Dr Neil Cashman looks at the potential impact of US FDA approval for Biogen’s aducanumab on the search for Alzheimer’s Disease (AD) treatments, and how Canada is playing a leading role in the development of the next generation of AD therapies.
We’re at the advent of a potential landmark year in the search for Alzheimer’s disease (AD) treatment after decades of dashed hopes. If Biogen’s aducanumab receives US Food and Drug Administration (FDA) approval, the newly reanimated drug candidate will be the first disease-modifying therapy for AD. Significantly, approval will also validate aducanumab’s target, amyloid-beta (Aß), the protein numerous scientific and clinical studies implicate in the development of AD. While data show aducanumab is only moderately effective in slowing progression of AD, it’s reanimation has already propelled the necessary innovation driving the next generation of therapies. These second-generation, improved therapies will incorporate the learnings and consensus of two decades of drug development struggles, including aducanumab’s. In this arena, Canada is leading the charge and in doing so, attracting the attention of a global community of investors.
A storied history that’s familiar
It’s been impossible to miss the drama and intrigue surrounding aducanumab’s tortuous journey to this point. It reveals its Achilles heel (and that of just about every other failed drug candidate targeting Aß): aducanumab cannot selectively target the toxic species of Aß, the amyloid beta oligomer (AßO). Instead, it targets Aß plaque, once believed to be the correct target. However, data now show that plaque is minimally neurotoxic and therefore, incapable of causing the massive neuronal cell death found in AD. When in March 2019 an interim futility analysis showed that aducanumab’s chances of slowing AD progression were less than 20%, Biogen cancelled both its phase 3 clinical trials. The Alzheimer’s community, particularly the patients and families whose multi-year sacrifices permitted the trials’ advancement, were devastated.
However, in a stunning reversal, Biogen resuscitated aducanumab in October 2019, explaining that at higher doses, it was in fact effective in slowing AD. At the Clinical Trials in Alzheimer’s Disease (CTAD) meeting in December, Biogen released data that strengthened aducanumab’s potential to become the first disease-modifying therapy for AD. While the move ignited hope for a near-term therapy, it also re-affirmed the persistent gap in therapy development efforts: the lack of specific selectivity for AßOs. Biogen’s higher dose suggests more drug reached AßOs. However, at this therapeutic level, the incidence of adverse ARIA-E (brain swelling) affected 35% of study participants despite attempts to minimize it with drug titration.
The rationale for AßO selectivity
Since 2013, more than 2000 scientific papers have shown that soluble, toxic Aβ oligomers propagating in a prion-like manner are the drivers of neurodegeneration and cognitive decline in patients with AD, confirming that AßOs are the causative agent, not Aβ plaque. However, traditional approaches to developing antibodies are unable to isolate and target the highly unstable toxic oligomer with adequate precision. Enter Canadian science, which is driving the innovation surrounding a next-generation of AD therapies that can offer highly precise targeting of AßOs, supporting safer, more effective treatment in the wake of aducanumab’s potential approval.
Importantly, the value of this highly selective targeting extends beyond AD. A broad array of neurodegenerative diseases are the result of misfolded proteins. When otherwise normal proteins misfold, and the body cannot correct the misfolding, small clumps of misfolded protein arise that are called oligomers. These are very toxic to neurons and can seed their own propagation. They spread throughout the brain, killing neurons in their path, which leads to the degeneration associated with diseases like Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), frontotemporal dementia and others. The protein implicated in each disease is different but the misfolding process leading to toxic oligomers is the same.
The future of AD therapy in a post-aducanumab world
Next-generation AD drug candidates that demonstrate superior selectivity for toxic AßOs should provide greater clinical benefit and safety. Such drugs in development demonstrate a high degree of binding to toxic oligomers without binding to non-toxic forms of Aß, offering the potential to avoid ARIA-E and allow for higher dosing to achieve greater efficacy. Preclinical data demonstrate that next-generation AßO-targeting drug candidates have greater therapeutic potency compared with other Aß-directed antibodies. Moreover, new blood and cerebrospinal fluid (CSF) biomarkers that objectively measure disease progression will expedite clinical trials by dramatically improving the speed and cost-effectiveness of development. And, Canadian researchers, institutions and small biotech are leading the way.
If approved by the FDA, aducanumab will indeed be the first treatment for AD, establishing—once and for all—that removing amyloid from the brain has a beneficial impact. However, it won’t be the best. Nonetheless, aducanumab’s reanimation has validated AßO-targeting innovation in the fight against AD. Aducanumab’s anticipated progress, the promising findings of next-generation AßO-targeting drug candidates, and the emergence of fluid-based biomarkers for rapid and cost-efficient clinical trials have compelled a resurgence of both financial investment and enthusiasm in finally making meaningful strides toward a treatment. Canada is at the forefront.
Dr Neil Cashman is chief scientific officer and co-founder of Toronto-based ProMIS Neurosciences, Inc. (TSX: PMN) (OTCQB: ARFXF), which is advancing an investigational antibody that binds to neurotoxic Aβ oligomers as well as several antibody candidates that target the toxic oligomers of other misfolded proteins implicated in a variety of neurodegenerative diseases.
