Pankit Vachhani, MD: The management of polycythemia vera is a risk, takes a risk-adapted approach, whereby we categorize our patients at present in two categories, low-risk polycythemia vera and high-risk polycythemia vera. High-risk is any patient who is about the age of 60 or has had a history of prior thrombosis, arterial or venous, or of course, both age and prior history of thrombosis. Now, irrespective of the risk categorization and, the risk there being that for future episodes of thrombotic events. Irrespective of the risk categorization, the one key thing to note is to have a hematocrit goal of 45% or less. Some may argue and say that we should target a hematocrit goal of 42% or less in women. Now, the historically most used, often used, treatment and something that we continue to do is therapeutic phlebotomies, generally considered as a 500 mL [milligram], 1-unit phlebotomy, which should theoretically decrease the hematocrit by about 3 percentage points.

Now, there have been studies done looking into the effect of phlebotomies. A prospective trial, in fact, was done in about 365 patients with polycythemia vera, where the patients were randomized to a more intensive treatment, that being a target hematocrit of less than 45%, versus a less intensive hematocrit goal of somewhere around 45% to 50%. And the time to death from cardiovascular causes or major thrombotic events was substantially higher in those who had a less intensive treatment. More specifically, the hazard ratio was 3.9. Thus, it favored overall having a more strict or more intense treatment approach. The patients, of course, were allowed to have in the hematocrit goal, either using phlebotomy or Hydrea. But that point aside, the key point to take away is having a hematocrit goal of 45% or less. One additional thing that goes hand in hand, irrespective of what risk categorization the patient falls under, is also the use of low-dose aspirin.

Now, low-dose aspirin here refers to a dose somewhere around 40 to 100 milligrams, most commonly that being 81 milligrams. All patients with polycythemia vera should be on a low-dose aspirin, with the exception of those who have insensitivity or, for example, have acquired von Willebrand syndrome. That generally tends to happen when the platelet counts are around 1 million or more, but certainly not definitely restricted to that. But the data behind the use of aspirin comes from many older studies. For example, there was an Italian study that randomized about 112 patients with polycythemia vera to either aspirin or placebo. It was quite well-tolerated, and what it showed was that low-dose aspirin was able to suppress the thromboxane synthesis nearly completely in vivo in the low-dose aspirin treated patients. Also, there is the ECLAP [European Collaboration on Low-dose Aspirin in Polycythemia Vera] study which randomized more than 500 patients to low-dose aspirin versus placebo, and this too, showed that there was a reduced risk of combined end point of nonfatal myocardial infarction, a nonfatal stroke, pulmonary embolism, major venous thrombosis or death, from cardiovascular causes. And the relative risk there was 0.4, which was statistically significant.

Now, moving on to some additional drugs, which are beyond the points of phlebotomy or hematocrit control and aspirin, we have the different cytoreductive agents. These are in general used for those patients who have high-risk features or have a low-risk polycythemia vera, but they have a progressively increasing leukocytosis or platelet counts, or happen to have symptomatic or progressive splenomegaly, intolerance to phlebotomy, or uncontrolled PV [polycythemia vera] related symptoms. And there the drug of choice for many years and decades has actually been hydroxyurea. Important to note that the data for the use of hydroxyurea actually is largely extrapolated from randomized studies performed in the field of essential thrombocythemia. Nevertheless, there is data from a PVSG [Polycythemia Vera Study Group] study that supported that hydroxyurea-treated patients had fewer thrombotic events. Additionally, there were a couple of other European studies which also showed that hydroxyurea in comparison to another alkylating agent showed no difference in thrombotic events. Although the other agent, pipobroman, had leukemic transformation rates higher than that of hydroxyurea. Overall, hydroxyurea is one of the most commonly used cytoreductive agents in those who need it. But there also has been increasing recognition of interferon. Interferon alpha is a naturally occurring biologic response modifier. It has anti-angiogenic, antiproliferative, also immunomodulatory differentiating properties. There is data to support that it more specifically targets the myeloid clonal population.

Now, interferon has been used for many decades at this point. There are various interferon products available as well. The more classical interferon is the interferon alpha. PEGASYS [Pegylated Interferon Alfa-2a], which is one of the products, or pegylated interferon alpha, has also been in used. But more recently, and I want to point this out, is the more recent FDA approval in November 2021 of BESREMi, which is a ropeginterferon alpha-2b product. It was initially approved in Europe, and in November 2021, FDA granted approval for ropeginterferon for the treatment of patients with polycythemia vera. Now, the decision for that came about from the safety data from the phase 1/2 PEGINVERA [Pegylated Interferon Alpha 2b to Treat Polycythemia Vera] trial and the phase 3 CONTINUATION-PV and PROUD-PV trials, while the efficacy data came primarily from the PEGINVERA trial in patients with PV. Thus, BESREMII, or ropeginterferon, is actually a novel monopegylated interferon alpha-2b, with an extended administration interval of 2 to 4 weeks. Initially, it’s used on a 2-week basis and subsequently, it can be used on a monthly basis.

Now, after 7.5 years of treatment, in the PEGINVERA study ropeginterferon alpha-2b was able to induce complete hematological responses in 61% of patients. Also, worth noting, 80% of patients who got the drug achieved some form of hematological response on therapy. The vast majority did benefit. Data from PROUD-PV and CONTINUATION-PV is also very encouraging. That was the phase 3 study, PROUD-PV leading to its counterpart, where the patients continued on to the CONTINUATION-PV study. And after 5 years of treatment, 53 out of 95 patients on the CONTINUATION-PV study, which forms about 56% of patients on ropeginterferon alpha-2b, had complete hematological response, which is more than that achieved in the control arm, which was 44%. But I think the most striking data is actually about the molecular responses over there. Hence, 69.1%, as opposed to only 21.6%, of patients had a molecular response with ropeginterferon alpha-2b as compared to the control arm. More importantly, equally importantly, is the median JAK2 V617F allele burden, which is a marker of the disease, continued to decline on a continuous basis, steadily from baseline to the study follow-up time period. For example, it went down from 37.3% at baseline to 8.5% at 60 months. Contrast that to the control arm, where it initially decreased but then rebounded to actually 44%.

Transcript edited for clarity.