Patients with polycythemia vera (PV), a myeloproliferative neoplasm associated with JAK2 mutations and overproduction of red blood cells, often require regular therapeutic phlebotomies to avoid thrombosis. The most common presentations of thrombosis in PV include stroke, myocardial infarction, peripheral arterial thrombosis, transient ischemic attack, peripheral vein thrombosis, pulmonary embolism, and thrombosis in unusual venous districts.1
To achieve acceptable disease control, patients with low-risk disease may need to undergo phlebotomy up to 5 times per year, which can lead to adverse effects (AEs) such as iron deficiency. Those with high-risk disease require cytoreduction and correction of cardiovascular risk factors with or without phlebotomy.1,2
Alternative interventional treatments to reduce the risk of thrombosis represent a significant unmet need in the community setting as phlebotomy and cytoreductive therapies including hydrea, ruxolitinib (Jakafi), and interferons have not demonstrated consistency in efficacy or tolerability.2
“Many patients who use pills, injections, [or] cytoreductive therapies, to minimize the need for phlebotomy. [However,] it seems that the achievement of the goal [to] control the hematocrit [levels] below 45% is not readily achieved in the community setting,” Srdan Verstovsek, MD, PhD, said in an interview with OncologyLive®. “Many times, we considered PV a benign condition, [but] when you dig in and analyze the results it’s not so. Individuals are unnecessarily exposed to uncontrolled blood cell counts, which leads to untimely death from the thrombotic events. To optimize care in a community setting for patients with PV, we should all engage in developing new drugs.” Verstovsek is the United Energy Resources Inc, professor of medicine, director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms, and chief of the Section for Myeloproliferative Neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.
Assessing the Unmet Need for Patients with PV
“Most patients with PV will get at least 1 phlebotomy during the course of their treatment,” Aaron Gerds, MD, said in an interview with OncologyLive®. “Even if they are going to [receive] alternative medication we may use phlebotomy early on to quickly get hematocrit down after diagnosis. Patients who are lower risk for thrombosis would be treated with phlebotomy alone and patients who are higher risk for thrombosis are treated with a medication, which can free them from the need for phlebotomy. But there are still a significant proportion of patients who require phlebotomy in addition to a medication to control counts. They’re really getting 2 treatments at once, which is complicated to manage, and can lead to multiple adverse effects.” Gerds is an assistant professor in medicine (hematology and medical oncology) at Cleveland Clinic Taussig Cancer Institute in Ohio.
A phase 3 study is underway to assess outcomes for patients with previously diagnosed PV who require phlebotomy on a regular basis. VERIFY (NCT05210790) will evaluate whether the addition of the novel hepcidin mimetic rusfertide to ongoing therapy for PV will eliminate the need for patients to receive or prolong time between phlebotomies.2,3
“The phase 3 study is built on the experience from the phase 2 study [REVIVE; NCT04057040],” Verstovsek said. “It includes patients from a variety of backgrounds. They don’t necessarily need to be on any therapy at all, if they fulfill the requirement of too many phlebotomies, which is certainly harmful for them. The patients would come often at the beginning to make sure that they are [treated] optimally with rusfertide, [and determining the] optimal dose without the adverse effects [may] require a few months of adjustments. [There is planned] long-term follow-up, almost a year and more, because PV is a lifelong condition.”
Rusfertide works by suppressing PV erythropoiesis. “Basically, it tricks the bone marrow into thinking it’s already iron deficient when it isn’t, thus slowing down the production of red blood cells keeping the hematocrit under 45%,” Gerds explained.
REVIVE assessed the ability of rusfertide to maintain hematocrit levels below 45%. All patients underwent phlebotomy to achieve hematocrit below 45% prior to prior to the first dose of rusfertide dose. Seventy patients received rusfertide at a median dose of 40 to 60 mg weekly via self-administered subcutaneous dosing.
Among 63 evaluable patients, during the first 28 weeks of treatment, 84% of patients did not require a phlebotomy. Of those who did proceed to phlebotomy, 14% required 1 and 2% required 2 phlebotomies.2 Rusfertide demonstrated similar efficacy in all categories of patients, independent of the PV patient risk category or concurrent therapy with hydroxyurea, interferon or ruxolitinib. In terms of safety, the most common AE was injection site reaction (33%) but no patients discontinued because of injection site reactions.
