VERIFY Trial PV: ASH 2022 Phase 3 Study on PTG-300 Srdan Verstovsek

VERIFY Trial PV: ASH 2022 Phase 3 Study on PTG-300 Srdan Verstovsek

By Srdan Verstovsek, MD, PhD

How will the VERIFY clinical trial of PTG-300 help patients with polycythemia vera? I'm going to talk about this poster number 1709, which is a presentation of the VERIFY study, a phase 3 study of the Hepcidin Mimetic Rusfertide, also known as PTG-300. In patients with polycythemia vera, this is the study that is underway based on the outcome of the phase 2 open label study with this particular medication.


Now, Rusfertide is hepcidin mimetic. What that means is that it is acting as hepcidin in the body of the person, and hepcidin is the marker and major player in the iron metabolism. As you mimic hepcidin activity, you would keep the iron inside the spleen, liver, or lining of the GI tract. And there will be less iron for blood making and less iron for blood making, meaning less of the production of the red blood cells, and less of a need for phlebotomy.


And phlebotomy is the primary way how we manage higher red blood cell count patients with polycythemia vera. So in the phase 2 study, the hepcidin mimetic Rusfertide, which is, by the way, given as an injection under the skin once a week by the patients, was able, through this mechanism of action, to immediately, within 2 or 3 weeks, eliminate the great majority of the patient's eliminate need for bloodletting and eliminate the need for phlebotomy.


So iron is not available for red blood cells, no need for phlebotomy because red blood cells do not grow. It's a very simple, straightforward therapy (therapeutic intervention), and the quality of life certainly may improve along the way because, when you have too many red blood cells in circulation, you don't feel well, concentration issues, shortness of breath, and fatigue. These issues improve, and therefore, today I'm talking about this VERIFY phase 3 study, because through the knowledge we gathered through the phase 2 open label study, we are very confident this may be a new therapy for patients with polycythemia vera who need too many phlebotomies. A blind random study is underway, it's called VERFIY study.


Common Questions

Many of my colleagues ask about the real mechanism action of the Russert type because it's so much different than any other mechanism action of any other drug that we have tried so far to treat the patient with polycythemia vera. Remember polycythemia vera is clinically, presenting with too many red blood cells, it can sometimes have too many vitals in the platelets, it can cause symptoms through circulation being affected through inflammation that comes with the disease (progression) itself. Occasionally it can have a big spleen, and we typically use in evident management Hydroxyurea, which is a chemotherapy that kills growing cells simply. We also may use interferon, which is biological agents that modifies the growth of the cells in the bone marrow, or Ruxolitinib, which is a JAK inhibitor, it inhibits the growth and inflammation in the body of the patients and it's approved after Hydrea.


But this particular drug, through being a mimic, our hepcidin master iron metabolism protein in the body have a completely different way of controlling what is the number one problem in PV (polycythemia vera) patients, and that's uncontrolled red blood cell growth, a need for phlebotomy. And through that unique mechanism action, as I explained to my colleagues, it works right away and it's very effective, safe, and it seems to improve the quality of life as well. 


The other question is how is this going to compare to other agents that we use? And as I mentioned, we use Hydria, Interferon, and Ruxolitinib, but this is different, this is a drug that can be used alone, in people, polycythemia vera patients that require too many phlebotomies 3, 4, 5 in 6 or 12 months, where the goal would be to eliminate that need and have a controlled the hematocrit below 45 all the time, which is proven to decrease the risk of blood clotting and the risk of dying.


Or it can be adjunct to a therapy that is already in place. There are many patients that are given Hydroxyurea, for example, and you can control to some degree the whites and plates and the red blood cells. But there is still need for phlebotomy. We can add the Rusfertide to Hydroxyurea as a adjunct to eliminate the need for phlebotomy.


In fact, I think there are many patients like that, that are on Hydroxyurea as a standard first line choice, that I have now achieved that optimal control of the red blood count and need another agent to a completely eliminate need for phlebotomy and maintain a hematocrit grid below 45% a standard goal of therapy.


6 Key Takeaways of the VERIFY Clinical Trial in Patients with Polycythemia Vera

  1. Part 1a: 32-week, randomized, placebo-controlled, double-blind add-on phase with parallel groups.

  2. Part 1b is an open-label treatment phase with cross-over for patients previously treated with placebo. During this phase, all patients who have successfully completed Part 1a get rusfertide for 20 weeks (week 32 to 52).

  3. Part 2: Long-term extension phase in which all patients who have completed Part 1b continue to take rusfertide for 104 weeks (week 52 to 156).

  4. Important exclusion criteria include clinically severe thrombosis, current or chronic bleeding deemed clinically significant by the investigator within 2 months prior to randomization, and a history of invasive cancer within the past 5 years.

  5. Investigations were performed: Rusfertide - Rusfertide (32 Weeks) - Rusfertide (124 Weeks Open-label).

  6. Investigations were performed: Placebo - Placebo (32 Weeks) - Rusfertide (124 Weeks Open-label).


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Will This Data Affect Clinicians Today?

