Thomas Edison once said, “I have not failed. I've just found 10,000 ways that won't work.” There is a divine nature to failure which helps the tenacious find a better way. This universal truth is never more important than it is in medicine and more specifically, the fight against deadly neurodegenerative disorders like Alzheimer’s Disease (AD). When research in the 90s pointed to Amyloid beta (Aß) peptides and amyloid plaque as the likely bad actors behind the onset and progression of AD, pharmaceutical giants spent billions searching for amyloid-related therapies.
Biogen and Eli Lilly recently released trial results regarding their respective monoclonal antibody candidates (mAb), Aducanumab and Solanezumab. In short, Aducanumab failed to work safely and Solanezumab failed to work effectively. Debate sparked over whether the amyloid hypothesis was worth pursuing. In the spirit of Edison, Biogen and Lilly had only pointed out what didn’t work about their approach. What they ended up proving in their “failure” may hold the key to the world’s first effective AD therapy. This key involves the fact that there are three forms of Aß: monomers, single molecular chains of approximately 40 amino acids; oligomers, some of which are misfolded neurotoxic aggregations of monomers, and amyloid plaque, a waste dump of worn out Aß.
Aducanumab targets oligomeric or prion-like forms of Aß as well as amyloid plaque. During Biogen’s Phase 1b trials, a portion of the participants were given high doses, approximately 10mg/kg. This elevation significantly slowed cognitive decline, but also caused neurovascular edema or swelling of the brain related to plaque break up.
Critics tried to close the book on the amyloid hypothesis, citing Aducanumab as an example, but Dr. Elliot Goldstein, President and CEO of ProMIS Neurosciences (TSX: PMN), a leading-edge bio-tech firm working on a proprietary amyloid-related therapy, explained how Biogen had contributed to, and not crippled, the amyloid argument, “Biogen’s results proved two very important things. One, amyloid plaque isn’t a target. Two, a successful drug candidate would have to be selective toward prion-like forms of Aß.”
Solanezumab came from the other direction. Eli Lilly intended to neutralize Aß monomers and the neurotoxic prion-like forms of Aß. Unfortunately, the Expedition III trial failed like its two predecessors, labelling Solanezumab as weakly effective.
Once again, critics sounded off, but Dr. Goldstein held a different view of the results, “The Lilly trials were another affirmation of an amended amyloid hypothesis. Remember that Solanezumab targeted monomers as well. There are approximately one thousand monomers for every prion-like form of Aß and in all that target distraction, it’s incredibly difficult for the antibody to encounter and bind to the prion-like forms, even at high doses. This explains the low efficacy. So, what does this mean? It means that monomers are definitely not a target. It also means that a successful antibody candidate must exquisitely select prion-like forms of Aß. Both series of trials by Lilly and Biogen revealed a pattern we were able to recognize. This pattern confirms neurotoxic prion-like forms of Aß are the sole bad actors in the onset and progression of AD – not plaque and not monomers.”
That would mean a successful monoclonal antibody (mAb) candidate would have to possess the following attributes:
- Must NOT bind to amyloid plaque
- Must NOT bind to Aß monomer
- MUST exquisitely target neurotoxic prion-like forms of Aß
- MUST stop prion-like forms of Aß from propagating
- MUST block neurotoxic effects of targeted prion-like forms of Aß
Big pharma faces an almost insurmountable challenge in meeting these requirements. First, they would have to identify the unique shape of these killer prion-like forms of Aß to craft an antibody specifically targeting them. Unfortunately, oligomeric forms of Aß are flexible and soluble, making it impossible to study their structure using traditional methods like crystallography. So how are we going to find this thing that we so desperately need to stop? We have to thank oligomeric Aß’s nastiest attribute.
When Aß monomers aggregate into oligomers, they lose energy, misfold and become neurotoxic. It is this misfolding that reveals something to the immune system that wouldn’t be visible if it hadn’t misfolded. Think about it like a loop coming loose on your sweater. All that had to be done was determine where along the line that loop would pop up.
ProMIS Neurosciences turned to the exciting new discipline of precision medicine. Chief Scientific Officer & Co-founder, Dr. Neil Cashman, a leading physician and scientist focused on neurodegenerative disorders, and Chief Physics Officer, Steven Plotkin, Ph. D, a theoretical and computational biophysicist focused on protein folding and misfolding in neurodegenerative disorders, made the perfect pair in this hybrid of hard and soft science. They employed the company’s proprietary thermodynamic, computational discovery platform, ProMIS™, as well as Collective Coordinates to identify epitopes or “loops” representing five distinct target sites on prion-like forms of Aß.
Then in less than a year, ProMIS went from computer-generated models of epitopes to creating five mAb candidates proven to exquisitely target neurotoxic prion-like forms of Aß. ProMIS’s candidates turned out to be masters of this high stakes game of Where’s Waldo. In achieving this milestone, ProMIS had produced three characteristics of the five-point profile. But more was to come. At the end of November, the company published even more good news, announcing that all five antibody candidates successfully blocked propagation of prion-like forms of Aß in vitro. Okay, now that’s four of the five characteristics.
Result from tests being conducted on ProMIS’s candidates to gauge their ability to block the neurotoxic effects of prion-like forms of Aß were released Tuesday morning and announced the company’s lead mAbs were successful in blocking said neurotoxicity. Not only has ProMIS Neurosciences satisfied all five requirements of the optimum mAb candidate, but it reached this incredible milestone in record time. Dr. Goldstein commented, “We couldn’t be happier with these results. In all my years in this industry, I have never been involved in an endeavour like this that has gone so quickly and according to plan.” We both found some wood to knock on.
Dr. Goldstein continued, “Once we are able to select the final monoclonals for drug development, we will humanize, do the process development, scale up and manufacture. It’s all well-codified. A lot of companies can manufacture high quality monoclonal antibodies, so that risk is taken out. It’s just a matter of execution at this point based on the upcoming results.”
ProMIS’ unique approach will also allow for companion testing to ensure that the antibodies being administered are optimum in binding and neutralizing the specific prion-like forms found in the patient’s cerebrospinal Fluid (CSF). Dr. Goldstein still dreams of the holy grail in AD therapy – prevention, “Since clinical signs of AD can take up to 17 years to materialize, current therapies can only manage the progression. If we develop something like a blood test for screening, which detects these prion-like forms of Aß or potential of their presence long before clinical signs appear, we can begin early antibody treatment and effectively prevent the onset of AD.”
AD is set to cost the U.S., directly and indirectly, more than one trillion dollars by 2050. That’s right, more than $1.0 trillion. Enough to bankrupt the medical system. If ProMIS can successfully combat the public’s perception that the amyloid hypothesis is dead, continue raising money through the markets and move downstream with trials, it stands the chance of slamming the brakes on an AD epidemic that claims another American every 66 seconds. Oh yeah, I forgot to mention the work ProMIS Neurosciences is carrying out can be utilized against other deadly neurodegenerative disorders like ALS and Parkinson’s. All of this success, because someone “failed”, thank you Mr. Edison.
--Gaalen Engen
https://twitter.com/gaalenengen
DISCLAIMER: ProMIS Neurosciences is a client of the author.