Urgency, discontent, and innovation: How the Aducanumab drug approval calls for novel perspectives of Alzheimer’s Disease pathogenesis

10th of June 2021. Dr Aaron Kesselheim, a member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee resigns over the agency’s controversial accelerated approval of Biogen’s drug Aducanumab. He is the third member of the panel to resign since the approval of the Alzheimer’s drug 3 days ago.

For years, the development of a drug targeting neurodegenerative progression seemed impossible. However, in 2015, Biogen Inc. seemed to have achieved exactly that; a drug designed to clear amyloid plaques and reduce tau deposits in the brain of Alzheimer’s disease patients (AD). It was sensational.

In August 2015, two phase III clinical trials were initiated. But two years and several dosage increases later, both studies were terminated as the result of a futility analysis. Shockingly, three months later, Biogen stated that subsequent trials provided proof of sufficient clinical efficacy to pursue a new drug approval application.

Advertising is a powerful tool; the proof in question was obtained from data from two new high-dose trials, with only one of them showing significant effects on several clinical outcomes. The advisory committee found that when pooled, the evidence did not convincingly show that the drug could slow cognitive decline in the early stages of AD. Furthermore, it was concluded that the drug could cause potentially serious side effects like brain edema and haemorrhage. Alongside one undecided expert, ten committee members voted against approval.

7 months later, in a shocking turn of events, the FDA issued a press release informing of the accelerated approval for the prescription of Aducanumab in AD treatment. The agency expressed that the green-light decision was based on the drug’s reduction of amyloid plaques as an indication of clinical efficiency. The announcement concerned the committee experts, as following their verdict, agency officials had informed them that biomarker indicators wouldn’t be used as a justification for a go-ahead. “Accelerated approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval”, expressed Dr. Kesselheim.

Was the fact that the drug could potentially slow AD progression by targeting amyloid plaques enough to overlook the side effects and grant approval, for the sake of possible patient benefit?

These senile plaques have been considered an underlying cause of AD for a while now, but as a multifactorial and multimodal disease, targeting amyloid deposits would remain insufficient to produce a large clinical effect. As pointed out by Dr. David Knopman in his resignation email; “The small benefits of Aducanumab pose a real challenge for justifying the large investment in time and effort on the part of the patient and family, as well as the health care system”.

Considering the aspects beyond the established disease hallmarks provides new strategies to approach treatment. A major recognised risk factor of AD is diet-induced obesity, as abnormal glucose metabolism leads to the increased production of reactive oxygen species (ROS). These free radicals induce the oxidative degradation of lipids that ultimately causes the neuronal damage and cell death thought to contribute to AD progression. Variations in the amino acid sequence (isoforms) of Apolipoprotein E have also been identified as AD risk factors, as the protein’s role in delivering cholesterol and complex lipids to neurons for membrane maintenance, neurogenesis, and repair can be disrupted by changes to its structure.

However, all the theories and associated factors surrounding the origin of Alzheimer’s disease are just that, theories. As seen with Aducanumab, even pharmacological therapies targeting the most settled hypotheses fail to reverse neurodegeneration and cognitive decline.

But what if Alzheimer’s were avoidable? Experts have started to consider clinical solutions striving away from targeting the disease hallmarks. They are choosing to focus instead on the use of biomarkers to enable early diagnosis during the premature stages of AD symptomatology, referred to as mild cognitive impairment (MCI).

A range of volatile organic compounds (VOCs), the by-products of normal metabolic activity, can be used as specific markers of disease. In 2020, Tiele and colleagues found acetone to be one of the crucial VOCs for exhaled breath sample characterisation of patients exhibiting MCI symptoms. Supplementary acetone is usually produced from fat stores when glucose is unavailable, which is the case in early AD stages, where specific cerebral regions experience reductions in brain glucose metabolism.

Emam and colleagues have found further associations between exhaled VOCs and risk factors of AD. They identified butylated hydroxytoluene, pivalic acid, and 2,3-dimethylheptane sensors to be sensitive to the breath of rats with genetically mutated APOE4 when kept on a high-sugar-high-fat diet.

The significant VOCs differences enables characterisation between patients and controls, shedding new hope into the detection of a prodromal stage of AD, before the unreversible neurodegeneration cascade starts. Perhaps in the avoidance of progression we are able to find a way to eradicate this debilitating, fatal disease.

Sources:

Lovelace Jr., B. (2021). Third member of prestigious FDA panel resigns over approval of Biogen’s Alzheimer’s drug. CNBC. From https://www.cnbc.com/2021/06/10/third-member-of-prestigious-fda-panel-resigns-over-approval-of-biogens-alzheimers-drug.html#:~:text=A%20third%20member%20of%20a,Dr.

Belluck, P., & Robbins, R. (2021). Three F.D.A. Advisers Resign Over Agency’s Approval of Alzheimer’s Drug. Nytimes.com. From https://www.nytimes.com/2021/06/10/health/aduhelm-fda-resign-alzheimers.html.

Mahase, E. (2021). Three FDA advisory panel members resign over approval of Alzheimer’s drug. BMJ, n1503. https://doi.org/10.1136/bmj.n1503

Knopman, D., & Perlmutter, J. (2021). Prescribing Aducanumab in the Face of Meager Efficacy and Real Risks. Neurology, 97(11), 545-547. https://doi.org/10.1212/wnl.0000000000012452

Tiele, A., Wicaksono, A., Daulton, E., Ifeachor, E., Eyre, V., Clarke, S., Timings, L., Pearson, S., Covington, J. A., & Li, X. (2020). Breath-based non-invasive diagnosis of Alzheimer’s disease: a pilot study. Journal of breath research, 14(2), 026003. https://doi.org/10.1088/1752-7163/ab6016

Emam, S., Nasrollahpour, M., Colarusso, B., Cai, X., Grant, S., Kulkarni, P., Ekenseair, A., Gharagouzloo, C., Ferris, C. F., & Sun, N. X. (2020). Detection of presymptomatic Alzheimer’s disease through breath biomarkers. Alzheimer’s & dementia (Amsterdam, Netherlands), 12(1), e12088. https://doi.org/10.1002/dad2.12088