Aducanumab: Third Time’s the Charm?

Posted on January 22, 2021March 4, 2021 by Michael Mega

This week we review the current status of a previously tested investigational treatment for Alzheimer’s disease (AD) reflecting the clinical trial approval process. In March of 2019 two phase III clinical trials of Biogen’s Aducanumab, a monoclonal amyloid-clearing antibody, terminated due to lack of efficacy after an interim futility analysis. As disappointing as these initial results were, the Aducanumab story most likely won’t stop here.

Biogen, has appealed the FDA to receive approval for the drug after sub-group analyses showed possible efficacy. These analyses were required because, of two parallel phase III trials (301 and 302), only one showed efficacy while the other failed to meet its endpoints. The FDA review board, and the academic community at large, are divided as to whether approving this drug would be a progression in AD treatment or a roadblock to future progression. Approving an ineffective drug “will slow down finding something that does work” says Michael Greicius, a professor of Neurology at Stanford. Let’s look at both sides of the issue.

Biogen, having had one phase III trial that showed efficacy and one that did not, explained that these differential results may be due to variance in the study sample as the 301 trial had changed dosing directions mid-study and also had a large sample of “rapid progressors”. This left the review board to ponder whether the single successful 301 trial, if viewed on its own, provided sufficient evidence that the drug worked as intended. Only one member voted that the 302 trial supported approval of the therapy. Five members agreed that the treatment reduced amyloid-beta plaques in the brain, however, they were not convinced that the reduction of amyloid correlated to clinical improvements in cognition.

One review board member, Joel Perlmutter, stated he “recognized the urgent, unmet need for treatment […] However, approving a treatment that ultimately does not work can be harmful” due to the fact that approval of this drug would “substantially slow recruitment into ongoing and future studies” and could reduce “enthusiasm and support for testing other potentially more effective treatments”. With this in mind, it seems reasonable to maintain skepticism when it comes to inconsistent results like those in the Aducanumab trials.

Furthermore, Perlmutter explains an even larger concern, being that if it were approved “we may be required to test any new treatment not against placebo but against this drug”. In other words, if this drug is not effective in treating AD but is approved, all future treatments simply have to show more improvement than Aducanumab, meaning that other less effective drugs could continue to be approved and administered to patients simply because they are less ineffective. However, if Aducanumab really does work, we could be setting ourselves back years while we wait for another effective treatment to successfully complete phase III in the clinical trial process. As you can see, the research and clinical review processes are quite complicated and must proceed with caution. Making an incorrect decision at one stage has the potential to fully derail a field of study such as AD treatment. We hope the FDA requires a new Phase III trial for Biogen’s Aducanumab to prospectively test its effectiveness.

Source:

Talan, J. FDA Panel Votes ‘No’ to Approving Aducanumab for Alzheimer’s, Citing Inconsistent Data [Internet]. NeurologyToday. 2020. Available from: https://journals.lww.com/neurotodayonline/Fulltext/2020/12030/FDA_Panel_VotesNoto_Approving_Aducanumab_for.1.aspx#:~:text=An%20advisory%20panel %20of%20the,and%20more%20research%20is%20needed.

Iron and Amyloid: Correlations to Entorhinal Cortex Degeneration

Posted on January 15, 2021March 4, 2021 by Michael Mega

Research into the prevention and treatment of Alzheimer’s disease (AD) frequently starts small, with the discovery of risk factors that correlate with elevated deposition of AD biomarkers: amyloid (Aꞵ) plaques and neurofibrillary tangles (NFTs). Recently, researchers observed one such phenomenon involving the build-up of iron in the brain and the localization of Aꞵ.

Firstly, it has been known that iron, a vital mineral in the body, has the capability to build up in the brain as we age. Normally, iron is bound in heme, a component of red blood cells, in order to aid in the binding of oxygen for distribution throughout the body. When there is too much iron in the body it forms iron deposits that can induce oxidative stress and cell damage. Furthermore, iron is also found within the molecules of Aꞵ and NFTs, and previous studies suggest iron deposits may encourage AD pathology.

In the current study, researchers used Amyloid-PET and T2-weighted MRI imaging of 70 cognitively normal participants to measure cortical amyloid burden and non-heme iron deposited in the striatum of the brain. They did not find a direct correlation between amyloid burden and striatal iron concentration, and hypothesized this may be due to striatal iron deposition being limited until the later stages of AD. They did, however, notice that in cases of high amyloid and high striatal iron the entorhinal cortex degenerated in relation to age, while those with amyloid but low iron levels in the brain had larger entorhinal cortices suggesting reduced degeneration.

