Last week the FDA approval of the Alzheimer’s Disease (AD) focused drug aducanumab (or Aduhelm, the brand name chosen by Biogen) was all over the news. It is clear that the decision impacts many greatly, from AD patients, to relatives, to pharmaceutical companies and physicians alike. But what makes this approval so special? What are the claims and the doubts associated with aducanumab? And how does this influence the AD diagnosis and treatment trajectory from a neurology and neuroradiology standpoint?
What makes (the approval of) aducanumab so special?
Aducanumab is the first approved drug that has proven to clean-up amyloid-β plaques in the brain as seen on amyloid PET scans. These brain scans of patients receiving aducanumab showed a significant decrease in amyloid over the course of the treatment. Amyloid-β proteins are believed to be a root-cause of AD, although this hypothesis is not undisputed. Research has shown that elevated levels of the protein correlate with early dementia stages and cognitive decline or an increased risk thereof1–3. Hence, pursuing a drug that tackles amyloid-β (while research aimed at confirming the amyloid hypothesis further) seems a promising path to embark on. Which is exactly why aducanumab is not the only drug of this type in the pipeline. Many other pharmaceutical companies are working on similar therapies and it is not unlikely these will also seek FDA approval in the foreseeable future 4,5.
What are the claims made about aducanumab?
Two clinical trials underpin most of the evidence used in the FDA’s decision to approve aducanumab: the EMERGE trial and the ENGAGE trial. Both trials were halted early by Biogen because the effect of aducanumab on the endpoint CDR-SB (a neuro-psychiatric rating) was insignificant. However, after re-analyzing the results, a significant effect on the amyloid-β levels in the brain of the participants that received the highest drug dose was found6,7.
What causes doubts around aducanumab?
The end-point results were meager, causing an advisory panel to the FDA to vote against approval on November 6, 2020. Despite this advise the FDA decided to approve the drug through the accelerated approval process. This is a special procedure that can be applied when a drug targets a serious or life-threatening disease for which there is currently no sufficient therapy available. Or put differently: it is to be expected that the benefits of providing this drug to patients will outweigh the current downsides of not providing it. This means that the FDA requires an extensive phase 4 trial to confirm the hypotheses that cleaning-up amyloid-β results in better cognitive outcomes.8.
Another issue raising doubts are the side effects of aducanumab. Of all side effects ARIA (amyloid related imaging abnormalities, referring to cerebral edema or microhemorrhages) was by far the most common one, occurring in 41% of the subjects that received a high dose. However, of this 41% only 20% was symptomatic and Biogen claims that “the majority of patients who experienced ARIA were able to continue investigational treatment”. Nonetheless, symptoms of ARIA (headache, dizziness, visual disturbances, nausea and vomiting) can influence someone’s live severely6,9.
So what effect can neurologists expect from the introduction of aducanumab?
Now that aducanumab is clinically available in the United States, neurologists there can subscribe it and patients will most likely start asking for it. How will this impact the way neurologists diagnose and treat patients suffering from AD?
First of all many patients will likely ask for a more definitive (differential) diagnosis because they want to know whether they would be a candidate for the new treatment. Secondly patients will likely want to get the diagnosis earlier as it is hypothesized that the effect of aducanumab will likely be higher in a mild cognitive impairment (MCI) stage of the disease avoiding major damage from exposure to the amyloid-β plaque. Neurologists will have to be prepared for an increase in patients suspected of early stages of AD.
Third, patients are not blind the controversy surrounding the new treatment so neurologist will need to be prepared to clearly articulate the current status of this new treatment and the challenges involved with the approval.
Finally, the aducanumab treatment process is far from a one-time event. Patients will get the drug administered intravenously every four weeks and especially in the early phase of the therapy patients need to be monitored closely, resulting in more AD-related work for neurologists10,11.
And what will be the impact of aducanumab’s clinical introduction for neuroradiologists?
The AD diagnosis and treatment selection process will include brain scans, with the amyloid PET scan as the most important modality for determining the presence and amount of amyloid-β plaques. This scan is costly and invasive therefore is can be expected that lower-cost, less invasive MRI scans will start playing a bigger role in early detection of abnormal brain degeneration. Additionally, therapy monitoring will also require regular examination leveraging medical imaging. Current guidelines advise an MRI before the 7th and the 12th infusion11. To get the most information out of the MRI scans and to follow the disease development in detail, volumetry based on MRI is expected to gain importance. In conclusion, neuroradiologists will play an increasingly important role in diagnosis and treatment follow up of AD potentially in a similar fashion in how MS treatment options increased the workload when they became available9.
What can AI do to support assessment of patients receiving aducanumab?
To manage the increased workload, it is important to consider AI support options early on. What solutions could be developed or are already available that will help physicians to handle the upcoming rise in Alzheimer’s related examinations?
Artificial intelligence has made its way to the healthcare sector already and will increasingly be implemented in medical facilities in the coming years. Also in the context of neurology and radiology various applications have seen the light of day and are increasingly adopted in clinical practice. To improve the care pathway for patients with an AD suspicion and ease the burden on involved clinicians AI could be leveraged in many ways, such as automated analysis of amyloid PET calculating relevant metrics for disease monitoring, but also algorithms that quantify results from MRI such as atrophy tracking or microbleed detection12.
Concluding
The approval of aducanumab is a big step for the medical field. It is the first amyloid-β targeted drug to make it to the market, and although the evidence used by the FDA is not extensive, biomarker results look promising and further trials will be implemented to gather more proof. It is safe to say that the availability of aducanumab, and most likely similar drugs to come, will influence diagnosis trajectories and treatment monitoring. AD-related workload will increase for both neurologists and neuroradiologists making it essential to keep innovating in this space to take away unnecessary burdens from the clinicians. At Quantib we believe AI will play a major role in quantifying disease onset as well as treatment effectiveness.
Bibliography
- Näslund, J. Correlation Between Elevated Levels of Amyloid β-Peptide in the Brain and Cognitive Decline. JAMA 283, (2000).
- Roe, C. M. et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 80, (2013).
- Rowe, C. C. et al. Predicting Alzheimer disease with β‐amyloid imaging: Results from the Australian imaging, biomarkers, and lifestyle study of ageing. Annals of Neurology 74, (2013).
- Haeberlein, S. B. What have we learned from aducanumab? http://www.alz.org/documents_custom/2017-facts-and-figures.pdf. (2018).
- Cummings, J. et al. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimer’s Research & Therapy 13, (2021).
- Haeberlein, S. B. et al. EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease. https://clinicaltrials.gov/ct2/show/NCT02477800.
- Haeberlein, S. B. et al. Emerge and Engage topline results: Phase 3 studies of aducanumab in early Alzheimer’s disease. Alzheimer’s & Dementia 16, (2020).
- Cavazzoni, P. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease (2021).
- Scheltens, P. Extra Lunch & Learn over toelating alzheimermedicijn. (2021).
- Scheltens, P. Op1. (2021).
- Medscape. Aducanumab. https://reference.medscape.com/drug/aduhelm-aducanumab-4000138.
- Mormino, E. C. & Papp, K. v. Amyloid Accumulation and Cognitive Decline in Clinically Normal Older Individuals: Implications for Aging and Early Alzheimer’s Disease. Journal of Alzheimer’s Disease 64, (2018).