions.

Health experts argue that what happened with Tominersen could happen to aducanumab, but at a much larger scale since it is on the market. Not only is the drug extremely expensive, at $56,000 a year, but it relies on false hope instead of scientific evidence, providing little to no benefits or, even worse, endangering a patient’s health. The drug’s approval also came with criticism of the amyloid cascade hypothesis, which states that the build-up of beta-amyloid is the main disruptor of neuronal function and has been acting as the foundation for pharmaceutical research. Yet, the true function of amyloid in Alzheimer’s is still unclear. One theory states that amyloid is not a cause of Alzheimer’s but rather a response to the brain’s degeneration, while others mention that Alzheimer’s is a heterogeneous disease that includes several root causes besides beta-amyloid aggregates, such as tau tangles, formed by aggregation of a protein called tau, and vascular abnormalities, changes in blood flow of the brain.

Regardless of whether approving aducanumab was right, the scientific community has taken a big step. Aducanumab represents a bright light for Alzheimer’s patients who have never seen a glimmer of hope after being diagnosed with this terminal disease. If aducanumab is successful, it could set a precedent for other drugs treating serious diseases that need conditional approval. This optimism is also a double-edged sword, however. If it fails, the hopes of patients and scientists alike could be crushed, and therapy regulations would likely become stricter. In any case, the best thing to do is wish for aducanumab to be the miracle drug that paves a promising future for neurodegenerative diseases.