Most of us know someone who has been affected by Alzheimer’s disease. It’s a devastating, brain-wasting affliction and the most common form of dementia. The 2018 World Alzheimer’s Report reveals there are 50 million people in the world with dementia, a global community around the size of South Korea or Spain. About two thirds, have Alzheimer’s disease. These numbers are expected to more than triple by 2050.
There’s no effective therapy for Alzheimer’s but that’s not for lack of effort. Some of the most successful pharmaceutical companies in the world have exerted considerable effort to find a cure, but they’ve yet to cross the finish line. Thankfully, this could be about to change. Canadian researchers at a young, Toronto-based biotech firm, have received several patents for a new drug discovery platform that allows them to develop medicines that very precisely target the root cause of Alzheimer’s and other neurodegenerative diseases. The Canadian Business Quarterly spoke with CEO Dr. Elliot Goldstein about his team’s approach to what experts are calling a pivotal shift in drug development that’s renewing hope for an Alzheimer’s cure.
“This is a very exciting time in the Alzheimer’s community,” explained Dr. Goldstein. “We’ve learned some hard-won lessons over the past decade or so. Now, better understanding of what causes Alzheimer’s has spawned a new generation of drug development efforts that are focused on the right target.”
For decades, the Alzheimer’s drug development community believed amyloid beta—a naturally occurring substance that forms clumps in the brain—could become dangerous for some people as they aged; much like how a normal cell might become cancerous. The so-called “amyloid hypothesis” held that sometimes these clumps—commonly known as “plaque”—would strangle brain cells, leading to their death. The amyloid hypothesis alleged that by targeting plaque in the brain, researchers could halt Alzheimer’s disease. This belief guided Alzheimer’s drug development for nearly 25 years.
10 clinical trials that never produced an effective medicine called this theory into question. However, these “failures” deepened the research community’s knowledge of Alzheimer’s in some important ways. Namely, that there are many kinds of amyloid in the brain; most kinds are benign. However, one kind is particularly toxic, the toxic oligomer. In 2017, Dr. Eliezer Masliah, director of the U.S. National Institutes of Health’s National Institute on Aging, Division of Neuroscience, urged drug developers to redirect efforts at the toxic oligomer.
“The amyloid hypothesis is sound, but it needs a very important update,” explained Dr. Goldstein. “It’s not plaque that causes Alzheimer’s disease—as we had long thought—it’s the toxic oligomer. The resulting shift in drug development that we’re starting to see is predicated on what we’re calling Version 2 of the amyloid hypothesis. V.2 reflects our matured understanding of the deadly role the toxic oligomer plays in Alzheimer’s progression.”
There are now several hundred articles that implicate the toxic oligomer as the root cause of Alzheimer’s. Significantly, data also show it’s a root cause of other neurodegenerative diseases like Parkinson’s, a nervous system disorder that affects movement, and ALS (amyotrophic lateral sclerosis), in which nerve cells in the brain and spinal cord deteriorate. The good news: ProMIS is developing new medicines for all three. It’s the clear front-runner in the race to stop Alzheimer’s by selectively targeting the toxic oligomer. Initial data show ProMIS’ potential therapy, called PMN310, effectively neutralizes the toxic oligomer and prevents brain cell death.
How ProMIS is able to scale this summit ahead of many heavy hitters in drug development is where the real story begins. In order to develop a precise way to attack the toxic oligomer, ProMIS had to build a better mousetrap. That’s because today’s methods for working with highly unstable drug targets like the toxic oligomer don’t work. Enter Dr. Neil Cashman, professor of medicine at the University of British Columbia (UBC), neuroscientist at the Brain Research Center, academic director of the Vancouver Coastal Hospital ALS Center, and a past recipient of the prestigious Jonas Salk Prize for biomedical research. Dr. Cashman has dedicated his academic career to finding new ways to attack bad proteins like the toxic oligomer.
“Today’s drug discovery methods have developed some wonderful medicines but for the toxic oligomer, they deliver drug candidates that are as precise as a shotgun: You hit a lot of things, and maybe you hit your target,” explained Dr. Goldstein. “Our unique platform delivers drug candidates that act like a sniper. This allows exacting precision on the toxic oligomer, reducing the potential for side effects related to targeting the non-toxic forms of amyloid beta. This kind of precision hasn’t been available before. Not only could we potentially avoid the side effects of prior therapies in development, we could also offer patients higher doses, which would have a positive impact on effectiveness. A highly effective dose of medicine is truly the holy grail of any therapy, and this is what our platform could allow us to do for these terrible diseases.”
The ProMIS™ platform is a unique marriage between physics and medicine. On the medical side, the platform incorporates two decades of Dr. Cashman’s research, patents and publications (more than 300 and counting). But it doesn’t end there. Dr. Cashman works hand-in-hand with his physics counterpart, Dr. Steven Plotkin, a professor at the University of British Columbia in the Department of Physics and Astronomy. Dr. Plotkin has held the Canada Research Chair in Theoretical Molecular Biophysics, is a past recipient of the prestigious Sloan Fellowship, and is an associate member of the Genome Sciences and Technology and Bioinformatics programs at UBC. Together, Drs. Cashman and Plotkin, ProMIS’ Chief Scientific Officer and Chief Physics Officer, respectively, are hard at work developing a generation of medicines that can selectively target these highly unstable, “shape-shifters,” as Dr. Goldstein describes the toxic oligomer.
“ProMIS’ drug discovery platform reflects the groundbreaking scientific discoveries of some of the best minds in Canada,” said Dr. Sharon Cohen, medical director of Toronto Memory Program. “The result is a radically new way to target the root cause of Alzheimer’s disease, which we desperately need. Our deepest hope is that this can successfully deliver long-awaited disease modifying treatment. When it does, we can share in the pride of knowing that it began here in Canada.”
In late 2018, ProMIS announced new drug candidates for Parkinson’s disease. Next up, ALS. “Research shows the toxic oligomer is also a root cause of these diseases,” shared Dr. Goldstein. “Simply substitute ‘amyloid’ for the protein involved in the disease. For Parkinson’s, the toxic oligomer derives from the protein alpha synuclein. For ALS, the toxic protein derives from TDP43 (Tar DNA Binding Protein). We plan to develop highly validated drug candidates for each disease. And, because our platform is so powerful, we believe we can progress these candidates very quickly.”
To say this is welcome news to the desperate disease communities currently without effective therapies would be an understatement. While developing new drugs is risky business, Canada has a strong international reputation for delivering breakthrough, best-in-class medications for several diseases without effective therapies. We look forward to adding ProMIS to this long list of accomplished biotech firms that call Canada their home.