Patients with polycythemia vera are at increased risk for cardiovascular events. One of the main ways we mitigate that risk and reduce their thrombotic risk is actually by controlling their red blood cell count or their haematocrit. This has been shown to reduce their risk of thrombosis by about fourfold but unfortunately the way we do this a lot of times is we do something called therapeutic phlebotomies where we actually drain them of blood repeatedly, over and over and over, to keep that number down. Not surprisingly, patients don’t always tolerate that well. Oftentimes they feel very fatigued from the consistent taking of blood, it can produce fluid shifts that aren’t well tolerated and obviously it ties them to the healthcare system so they lose a little bit of that freedom.
So in this study we actually were utilising an agent called rusfertide. This is actually leveraging our understanding of iron homeostasis and it mimics an agent called hepcidin. Hepcidin is the master regulator of iron and it actually is responsible for allowing iron to be distributed to the bone marrow for continued red blood cell production. Interestingly, rusfertide when it mimics hepcidin actually binds to ferroportin, which is this protein that shuttles iron to the bone marrow. It actually downregulates that, it doesn’t allow iron to be delivered to the bone marrow, therefore red blood cells can’t be made and we’re able to control the haematocrit without the need for these phlebotomies, just by restricting iron delivery to the bone marrow.
We performed this study looking at patients with polycythemia vera who were requiring consistent phlebotomies to see if it was able to do that. In the phase II study we saw a drastic reduction so it led us to do the verify which was the phase III trial. Again, compared to placebo we saw the ability of rusfertide to drastically reduce phlebotomy eligibility in these patients. It also really consistently controlled their haematocrit. Quite interestingly, it also improved some of their patient-reported outcomes, some of the symptoms they would associate with the disease, things that are challenging to treat such as fatigue. We saw that there was more of an improvement in rusfertide treated patients than those with placebo and we think it may be related to that impact on iron deficiency.
What was the methodology and the findings?
The methodology for the study, this phase III study called VERIFY, we looked at patients who were requiring consistent phlebotomies and they were randomised 1:1 to either go on rusfertide or placebo in addition to their current standard of care. The primary portion of the study lasted 32 weeks. The first 20 weeks we dose optimised the rusfertide and then the primary endpoint was assessed from weeks 20-32. Thereby the primary endpoint was the absence of phlebotomy eligibility, so the need for a phlebotomy, if you will. That’s where we saw the key differences.
We also looked at key secondary endpoints such as the ability to maintain a haematocrit less than 45% for weeks 0-32 and actually the mean phlebotomy rate over weeks 0-32. Lastly, the other key secondary endpoints looked at patient-reported outcomes. We used two patient-reported outcome tools called the PROMIS Fatigue score which really assesses fatigue and the impact it has on patients’ lives, as well as the Myelofibrosis Symptom Assessment Form, or Total Symptom Score 7, which looks at things like fatigue, including night sweats, itching, abdominal symptoms and bone pain. In both of those we saw significant improvements.
What are the clinical implications of these findings?
Right now our standard of care for patients with polycythemia vera is to offer them anti-platelet therapy with aspirin, therapeutic phlebotomy to maintain a haematocrit less than 45% and in a subset of patients we offer them cytoreductive therapy. This could be hydroxyurea, interferon or ruxolitinib in the second line. These agents are helpful in some sense but all come with their own side effect profile, toxicity and challenges in dosing. Here, I think the impact of rusfertide in clinic is that we won’t have to necessarily do repeated phlebotomies in patients that aren’t tolerating those. Here we can offer something that gives patients a little bit more freedom, maybe able to offer more consistent control of their blood counts to offer them increased thrombotic risk reduction.
In patients that are dealing with problematic symptoms such as fatigue and they’re known to be really iron deficient from these phlebotomies, rusfertide offers an option that can do a couple of things – it can control that haematocrit, control that haemoglobin, increase their freedom because they’re not coming in and getting phlebotomies and may address some of those problematic symptoms that let them have a better experience with their disease.
