The Life Sciences Report: Dr. Goldstein, your company, ProMIS Neurosciences Inc. (PMN:TSX), recently presented information on its preclinical development program addressing Alzheimer's disease. Please describe that.
Elliot Goldstein: Our most recent news is a poster presentation, which was given April 28 at the American Academy of Neurology annual meeting in Boston. It's an overview of the current status of our program, and focuses first on our unique proprietary technology, thermodynamic algorithms that run on supercomputers. Using this technology, we've been able to identify five distinct sites, called epitopes, on misfolded toxic forms of Amyloid beta, a known root cause of Alzheimer's disease. An epitope is a target on a molecule, usually a protein, that antibodies can attach to and then neutralize.
The poster also focuses on the cause—the misfolded forms of Amyloid beta. Also called toxic oligomers or prion-like forms, these toxic forms do two things. They're like gang members in the neighborhood. They're directly toxic to neurons. When they're in the vicinity of neurons, they kill them.
Not only are the oligomers toxic, they propagate, like viruses or prions, throughout the brain. This usually begins in the region of the brain called the hippocampus, where short-term memory is stored. That's why the first signs of Alzheimer's disease involve short-term memory loss. They then spread to the frontal lobes, where cognition, judgment and emotion reside.
"Our objective is to develop best-in-class therapy for Alzheimer's."
We can follow the propagation of these misfolded toxic oligomers or prions. On average it's about 17 years before any symptoms emerge, as these toxic forms of Amyloid beta slowly spread (propagate), destroying billions of neurons. And they propagate in a very simple manner. When they misfold, they lose energy, and become toxic, killing neurons. Any monomer, which is a single strand of normal Amyloid beta in the neighborhood, takes on the same misfolded, toxic shape. The toxic form acts like a template. So now you have two bad actors in your neighborhood; two toxic misfolded oligomers. And those two will then create four, and so on. . .
The poster points out that we've used our two proprietary thermodynamic algorithms to identify five unique targets (epitopes) on the misfolded toxic forms of Amyloid beta. The problem is that these forms are relatively unstable, so traditional pharmaceutical techniques cannot be used to identify sites to attack. To our knowledge, the ProMIS thermodynamic algorithms are the only way to identify these specific targets.
Using our algorithms, not only do we identify the amino acid sequence in the region of misfolding, we also identify the shape, or conformation, of the misfolding. That's really important—not just the sequence of amino acids exposed, but also the shape of the exposed sequence. We take that misfolded sequence, or epitope, synthesize it, and then use it to immunize mice, thereby raising monoclonal antibodies (mAbs) that are specifically and uniquely directed only against the amino acid sequence and shape of that sequence in the misfolded region. The final result is we now have antibodies that are specific and unique to the toxic misfolded forms of Amyloid beta.
We've also tested to make sure our antibodies don't bind to Amyloid beta monomer or plaque. Indeed, results of prior large pharma trials indicate that products targeting monomer suffer from lack of efficacy, and those targeting plaque are associated with significant adverse effects.
You could say, "Great, your antibodies bind specifically to the right targets, but does this have a beneficial effect?" The answer is yes. The poster also shows that, both in vitro and in vivo, our antibodies block the two hallmarks of the toxic forms of Amyloid beta in Alzheimer's disease. They directly block the neurotoxicity. If you put toxic oligomers into cultures of neurons, the latter are killed within 24 hours. If you put each of our antibodies in the culture medium with the toxic oligomers, the neurons survive perfectly well. In other words, our antibodies clearly directly block the toxicity. Our antibodies also block the propagation (spreading) in vitro, the second critical feature of toxic forms of Amyloid beta.
With our lead product, PMN310, we did an animal experiment where toxic oligomers of Amyloid beta were injected directly into the brains of mice, and within three to five days, short-term memory retention was lost. Conversely, injection of PMN310 into the brains of mice at the same time as the toxic oligomers preserved cognitive function in this animal model evaluating short-term memory retention (a dual object recognition test).
TLSR: Can you address the personal medicine aspect of your therapy?
EG: Yes. We know that, generally, almost all chronic diseases, whether they're autoimmune, neurodegenerative, cancers or others, are not single unique entities but are heterogeneous and consist of several different subgroups. And we've also seen that precision medicine, particularly in certain cancers, has driven successful outcomes from 20% to 70%.
Precision medicine involves identifying what's unique and special about a group of patients, and determining what product is unique and special for that group. The right drug, the right patient.
"Both in vitro and in vivo, our antibodies block the two hallmarks of the toxic forms of Amyloid beta in Alzheimer's disease."
For Alzheimer's disease, ProMIS has identified five different targets on strains of toxic, misfolded Amyloid beta. We are in the initial process of studying which patient has which target, by evaluating samples of cerebrospinal fluid from Alzheimer’s patients. Using our antibodies, we are looking to detect in the cerebrospinal fluid which target an individual patient might have. We want to learn the prevalence of these five targets in Alzheimer's.
