Sir Issac Newton’s
Principia defined our physical world with an insight which had eluded scholars for all of recorded history. However, his ideas regarding motion and gravity, didn’t spring independently from the void. They formed in the intellectual current of previous great thinkers like Kepler and Copernicus. Newton understood his position within the bigger picture, “If I have seen further than others, it is by standing upon the shoulders of giants.” Almost two hundred years later, Einstein did just that. Now, quantum mechanics continues to build on Einstein’s base. The cycle of achievement remains endless and we are better for it.
The world of medicine is no different. Alzheimer’s Disease (AD) has darkened the lives of 5.4 million people in America alone, putting its victims and their loved ones through a torturous irreversible nightmare. It is incurable and up until recently had no possibility of treatment, but back in 2012, researchers at Biogen put together a study using the latest origin theories at the time for Alzheimer’s. These theories involved senile or neuritic plaques, which are extracellular deposits of amyloid beta (Aß) in the grey matter of the brain. The thought at the time was that these plaques, along with neurofibrillary tangles, were bad actors in the formation of Alzheimer’s and its progression.
Biogen had developed an antibody, called aducanumab, that would eradicate these bad acting plaques and for the first time in human history provide a therapeutic treatment for the deadly neurological disorder. So, based on this study it had designed in 2012, Biogen scientists gave aducanumab to 165 patients in a placebo controlled, double blind clinical trial. This trial would change the way we look Alzheimer’s forever. Patients were given high doses of the drug and it eliminated much of the plaque, halting the progression of mild cognitive impairment, an early stage of AD. However, it also caused neurovascular edema, or swelling of the brain, due to the high dosage. So, aducanumab seemed to work, but it was like taking out a chicken coop with an atom bomb. Like Newton did for physics, Biogen built a solid base for continued research into a safe and effective treatment of Alzheimer’s.
Biogen’s PRIME study, completed in 2015, proved that extracellular amyloid beta is indeed involved in the progression of AD, but deeper in the study, it is clearly stated that researchers felt that the binding of aducanumab to oligomeric forms of Aß, or prions, rather than plaque may have had a functionally relevant impact on cognition in the study. So Biogen had a good thing, with billions of dollars of big pharma research backing it up and the accomplishment of developing aducanumab was truly awesome in both scope and vision, but it only opened the door, it didn’t provide the solution.
Unfortunately, there was a publication in a widely respected scientific journal,
Nature, that placed this story in front of the masses with a misleading headline that only talked about the elimination of Aß plaque with no mention of prions. The general public was soon under the distinct impression that plaque alone was behind AD’s terrible advance. This story keeps reappearing, and because of the initial faux pas, no one is talking about the prions.
ProMIS Neursciences (TSX: PMN, Forum) has just released a white paper that finally balances the plaque vs. prion argument. The paper, penned by Dr. Johanne Kaplan, ProMIS Chief Development Officer, is entitled, “Critical Insight - Toxic soluble Amyloid beta oligomers ("prions"), not plaque, drive pathogenesis in Alzheimer's disease.” The paper delves into the lessons learned during the PRIME study as well as describing the optimal target profile for Aß antibodies.
In the piece, Dr. Kaplan states, “…a mounting body of experimental and clinical evidence has shown that soluble toxic Aß oligomers, and not plaque, are actually the primary drivers of neurodegeneration and cognitive decline in AD patients. Histological and imaging studies clearly show that synaptic loss and memory impairment correlate poorly with plaque burden in both human and mouse AD.”
The paper goes on to state, “An encouraging signal for the slowing of cognitive decline was also observed in this trial and was widely attributed to plaque clearance in the ensuing press coverage, perhaps driven by the title of the publication:
The antibody aducanumab reduces Aß plaques in Alzheimer’s disease. However, the thorough analysis presented in the article goes well beyond the title and presents a picture consistent with the latest scientific thinking on the role of toxic oligomers.”
So why should we avoid eliminating plaque? Well, beyond the fact that it’s probably a minor player in AD, treatments that focused on eliminating plaque, all created neurovascular edema. Obviously, it seems the focus should be on prions. So what would be an optimal treatment candidate? Dr. Elliot Goldstein, CEO of ProMIS, explains, “The weakness of aducanumab is it’s an IgG 1 antibody, which activates the immunological system and helps create the neurovascular edema. It also targets and disrupts plaque which contributes to the edema and it isn’t strain specific. This is not to say that Biogen is completely wrong. They’ve done great work. There are even some studies which show binding to some plaques is beneficial, but the bottom line it’s really the prion and not the plaque.”
Dr. Goldstein went on to explain what the perfect antibody candidate would be, “Well, first, it would have to bind only to toxic oligomers of Aß, not plaque and not monomers. Next it would have to be disease specific and an IgG 4 antibody that doesn’t activate the immune system. This is what we’re doing at ProMIS.”
Firmly on the leading-edge of precision medicine, ProMIS has employed complementary computational algorithms, ProMISTM and Collective Coordinates, to predict structurally integral misfolding and identify disease-specific epitopes in Aß and other misfolded prion-like proteins. In short, they’ve won one of the most challenging games of Where’s Waldo known to humanity. Using this method, the company has identified six distinct disease-specific epitopes for Aß.
Not only have they found Waldo, ProMIS Neurosciences has generated monoclonal antibodies against the first three epitopes. The resulting drug candidates will bind easily to their target prions with little or no binding to monomers or to plaque in AD brain tissue. All the potency and none of the side effects experienced in the PRIME study. The company continues to generate and evaluate antibodies for the three remaining epitopes.
So what does this mean to you as both a member of the general public and an investor? It should be remembered that Biogen broke some very important ground and without their work, the science of Alzheimer’s treatment may not have progressed to where it is now. The point is, the PRIME study proved there’s more work to be done and it’s companies like ProMIS Neurosciences, who position themselves squarely on the shoulders of giants like Biogen, who help us reach the stars we only glimpsed at.
If ProMIS is able to continue bringing this revolutionary Alzheimer’s treatment to commercialization, it may very well become the next giant to help vault our species into the new century. Wise investors would do themselves a great service by putting this company on their radar, but don’t take my word for it. As always, do your due diligence before making any investment decision.
--Gaalen Engen
https://twitter.com/gaalenengen
The complete ProMIS white paper can viewed by clicking the link below:
https://promisneurosciences.com/commentary/
FULL DISCLOSURE: ProMIS Neurosciences is a Stockhouse Publishing client.