The researchers hypothesized that reduced degeneration of the entorhinal cortex in the presence of amyloid but low iron might be due to amyloid plaques’ tendency to surround iron deposits, effectively protecting nearby brain regions from the negative impacts of iron deposits. Unfortunately, this protective effect doesn’t last with continued iron deposition having a negative impact on entorhinal cortex size.

There are current and upcoming trials aimed at reducing/removing iron deposits prior to onset of neurodegeneration that show some promise as a preventative treatment. It is especially promising considering that the correlation between iron levels in the brain and entorhinal cortex degeneration were detectable even amongst non-impaired participants, suggesting that this method of treatment may work even in mildly symptomatic or even presymptomatic individuals, preventing brain volume loss before it has even begun!

Source:

Bilgel, M. & Bischof, G. N. Early role of iron in modulating amyloid’s association with neurodegeneration [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/95/18/809?sso=1&sso_redirect_count=1&oauth-code=BZ9uF6n9xCjHLHF8kd-f8zPfZ6Vgxd2gqxNz-SF3y2w

Anti-Depressant Drugs and Alzheimer’s: A Surprising Relationship

Posted on January 8, 2021March 4, 2021 by Michael Mega

Most of our blogs emphasize treatments that directly affect the mechanisms that induce Alzheimer’s disease (AD). However, recent research into the use of anti-depressant drugs and their relationship to AD has provided some interesting results. Namely, administration of escitalopram seems to reduce deposition of amyloid-ꞵ_42, which could, in theory, slow the onset or progression of AD.

Escitalopram belongs to a drug class called Selective Serotonin Reuptake Inhibitors (SSRIs) and is one of many similar molecules that are frequently used to treat depression by up-regulating serotonin signaling. Previous research on SSRIs in animal models found that increased serotonin signaling was associated with reduced amyloid-ꞵ₄₂ levels, leading investigators to study its possible benefits for use in older adults with AD.

The current study, a clinical trial, administered escitalopram under 4 conditions: 20 mg/day for 2 weeks, 20 mg/day for 8 weeks, 30 mg/day for 8 weeks, and placebo to cognitively normal older adults to see if it affected amyloid-ꞵ₄₂ burden during that time frame. The treatment groups, on average, experienced a 6.0% (± 1.2%) reduction in CSF levels of amyloid-ꞵ₄₂ while the placebo group experienced a 3.5% (± 2.2%) increase in amyloid-ꞵ₄₂ levels in the CSF. These results suggest that increased serotonin signaling decreases amyloid burden by the activation of a signaling pathway that ends in the production of α-secretase, which suppresses Aꞵ₄₂ generation. This is very important because the degree to which Aꞵ₄₂ produces plaques and impairs neuronal function is dependent upon the concentration of Aꞵ₄₂ present. In animal models, reductions of 10-25% in overall interstitial fluid Aꞵ₄₂ concentrations significantly reduced plaque deposition.

While those in the treatment group of the current study did not see reductions in the 10-25% range, they did see reductions in comparison to the placebo group who actually had an increase in Aꞵ₄₂, meaning that it is possible that SSRI administration may become a preventative strategy to reduce the initiation or progression of AD. However, we first need to determine if reductions in CSF Aꞵ₄₂ correlate to reductions in plaque formation rate in humans, as was shown in rats. On the bright side, many people already use SSRIs regularly so in terms of possible treatment options, this one is very safe and accessible, but only time will tell.

Sources:

Sheline, Y. I., Snider, B. J., Beer, J. C., et al. Effect of escitalopram dose and treatment duration on CSF Aꞵ levels in healthy older adults [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/95/19/e2658?sso=1&sso_redirect_count=1&oauth-code=AtOok5tDWVPGT3Tmk7Na0iVfQN-vP7YljIOYAQ7VLe8

Cirrito, J. R., Disabato, B. M., Restivo, J. L., et al. Serotonin signaling is associated with lower amyloid-ꞵ levels and plaques in transgenic mice and humans [Internet]. Proceedings of the National Academy of Science of the United States of America. 2011. Available from: https://www.pnas.org/content/108/36/14968