We don't have the data yet, but let's say one of our targets is present in 50% of the patients, and another is present in only 10% of the samples. That might tell you that the first group to go after in a clinical trial is the one that's the most prevalent. If it's the largest patient segment, then you solve a big part of the problem.
Another aspect we were looking at in personalized medicine is whether one or more of these targets is associated with very rapidly progressive disease. The very serious forms might be a good place to start, even if they're only a small percentage of the patients.
The bottom line is that we could use companion diagnostic antibodies to determine which target a given patient has, and then we could administer to that patient the antibody that specifically hits that target.
That's how personalized medicine works. It allows us to give the right drug to the right patient. And it allows us to ensure only patients who have the target we're looking for, and against which we have the antibody, are enrolled in a clinical trial.
TLSR: When do you anticipate going into clinical studies? Do you have a timeline for that?
EG: Our lead program PMN310 is on track to file an investigational new drug application (IND) by the end of 2018, which would give us permission to go into the clinic in the U.S. and elsewhere.
Between now and then, what's important is that, for investors and the company, the risks have been reduced to practice dozens of times with therapeutic antibodies.
The work to be done leading up to clinical trials is along two tracks. One, we need to finalize the process development and scale up so that we can manufacture the antibody in quantities sufficient for clinical trials and according to Good Manufacturing Practices (GMP). We're on track to do that.
As we're manufacturing product to scale and GMP, we also need to conduct preclinical safety- toxicology in animals. Generally, antibodies are very safe in animals. We anticipate the animal toxicology will be uneventful. One of the reasons goes back to targeting. If your antibody broadly targets Amyloid beta, it could be targeting normal forms and plaques. In prior clinical trials, antibodies targeting plaque have been associated with significant adverse effects, and those targeting monomer forms have been ineffective. By design, our products target only the toxic forms of Amyloid beta; they do not recognize the normal monomer form and they don't target plaque.
"Our lead program PMN310 is on track to file an investigational new drug application (IND) by the end of 2018."
Biogen Inc.'s (BIIB:NASDAQ) aducanumab engages plaque and toxic misfolded forms of Amyloid beta. To date, it's the only drug to have shown arrest of cognitive decline in Alzheimer's, especially early-stage patients, over a two-year period. The problem is that 35 to 55% of the patients, depending on the trial, presented edema—swelling of the brain—most frequently at the highest dose, which also gave the best efficacy. We believe the product will come to market because it works, and for a subset of the Alzheimer's population, which doesn't have this dose limiting adverse event, it could be effective.
Our plan is to be in the clinic in late 2018 or at the outset of 2019. We plan to have data available—proof of concept from Phase 2—at about the time aducanumab comes to market in 2021. Our objective is to develop best-in-class therapy for Alzheimer's.
We've learned from the results of earlier pharma trials what to target and what not to target, which should give the ProMIS therapies a best-in-class profile. Our antibodies are not expected to have the adverse events associated with engaging plaque because our antibodies don't target plaque. Likewise, we anticipate no loss of efficacy related to targeting Amyloid beta monomer, because our antibodies do not engage monomer, but target specifically the root cause—the toxic, misfolded forms of Amyloid beta.
Eli Lilly and Co.'s (LLY:NYSE) solanezumab failed three times in three Phase 3 clinical trials. We anticipated it each time. The drug showed some effect, but not enough because it targets mainly the very abundant monomer. So we've learned from Lilly's solanezumab.
And, we've also learned from trials with Johnson & Johnson (JNJ:NYSE) and Pfizer Inc.'s (PFE:NYSE) bapineuzumab, among others, indicating that targeting plaque is associated with brain edema, or other adverse effects.
So, we now have good understanding of what the best-in-class profile should be, and that is to specifically and selectively target the toxic, misfolded forms of Amyloid beta.
It is important to note that the world's largest selling drugs today are best in class, not first in class. Outstanding examples include Humira in rheumatoid arthritis and autoimmune disease, Solvaldi and Harvoni for hepatitis C, and Lipitor for lipid lowering.
And these drugs all came from small companies as well. Humira came from Cambridge Antibody Technologies, a small, originally private United Kingdom-based immunology company. Pharmasset Inc. developed Solvaldi (sofosbuvir), which was picked up for hepatitis C by Gilead Sciences Inc. (GILD:NASDAQ). In its first year on the market, tt broke all records at $10 billion in sales. Again, it was third or fourth to the market in hepatitis C, but with the right profile, best in class.
TLSR: Can you comment on partnership potential for PMN310 or other therapies ProMIS has in development?
EG: We have an amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) portfolio. We're in discussions for partnering that, and that's been communicated to the market.
A profitable exit for biotechs like ours is generally via some sort of major merger-and-acquisition (M&A) deal with a larger biotech or pharma. I'm not going to comment on who we might be talking to, but we regularly speak with the key pharmas and biotechs in the field. There are two times a year when that's done in a very organized way, and that's at the annual J.P. Morgan Healthcare Conference in January in San Francisco, and at the annual BIO meeting, which is in San Diego at the end of June this year. Those meetings focus on partnering, and we're very active at those meetings.