The information from the phase 2 open level study of Hepcidin is important to highlight a need for a better. Therapy of our patients better therapy in terms of optimizing the care of our patients to prevent the thrombotic events (adverse events), which are the leading cause of death in PV (polycythemia vera) patients. Otherwise, patients with PV (polycythemia vera) have a close to normal life expectancy somewhere about 15 to 20 years, which for 60 year old typical agent diagnosed with PV (polycythemia vera) for 60 year old would be close to normal.

The clotting events (adverse events) are related to uncontrolled blood cell count and particularly red blood cells, developing a specific drug to focus on the need of eliminating phlebotomy and normalizing hematocrit with the possible improvement quality of life, arise the awareness of what needs to be, really be done for patients with PV (polycythemia vera).


So even today, when we don't have results of the phase 3 random, I started to say, "Hey, this drug is so effective in what it's supposed to do, and it is now available for our use in every practice." Not yet, but even today, there is that influence of that study on our understanding of what is optimal care of patients with PV (polycythemia vera), and that is elimination of phlebotomy, normalizing the hematocrit below 45% to decrease that thrombotic risk.


What Is The Next Step For This Research in The VERIFY Trial?

With the much excitement, we are waiting for the phase 3 VERIFY clinical trial to accrue all the planned patients and proper follow up to be in place for us to learn whether we will have another approved drug for managing patients with PV. Remember, PV is chronic condition and it'll take some effort to approve a value of outside when it's compared to placebo.


We need to accrue a number of patients and monitor them for a longer period of time, almost a year for us to be certain that the phase 2 study results high response retinal, eliminating phlebotomy and implementing quality of life is achievable in a blind and randomized way, for approval to be given by the regulatory bodies in United States around the globe.


Now my feelings are that this is gonna be achieved and with enthusiasm we are looking forward to maybe a couple of years to have this drug available for our patients.


What Are The Key Takeaways From This Data?

The key takeaways from the whole concept of developing the hepcidin mimetic is that there are alternative ways of tackling the uncontrolled growth of the cells in the bone marrow. It doesn't have to be a chemotherapy or it doesn't have to be medication that may have some significant side effects.

In the Rusfertide we have what one may say a biological agents through a unique mechanism action mimicking what actually happens in the body of the patient. And with that, providing a substantial response that is the most important benefit to a patient.


Not only awareness of the goals of therapy, is something that we gathered from following the story of development of that. It is only about understanding, about the biology of the disease (progression) and which factors contribute to its existence and persistence in patients with these hematological neoplasms.


A discovery both in the biology as is in the clinical arena, are the benefits of us following the story of rusfertide and hopefully at the end we will be able to provide this valuable therapy to our patients in everyday routine management.


Final Thoughts

I would hope that everybody understands the ramifications of developing the alternative through different mode of action therapies for our patients with polycythemia vera, because there are patients that need a better different approach in their management, not only that hydroxyurea or interferon ruxolitinib are out there, there is a need for more, more specific different medications.


And I hope therefore, that we will all endorse this particular study in terms of accruing the patients and doing everything we can to possibly prove this therapy, be good enough and significantly beneficial to our patients so that we can utilize it without much of reservations if that drug is approved in the near future.


Srdan Verstovsek, MD, PhD - About The Author, Credentials, and Affiliations

Dr. Verstovsek is a hematologist-oncologist and United Energy Resources, Inc. Professor of Medicine at MD Anderson (research hospital, after his medical education in medical sciences). Dr. Verstovsek is a world authority on myeloproliferative neoplasms (MPN) and the founder and director of the largest MPN Clinical Research Center. Dr. Verstovsek has received international praise for his pioneering work in the development of MPN therapies. He oversaw more than 60 early/advanced phase clinical trials (registry) of innovative MPN treatments, such as ruxolitinib, the sole FDA-approved prescription for myelofibrosis (MF) until 2019 and the second-line treatment for polycythemia vera (including retrospective cohort study and statistical analysis).


He is directing a number of key phase 3 trials for promising MPN treatments. He has authored 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 primary author of more than 80 and 200 articles, respectively (h-index 91). He was awarded 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 (2015). (2010).


In 2015, he was elected to the American Society for Clinical Investigation. Numerous invitations to serve as an expert speaker/educator/chair at the most prominent national/international conferences attest to his contributions' global recognition. He routinely engages with MPN patient advocacy groups/societies on numerous levels. He is a co-founder and member of the International Working Group for MF Treatment and Research's executive committee.


  1. ASH Publications - Verify: A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera. ASH Publications, November 15, 2022

  2. Clinical Trials Gov - A Phase 3 Study of Rusfertide in Patients With Polycythemia Vera (VERIFY). Clinical Trials Gov, December 5, 2022


VERIFY Trial PV: ASH 2022 Phase 3 Study on PTG-300 Srdan ...

Dr. Srdan Verstovsek discusses Verify Trial PV: ASH 2022 Phase 3 Study on PTG-300