“Here is a drug that is effective, it is safe, it is self-administered, it is therefore simple, and it appears to be durable,” Verstovsek said of the phase 2 data.
VERIFY Aims to Extend Phlebotomy-Free Intervals
The double-blind, placebo-controlled trial will evaluate patients with PV randomly assigned 1:1 to ongoing therapy with either rusfertide or placebo. The primary efficacy will be evaluated during weeks 20 to 32, with primary end analysis reported at week 32. At that time the study will be unblinded. Durability of response will be assessed between weeks 32 to 52; all enrolled patients then will proceed with their ongoing therapy and rusfertide.2,3
At week 52, durability of response will be evaluated and patients will enter the long-term safety follow-up (weeks 52-156). Therapy administered during this portion of the trial will be PV therapy plus rusfertide. The end of treatment is week 156 with an additional safety follow-up period occurring for 4 weeks.2,3
Verstovsek noted that the aim of the trial is not to eliminate disease but control it. “We want to prove that rusfertide is effective, safe, simple, and long lasting. Studies such as [VERIFY] that cover [approximately] 1 year are the norm for PV and we are looking forward to this study to be open across the globe over the next couple of years. [We want to demonstrate] the value of eliminating the need for phlebotomy, improving the quality of life for these patients, and having it on the market for our patients in every practice,” he said.
Taking the Patient into Consideration
Gerds noted that patients may also benefit from the elimination of the multiple burdens associated with phlebotomy. “It leads to iron deficiency and [individuals] can be symptomatic from the iron deficiency—they can experience tiredness, achiness, changes in hair and nails, and the most famous adverse effect of iron deficiency being pica, the urge to eat dirt or ice. Additionally, [phlebotomy] takes time,” Gerds said noting that the scheduling and repeat tests are a “logistical hassle.”
Self-administration of the agent is also a key differentiator for patients with PV. “Patients [administer] the shot at home. Thinking about a systems-based approach to delivering of care, an infusion or injection room chair [remains free] in your cancer center,” Gerds said.
He added that there are several barriers to overcome, most of which rely on patient education. “When prescribing a medication such as rusfertide, you also have to prescribe the syringes and the needles, and you have to teach the patient how to do the injections,” he said.
At Cleveland Clinic, Gerds noted that they provide educational videos and offer nursing visits. “We also need to instruct them to on how to care for the medication at home—do not store it in extreme temperatures, how to draw from the vial, etc,” Gerds said.
In June 2021, the FDA granted breakthrough therapy designation to rusfertide as a potential therapeutic option for patients with PV to reduce erythrocytosis in those who do not require further treatment for thrombocytosis and/or leukocytosis.4
“I would envision, if we are successful in proving the value in eliminating phlebotomy and improving quality of life, that rusfertide would be a natural choice for individuals who are otherwise low risk, manage with phlebotomy alone, and have problems with it,” Verstovsek said. “Rusfertide appears to fulfill the purpose in patients who are low risk and for patients who are receiving some other cytoreductive therapy [such as] hydroxyurea in suboptimal responders. Adding rusfertide to optimize the care eliminates the need for phlebotomy and is a natural next step. I think there is a possibility of multiple different clinical scenarios where the drug may become valuable for low-risk to high-risk patients.”
Gerds noted that next steps for building on this research is improving the concurrent medications administered for this patient population as well as the identification of prognostic biomarkers. “We always want to [achieve] deep remissions and have [patients] live much longer than we would anticipate. And the truth is patients with PV often do very well…but we lack a lot of good biomarkers.”
References
- Vannucchi AM. How I treat polycythemia vera. Blood. 2014;124(22):3212-3220. doi:10.1182/blood-2014-07-551929
- Hoffman R, Ginzburg Y, Kremyanskaya M, et al. Rusfertide (PTG300) treatment in phlebotomy-dependent polycythemia vera patients. J Clin Oncol. 2022;40(suppl 16):7003. doi:10.1200/ JCO.2022.40.16_suppl.7003
- A phase 3 study of rusfertide in patients with polycythemia vera (VERIFY). ClinicalTrials.gov. Updated August 1, 2022. Accessed September 20, 2022. https://clinicaltrials.gov/ct2/show/ NCT05210790
- Protagonist Therapeutics receives FDA breakthrough therapy designation for rusfertide in polycythemia vera. News release. Protagonist Therapeutics. June 3, 2021. Accessed September 20, 2022. bit.ly/3R0Tir8
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