MARINA KREMYANSKAYA (NEW YORK)
HEPCIDIN AGONISTS IN POLYCYTHEMIA VERA
Polycythemia vera (PV) is characterized by increased and uncontrolled production of red blood
cells. Patients with PV are treated with periodic therapeutic phlebotomies (TP) in order to
keep hematocrit <45% to reduce the risk of thrombotic events. High risk patients are also
treated with cytoreductive therapies. Since patients are seen and evaluated periodically, it is
likely that they spend a good portion of their time with hematocrits that are not well
controlled. This may increase their risk of a thrombotic event.
Patients with PV are often iron deficient at diagnosis and iron deficiency typically gets worse
with frequent phlebotomies. Many patients become symptomatic from iron deficiency,
however iron supplementation is ill advised and managing these patients’ symptoms can be a
challenge.
We hypothesized that both expanded erythropoiesis and iron deficiency that is seen in PV
result in suppression of hepcidin, which in turns makes iron more available for erythropoiesis.
Hepcidin is a major negative regulator of iron flow. Under conditions of low hepcidin, iron is
able to freely flow through the ferroportin and into the plasma. However, when hepcidin level
is high, it binds to ferroportin which functions as its receptor causing internalization and
degradation of ferroportin. As a result, iron accumulates intracellularly in the form of ferritin
and iron egress into the plasma stops, thus making it unavailable for erythropoiesis.
PTG-300 is a hepcidin-mimetic which has been shown in pre-clinical studies to cause dose-dependent
anemia. In a phase II study in beta thalassemia, PTG-300 results in sustained
decrease in serum iron and Transferrin Saturation (TSAT). We are currently conducting a phase
II study of PTG-300 in patients with PV who require frequent phlebotomies. The study aims to
assess safety and efficacy of PTG-300 in reducing the frequency of phlebotomies in these
patients. A key secondary endpoint is response rate in Total Symptom Score (TSS). Eligibility
criteria include PV diagnosis (by 2016 WHO criteria) and ≥3 phlebotomies with or without
concurrent cytoreductive therapy to maintain hematocrit ≤45% in the 24 weeks prior to
enrollment. PTG-300 doses of 20, 40, 60 and 80 mg administered subcutaneously weekly are
titrated to maintain hematocrit <45%. This is a 3-part Phase 2 trial consisting of (1) a 28-week
dose-finding; (2) a 12-week blinded randomized withdrawal (1:1) PTG-300 vs placebo; and (3)
a 52-week open label extension (Figure 1).
18 subjects were enrolled to date. Of these, 67% are male, 88% have required 3-5
phlebotomies in the 6 months prior to enrollment, 56% were treated with phlebotomies plus
cytoreductive therapies, 44% are low risk, and 62% have JAK2V617F allele burden higher than
50%. During the dose finding period only 3 subjects needed a phlebotomy, but were able to
maintain hematocrit <45% after a dose increase (Figure 2). Red blood cell count also
decreased in all treated patients, while white blood count and platelets remained unchanged.
While all patients had baseline ferritin numbers that were in the iron deficiency range, as soon
as after 1 month of treatment, ferritin normalized. Finally, we examined MPN related
symptoms by assessing MPN-TSS at baseline and 28 weeks. Preliminary results indicate a
decrease in TSS at 28 weeks though data is limited at this point to a small number of patients.
PTG-300 was well tolerated. There were no grade 3 or 4 adverse events reported. Injection
site reactions were seen in 3 patients but decreased in severity or resolved with continued
treatment. No serious adverse events were reported. No study subjected discontinued
treatment due to adverse events.