PTG-300 Therapy for Phlebotomy-Dependent Polycythemia Vera

Ruben Mesa, MD, details an abstract presented at ASCO 2022 on an investigational agent filling an unmet need in polycythemia vera.

Rami Komrokji, MD: Ruben, there was an interesting abstract presented [at the American Society of Hematology Annual Meeting in 2021] by Dr Ronald Hoffman on PTG-300 [rusfertide] for phlebotomy-dependent patients. Can you walk us through it? This drug is different from other things we’ve used in PV [polycythemia vera].

Ruben Mesa, MD: Sure. I’ll get around to that in a moment, but I wanted to build a little on the theme you brought up. There’s an unmet need in PV. The risk of having a vascular event doesn’t tell the whole story. We’ve assessed a lot of individuals who have a lower risk of vascular events but still feel quite poorly. Understanding that and realizing that control of the disease can make a big impact is key. For some individuals, it’s a significant decrease in quality of life.

The advance of ropeginterferon is big. But I know from experience that for many people watching this video, their experiences with interferon in the earlier days in oncology were very negative. In my fellowship, we used it in melanoma. We used it in myeloma before we had all these wonderful drugs. We used it in CML [chronic myeloid leukemia] in doses that we now consider punitive: 15 million units daily or 3 times a day—very difficult things that had great toxicity. This isn’t that. Ropegylated interferon at low doses is a dramatically different therapy. If you haven’t tried it, don’t let that prior experience make you hesitate to try ropegylated interferon in PV. It’s quite helpful.

One thing that we haven’t had is a therapy that helps control the hematocrit in a stable way where we aren’t using cytoreductive drugs. Part of our conservative nature in MPNs [myeloproliferative neoplasms] had been our fear of overusing hydroxyurea. A lot of people are on phlebotomy and aspirin. What’s negative about phlebotomy and aspirin? It’s a hassle; it creates iron deficiency, which worsens symptoms; and it’s very uneven. If we’re doing phlebotomy and aspirin, your hematocrit goes up. We phlebotomize, and it goes down. It goes up and down repeatedly. We don’t know how long you’re in the target range. Maybe you’re in the target range only 10% of the time. It isn’t great.

Rusfertide is 1 of a series of drugs looking at hepcidin. Kudos to my colleagues at Mount Sinai [Hospital in New York] who have done beautiful work in the development of this therapy along with the folks at Protagonist [Therapeutics]. We’ll talk about decreasing hepcidin in myelofibrosis a little later. These drugs are trying to use hepcidin mimetics to simulate the anemia of chronic disease to create a state where you control the hematocrit without iron deficiency. What are the benefits? You might have more even counts. You might allow the iron levels to rise so that you have fewer symptoms.

Dr Ronald Hoffman and colleagues presented a nice abstract at the 2022 ASCO [American Society of Clinical Oncology Annual Meeting] with over 60 patients where they were able to show exactly that. In phase 2 data, there was control of the hematocrit and freedom from phlebotomy. If they’re on therapies, we’re still requiring phlebotomies. There was also improvement in symptoms. There’s likely some direct activity but also some benefit from control of iron. That’s going to be moving forward to phase 3 studies. The role of rusfertide or other drugs in that pipeline—there are some from Ionis [Pharmaceuticals] and others that are looking at this pathway—may expand our medical therapy to be more inclusive of all patients with PV.

This issue of phlebotomy is pretty antiquated. When we look at the history of medicine, phlebotomy was used for everything from infection to depression to cancer. It killed poor George Washington. They phlebotomized the poor man with epiglottitis, and they killed him by overphlebotomizing him. We can advance more. It’s exciting to see this moving forward. It will be exciting to see the phase 3 data from that.

Rami Komrokji, MD: Absolutely. We’ve treated many patients on the study, and patients feel better on this treatment. Fellows always ask me, “Are phlebotomies bad?” But I say exactly what you say. They aren’t bad per se, but they reflect that we aren’t controlling the disease. How do we know how long the patients are above a hematocrit of 45%? It’s how often you look into that. It’s a surrogate marker for the biology or the control of the disease.

Transcript edited for clarity.

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