By Stephanie Baringer

Medical history was made on June 7^th, 2021, when the FDA approved aducanumab, an anti-amyloid-β (Aβ) monoclonal antibody for Alzheimer’s disease (AD), a devastating neurodegenerative disease characterized by cognitive decline and memory loss¹. Aducanumab is the first AD drug to be approved in nearly 18 years and is the first to target the biology of disease progression rather than symptoms. However, the approval of aducanumab was full of controversy. Aducanumab is no stranger to debate over its efficacy, which I covered in my previous LTS article. Briefly, phase 3 trials showed conflicting results on the cognitive benefits of aducanumab that Biogen, the drug’s manufacturer, explained were due to differences in cumulative dosing. Despite the questions that remained over aducanumab’s efficacy, Biogen filed for FDA approved. On November 6^th, 2020, the advisory committee met to review the data and make a recommendation to the FDA. When asked if the clinical trials showed enough effectiveness for clinical treatment of AD, the committee of eleven field experts voted 0 yes, 10 no, and 1 uncertain². It seemed clear to the medical community that aducanumab’s journey was done, that is, until the FDA disregarded the advice of the committee and approved the drug anyways. Immediately following the approval, three of the advisory committee members resigned. Experts have spoken out that the anticipated cost of $56,000 per year per patient is uncalled for given that aducanumab removes Aβ but provides little or no cognitive benefit to AD patients³. Additionally, the decision from the advisory committee was followed up by scientists in the field who also did not support aducanumab’s approval. Since the backlash from researchers in the field, the FDA added stipulations that aducanumab must undergo post-marketing trials to confirm cognition improvement within nine years and that aducanumab will only be approved for patients with mild dementia and mild cognitive impairment, both precursors to AD⁴.

Overall, the decision to approve aducanumab has left many in the research and patient care spaces divided. Proponents of aducanumab argue that there is a desperate need for treatments for the 6.2 million people living with AD in the US⁵ and that the potential cognitive improvement aducanumab offers is better than no chance at all. Critics retort that approving aducanumab prematurely will result in AD patients dropping out of ongoing clinical trials for other drugs and drug developers abandoning potential viable targets⁶. Aβ-targeting therapies have made up about 22% of all AD clinical trials up to 2019, and until aducanumab, all anti-Aβ antibodies in phase 3 trials failed due to lack of efficacy⁷. Past failures paint a grim picture for the continued pursuit of Aβ-targeting therapies, such as aducanumab, and thus, it may be time to consider other therapeutic interventions. Here I explore a few alternative avenues for AD treatment and drugs that stand out in these areas of research.

Tau Immunotherapies

Despite tau tangles and Aβ plaques both being key pathologies in AD, Aβ clearance has been the therapeutic focus for decades. However, tau-targeting treatments are gaining attention. Tau is a microtubule protein important for maintaining the structure of neurons and in AD, tau becomes hyperphosphorylated, causing it to aggregate into tangles that damage neurons. Many in the AD field argue that tau is a better target than Aβ because tau correlates better with cognitive impairment than Aβ plaques do⁸ and because Aβ therapies have not yet delivered on their promise to cure AD. Initial tau-targeting therapies were based on inhibition of kinases that phosphorylate tau (in hopes of preventing tau aggregation); however, these efforts were abandoned due to lack of efficacy⁹. Current promising tau-targeting drugs in clinical trials are immunotherapies that attempt to clear already aggregated tau. One such therapy in clinical trials is zagotenemab by Eli Lilly. Zagotenemab is an anti-tau monoclonal antibody that binds to, renders inactive, and clears soluble tau aggregates¹⁰. Preclinical studies show that MCI-1, the mouse antibody that zagotenemab was derived from, causes a profound reduction in tau and restores motor function decline in tau transgenic mice¹¹. Additionally, others have shown that reduction of tau leads to improved cognition in mice¹². Zagotenemab showed no adverse effects in two phase 1 trials between 2016 and 2019 in healthy volunteers, mild cognitive impairment patients, and AD patients^13,14. Zagotenemab is now in a phase 2 trial set to run from April 2018 to August 2021 to test efficacy for cognitive improvement. It is still unclear if tau-targeting will upstage Aβ therapeutic efforts, but zagotenemab makes a case for further exploration.

