“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.