If I step back and put on my big pharma hat, there are three time periods to consider for partnering. You could wait until we have our Phase 2 proof-of-concept data in 2021. If those data are what we expect from the best-in-class targeting, you could imagine a very significant M&A deal.
"We are addressing a need to solve the Alzheimer's disease epidemic. Any contribution we can make, we believe, is highly valuable."
However, we believe there is potential for a major deal before that. Big pharma likes to run clinical programs themselves. Plus, if they get in early, it's less expensive. There might be interest when we file the IND, near the end of 2018. At that stage, either a company is interested in our Alzheimer's disease program, or may be interested more broadly in our discovery technology platform, which addresses multiple neurodegenerative diseases.
Finally, there may be a forward-thinking company trying to get into the Alzheimer's disease area, or into neurodegenerative diseases in general. That kind of company could engage earlier.
TLSR: Can you describe the recent increase in ProMIS stock, which has nearly doubled over the last month or so?
EG: We think the increase is about reaching a critical mass, if you like. The program's been moving forward as per plan. We've met all our milestones. That's just good performance and that's important, especially in this market because biotech is risky. It's not the same as fermenting yogurt, right? Not to be glib, but human disease is complex.
At the same time we've been demonstrating positive and exciting results, the scientific field has trended in exactly the same direction. Two or three years ago there was still debate about whether these toxic misfolded proteins were really the drivers of the disease. Today, there is broad agreement in the field that toxic, misfolded forms of Amyloid beta are an underlying key driver of Alzheimer's disease.
I would also point out that, when we launched the company in July 2015, we had a small core of dedicated Edmontonians—mainly oil and gas investors—who were invested in the predecessor company. We've expanded to other investors outside that group, across Canada mainly but also in the U.S. We then moved up to high net worth individuals, then family offices, and now are starting to talk to smaller funds, etc.
We're getting a lot more eyeballs on our program as well. We've been speaking at various small conferences in Canada and the U.S., and soon in Europe. We've been communicating our results at world-class symposia and conferences, beginning in 2016 in July in Toronto with the Alzheimer's Association International Conference, probably the No. 1 place where Alzheimer's disease specialists, clinicians and patients come together. Word is getting out.
One other thing I would point out: It's fairly easy to get in front of people, especially Baby Boomers, and talk about Alzheimer's disease. Why? Because everybody's worried about it. Everybody knows somebody in the family, or a friend, or a famous artist, who's suffering from this. We know this is the No. 1 problem we have to solve in chronic medicine. The Alzheimer's Association estimated that the direct plus indirect medical costs of Alzheimer's disease in 2013 was over $500 billion in the U.S. alone, expected to triple by 2025. This will bankrupt health care systems if we don't find a solution.
In terms of value, getting people's attention is also not difficult. People want to talk about this. Many of our high net worth individual investors are double-bottom-line investors. They obviously want to make an investment that's reasonably profitable, but they also want to invest in something that makes a difference.
So I think we have a general drive of interest, and as we're communicating more, and continue to progress as per plan, we're starting to see an effect on our valuation. That's our best interpretation of it.
TLSR: Is there anything you'd like to add?
EG: We are addressing a need to solve the Alzheimer's disease epidemic. Any contribution we can make, we believe, is highly valuable, especially to patients, caregivers, the health care system. Our shareholders will benefit as well.
I'd point out three things. First, there is value and opportunity in our proprietary thermodynamic algorithms, which allow us to identify sites unique to the toxic misfolded forms of proteins in multiple diseases, and specifically in the case of misfolded toxic Amyloid beta in Alzheimer's disease. Second, we have developed antibodies that are specific and unique for the toxic forms, enabling application of a precision medicine approach. Third, these technologies allow us to develop a best-in-class product program. These are three exciting bullets in the battle to conquer Alzheimer's disease.
TLSR: Thank you for your time.
Elliot Goldstein, president and CEO of ProMIS Neurosciences Inc., brings a unique track record in the clinical, regulatory and commercial development of new pharmaceuticals. Dr. Goldstein began his career with Sandoz Pharmaceuticals (now Novartis), a fourteen-year period on drug development in France, Basel, Switzerland Global Headquarters, including as head of Clinical R&D in the United States. He subsequently held positions as SVP of Strategic Product Development at SmithKline Beecham (now GSK), CEO of British Biotech (Oxford, UK), Chief Operating Officer and Chief Medical Officer (CMO) of Maxygen, and president and CMO of a startup biotech devoted to development of biosimilar monoclonal antibodies. Dr. Goldstein holds an M.D. from the University Aix-Marseille II, Marseille, France, and a B.Sc. from McGill University, Montreal.
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Disclosure:
1) Tracy Salcedo conducted this interview for Streetwise Reports LLC and provides services to Streetwise Reports as an independent contractor. She owns, or her family owns, shares of the following companies mentioned in this interview: None. She is, or members of her immediate household or family are, paid by the following companies mentioned in this article: None.
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3) ProMIS Neurosciences Inc. had final approval of the content and is wholly responsible for the validity of the statements. Opinions expressed are the opinions of Elliot Goldstein and not of Streetwise Reports or its officers.
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