By Srdan Verstovsek, MD, PhD
What were the results of the PTG-300 Verify phase 3 clinical trial in polycythemia vera patients? The study (design) of interest is the primary session report of the development of new antibody, and that antibody is against a mutated calreticulin. Now, what is the mutated calreticulin? In all the patients with myeloproliferative, neoplasms being ET or PV (diagnosis polycythemia vera) or myelofibrosis, there is a hyperactivity of intercellular signal.
JTA pathway, and this is because of our CE mutations in about 30% of the ET patients and 30% of myelofibrosis patients. The reason is a mutation in gene called calreticulin. This gene makes phenomenal protein and then this mutated protein is excreted outside the cell and binds to a cell surface to a receptor called methyl or MPL.
The methyl receptor is actually a receptor for thrombopoietin growth factor for platelets. Binding of the mutated Calreticulin two methyl receptor activates intercellular pathway, dejas that pathway. That's how it works because the mutated protein, mutated Calreticulin is visible on the surface of the cell, we now have ability to develop medications that will target these specific. Therefore we are now talking first time ever about development of a specific molecularly defined therapies for patients with nonproliferative neoplasms, specifically ETM myelofibrosis. And that would be antibody against mutated calreticulin with a potential to target specifically malignant nodes and potentially eliminate those malignant cells.
So the stakes are high, that's why that was a plenary session. We want to talk about the molecular response where we would be able to eliminate disease or eliminate at least malignant cells. Perhaps this indicating in the future of significant clinical benefit, even elimination of the disease. Now, the presentation was on preliminary findings in mice and test tubes.
We hope that we will have the clinical study for patients with calreticulin mutations, advanced ET or advanced Myelofibrosis opened during 2023. Preclinical testing showed that this antibody, naked antibody is quite effective in inhibiting a signaling through methyl receptor upon binding of the meter calreticulin, and in mice model that led slow slowly to decrease in the number of cells affected by the mutation.
In effect, what in the test. Inhibition of the growth and the cell death is expected to be seen in the mice. But now we know that the growth of these cells is inhibited and longer exposure to antibody mice would lead, hopefully to elimination of disease (polycythemia vera). And we would hope that this is then gonna be seen in the patients as well next year once we open the study.
So it's a tremendous change of thinking what we can do for patients with myeloproliferative neoplasms and prospects are high that this is a beginning of new era when we talk about the molecular response and potential for elimination of the disease
the most common question about this study is, when can I have it for my patients? The standard practice in modern patients with MPN and specifically, for example, with advanced myelofibrosis, is to control as much as we can the symptoms and then perhaps decrease the size of the spleen or improve the bone marrow function to alleviate problematic anemia, we have therapies that are what we simply say control the signs and symptoms of the disease.
There is no real potential to eliminate a disease. The only way to eliminate a disease and cure the patient is the bone marrow transplant, and that happens in less than 10% of the patients and the medications, the JAK inhibitors, for example, that inhibited the hyperactive JAK pathway and provide anti-proliferative and anti-inflammatory potential and therefore improve.
The signs and symptoms do not work for a long time. We know in the frontline setting, Ruxolitinib does this for about three years in clinical studies and perhaps in community setting, even shorter. Therefore, the advent of the specific therapy for specific patients with the specific mutation, with the prospect of eliminating that is extraordinary.
And my colleagues as was evidenced at the ASH order presentation when they all come up and say, can I have this study open in my sites for my patients? The prospects are good and the enthusiasm is extremely high.
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Their next step is really to transition from the preclinical to clinical work. Of course, nothing like this has ever been. And of course we will need to study the safety of the antibody first in most advanced patients, my fibrosis patients, to establish the safety and the side effects I hope would not be problematic because after all, this is the specific antibodies for particular protein only, then we will be able to expand it to perhaps earlier stage disease patients where I think the most of the clinical benefit would be.
Remember that the most advanced patients where the safety is done are those with advanced myelofibrosis, where disease is complex and this malignant cells in the body of the patient may not depend only on the carline mutation. There might be many different clones or different mutations as it's actually true and therefore there might be some but not optimal efficacy of this therapy. Even when we look at the safety, we look at efficacy we may not see extraordinary benefit right from the beginning. One really needs to be cautious and optimize not only safety at the beginning, but later on, optimize the efficacy by picking up the best patients for the therapy to succeed.
And that would be earlier on in the course of disease where the genetic complexity is not prominent and there is much more hope to possibly eliminate disease.
The key takeaway from the presentation is that we are on a brink of a new chapter in development of therapies for myeloproliferative neoplasms et myelofibrosis in this case by exploring the understanding of the biology of these diseases in much more. We did not at the beginning understand exactly how and why the hyperactive JAK pathway happens.
With the discovery of calreticulin in mutation, we fulfilled the question of what causes the activation of this pathway in patients that do not have a widely known and most common in JAK2 mutation. And now after about 8 years from that discovery of calreticulin mutation. We are actually talking about therapies that was specifically a touch rate.
So it's a new chapter and that the chapter may come, may become a book on its own on the specific molecularly targeted therapies for myeloproliferative neoplasms.
I'd like everybody to embrace what we are seeing here. It's completely novel, unprecedented. That's why it was plenary session at ASH. And I hope that we will not only enhance our participation clinical studies with this kind of therapy, but any other, because there is so much going on in the field of mild proof neoplasms and numerous phase 3 studies with the numerous different medications that have completely different mode of actions.
Not necessarily targeting only malignant but certainly with potential to eliminate malignant or suppress it in different ways. So please look carefully in your patient's pool and let's engage together in developing a new drug by referring patients to academic centers that have clinical studies open.
Srdan Verstovsek, MD, PhD - About The Author, Credentials, and Affiliations
Dr. Srdan Verstovsek is a hematologist-oncologist at MD Anderson Cancer Center and the United Energy Resources, Inc. Professor of Medicine. Dr. Verstovsek is a world authority in myeloproliferative neoplasms (MPN) and the founder/director of the world's largest MPN Clinical Research Center. Dr. Verstovsek has received international praise for his contributions to the development of ground-breaking MPN therapies. He oversaw more than 60 early/advanced phase clinical trials of new MPN medications, including ruxolitinib, the only FDA-approved prescription for myelofibrosis (MF) until 2019, and polycythemia vera patients second-line treatment.
He is in charge of numerous key phase 3 trials for promising MPN treatments. He has written 24 book chapters and over 600 peer-reviewed original articles/reviews in prestigious medical journals such as the New England Journal of Medicine, Blood, Leukemia, and Lancet. Dr. Verstovsek is the author of more than 80 and 200 articles, respectively (h-index 91). Among the honors he has received are the Distinguished Clinical Faculty Mentoring Award (2021), the Waun Ki Hong Faculty Award for Excellence in Team Science (2021), the Otis & Pearl Walters Faculty Achievement Award in Clinical Research (2017), the Seventh Annual Irwin H. Krakoff Award for Excellence in Clinical Research (2013), and the Celgene Young Investigator Award (2010). In 2015, he was elected to the American Society for Clinical Investigation.
His efforts have been widely recognized, with multiple invitations to serve as expert speaker/educator/Chair at major national/international conferences. He regularly interacts with MPN patient advocacy groups/societies on numerous levels. He is a co-founder and member of the Executive Committee of the International Working Group for MF Treatment and Research.
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