The FDA has granted breakthrough therapy designation to rusfertide (PTG-300), marking a significant milestone for patients with polycythemia vera who struggle with current treatment limitations. The designation supports the development of this injectable hepcidin mimetic as a potential therapeutic option for reducing erythrocytosis in patients who do not require further treatment for thrombocytosis and/or leukocytosis.
The breakthrough designation is based on compelling data from the ongoing phase 2 PTG-300-04 trial (NCT04057040), which demonstrated that rusfertide allowed the majority of patients to eliminate therapeutic phlebotomies while maintaining target hematocrit levels below 45%, reversing iron deficiency, and experiencing symptom improvements.
Novel Mechanism Addresses Unmet Medical Need
Rusfertide represents a novel approach to treating polycythemia vera through its mechanism as a synthetic hepcidin mimetic. The drug was engineered to provide stronger potency, solubility, and stability compared to the natural hormone, potentially resulting in better pharmacokinetic and pharmacodynamic characteristics.
"Rusfertide is a natural hormone mimetic and may stand out as the first non-cytoreductive therapeutic drug for polycythemia vera," stated Suneel Gupta, PhD, chief development officer at Protagonist Therapeutics. "We look forward to working closely with FDA regulators to advance and complete all relevant clinical studies, both ongoing and planned, as quickly as possible."
The mechanism works by addressing the underlying pathophysiology of polycythemia vera. In this condition, hepcidin levels are low, allowing ferroportin to remain open and enabling iron to freely flow into plasma, making it available for bone marrow erythropoiesis and resulting in uncontrolled red blood cell production. Rusfertide closes ferroportin, limiting iron availability for erythropoiesis and achieving hematocrit control.
Phase 2 Trial Demonstrates Efficacy
The three-part phase 2 PTG-300-04 trial includes a 28-week dose-finding portion, a 12-week blinded randomized withdrawal phase comparing rusfertide with placebo, and a 52-week open-label extension phase. The study enrolled patients diagnosed with polycythemia vera using 2016 World Health Organization criteria who had undergone three or more phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit levels of 45% or higher in the 24 weeks before enrollment.
At the time of data presentation, 63 patients with polycythemia vera had been dosed with rusfertide, with treatment duration ranging from 2 to 81 weeks and median exposure of 15 weeks. The median patient age was 56 years, with 72.6% being male and 48.4% classified as low-risk. Nearly half (46.8%) of patients had received 4 to 5 phlebotomies in the six months before the trial.
The results were striking. "The rate of phlebotomies was very high in this heavily phlebotomy-dependent patient population prior to initiation of therapy. As soon as patients initiated treatment with rusfertide, the rate of phlebotomy decreased dramatically (P <.0001)," reported Marina Kremyanskaya, MD, PhD, lead study author and assistant professor of medicine, hematology, and oncology at Mount Sinai Hospital.
During the dose-finding period, all patients except one were phlebotomy-free, with hematocrit levels maintained below 45% for 28 weeks in all but two patients. The study also demonstrated progressive increases in serum ferritin toward normal ranges, indicating reversal of iron deficiency that commonly affects polycythemia vera patients.
Symptom Improvement and Safety Profile
Beyond hematologic control, rusfertide showed promise in addressing disease-related symptoms. Results from the MPN Symptom Assessment Form Total Symptom Score revealed decreased symptom burden at week 28 compared to baseline, primarily driven by improvements in fatigue and concentration problems, with some contribution from reduced pruritus.
Patient-reported outcomes were encouraging, with 71% of patients experiencing improvement at 9 weeks of treatment according to the patient global impression of change assessment, with most reporting being "much improved" or "very much improved."
The safety profile proved favorable, with rusfertide being very well tolerated. The majority of treatment-related adverse events were grade 1 or 2 in severity. The most common side effect was injection site reactions, occurring in 28.1% of injections, but all reactions were transient and no patients discontinued due to these effects. Only two grade 3 adverse events were reported, neither determined to be drug-related, and no grade 4 toxicities occurred.
Clinical Significance and Future Outlook
The breakthrough therapy designation represents a significant step forward for polycythemia vera treatment. "These results provide additional evidence that rusfertide may have a clinical benefit for patients with polycythemia vera," stated Ronald Hoffman, MD, director of the Myeloproliferative Disorders Research Program at Mount Sinai. "The need for a new non-cytoreductive therapeutic option in polycythemia vera is urgent."
Polycythemia vera patients currently rely on periodic phlebotomy with or without cytoreductive therapy, often spending significant time with hematocrit levels above 45%, potentially increasing thrombosis risk. The condition frequently presents with iron deficiency at diagnosis, which worsens with repeated phlebotomies, creating a challenging treatment paradigm.
Rusfertide has previously received orphan drug and fast track designations from the FDA for polycythemia vera treatment. The breakthrough therapy designation will facilitate closer collaboration with FDA regulators to expedite the drug's development and potentially bring this novel therapeutic option to patients who need alternatives to current treatment approaches.