Iron Chelators

Iron homeostasis is vital to proper brain function and increased iron levels in the brain is an emerging hallmark of AD^15,16. In fact, excessive iron accumulation occurs prior to clinical symptoms and widespread distribution of Aβ and tau pathologies¹⁷ and can even predict cognitive decline better than these pathologies¹⁸. As such, clinical researchers have begun investigating the possibility of iron chelators as an AD treatment. Iron chelators bind to excess iron in the body to render the iron inactive and allow the iron to be excreted. Deferiprone is an iron chelator that was originally developed to prevent iron overload in patients with thalassemia and was approved for use by the FDA in 2011¹⁹. Importantly, deferiprone easily crosses the blood-brain barrier and thus may be a suitable method to remove excess iron in the brain of AD patients. In preclinical AD models, deferiprone lessened Aβ deposition and mitigated memory impairment²⁰. In 2018, a phase 2 trial began with AD patients taking deferiprone or placebo twice daily for one year. The trial plans to measure cognitive performance as its primary endpoint and is scheduled to finish in 2022. Even though researches have a while to wait for these results, other trials can give a bit of insight into the possible outcome. Several other neurodegenerative diseases also display increased iron accumulation in the brain, and deferiprone has been investigated for those diseases as well. Numerous pilot studies and case reports have shown safety with long term use of deferiprone and promising results have come from phase 2 trials for deferiprone use in Parkinson’s disease patients^21–23. In these clinical trials, patients on deferiprone showed a slower cognitive decline than those on placebo, as well as improved motor function. These trials support that deferiprone could be a potential therapeutic for AD and other neurodegenerative diseases that display iron overload in the brain.

Currently, there are about 168 therapeutics in clinical trials for AD and 31 of those are Aβ-related (Figure 1). Many in the field, including myself, said that 2021 would be an eventful year as aducanumab’s fate would be decided. There are additional Aβ-targeting antibodies with different mechanisms of actions than aducanumab in phase 3 trials that show promising results in improving cognition; donanemab by Eli Lilly and lecanemab by Biogen have both gained a large amount of attention. However, given the past failures of Aβ-targeting therapies, AD researchers and clinicians are looking forward to the future when other therapeutic targets will step into the spotlight. It is also possible that the best approach isn’t a single drug but a combination to attack both progression and symptoms from different angles²⁴. One example of this combination approach is the ALZT-OPT1 trial by AZTherapies that is utilizing a combination of an anti-Aβ agent (cromolyn) and an anti-inflammatory (ibuprofen) to target multiple disease pathways²⁵. The trial was completed in December of 2020; however, the results have not yet been announced. The road to effectively treating AD is difficult, but recent alliances of pharmaceutical, nonprofit, and government entities are partnering to share data from AD clinical trials, subsequently is speeding up progress²⁶. With this in mind, it is hard to deny researchers and clinicians are making tremendous advancements and a cure is on the horizon.

TL:DR

• The anti-amyloid-beta drug aducanumab was approved for Alzheimer’s disease despite questions over cognitive benefit
• Other promising therapeutic targets, such as tau immunotherapies and iron chelators, are being explored in clinical trials with the primary focus of cognitive improvement

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References

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14. Eli Lilly and Company. Multiple-Dose, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LY3303560 in Patients With Mild Cognitive Impairment Due to Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease. https://clinicaltrials.gov/ct2/show/NCT03019536 (2019).

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21. Martin-Bastida, A. et al. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Sci Rep 7, 1398 (2017).

22. Devos, D. et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 21, 195–210 (2014).

23. Abbruzzese, G. et al. A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica 96, 1708–1711 (2011).

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