Phase I Safety Study of Anti-Transferrin Receptor 1 Antibody (PPMX-T003) in Patients with Polycythemia Vera and Erythrocythemia

Background: Transferrin Receptor 1 (TfR1) has been thought to be an anti-cancer target by controlling iron supply for decades. Anti-TfR1 fully human monoclonal antibody (PPMX-T003) has a unique epitope on the ligand-binding domain of TfR1. This antibody can efficiently inhibit iron influx into cells compared to previously reported antibodies. PPMX-T003 can inhibit growth of erythroblasts and various cancer cell lines at subnanomolar level; both cells express high levels of TfR1. PPMX-T003 administered to normal cells expressing TfR1 at low levels had little effect. Prior to this study, safety profiles were evaluated at a low dose of P1a study in healthy volunteers (HV) (Ogama et al., Clin Pharmacol Drug Dev. 2023;12:579-587). In this study, we aimed to determine safety profiles at higher doses in patients with polycythemia vera (PV) and erythrocythemia by inhibiting elevation of erythropoiesis, followed by P1a study. Except for an antibody drug conjugate (CX-2029), this is the first-in-class trial of an unmodified human antibody other than a P1a trial using a murine antibody conducted in the 1990s. Methods: This was a multicenter, open-label, intra-patient dose escalation study (NCT05074550). Eligible patients were adult patients diagnosed with PV who received periodic phlebotomy (PLB) for 4 to 9 weeks. Due to the extremely small number of eligible patients after the start of the trial on PLB alone in Japan, patients with JAK2 mutation-negative erythrocythemia were included for safety confirmation. Patients who received cytoreductive therapy were excluded from this study. The primary objective of this study was to assess its safety and pharmacokinetics. The secondary objectives were to identify variations in pharmacodynamic and iron metabolism parameters such as hematocrit, erythrocyte count, hemoglobin, Fe and ferritin. As disease progression varies from patient to patient, an intra-patient dose escalation design was used. The starting dose (0.25 mg/kg) was determined from a previous P1a study in HV (n=40), in which hemoglobin levels fell from normal; PPMX-T003 was administered as a single 1-hour intravenous infusion the day after the scheduled PLB date. The doses were increased (0.25, 0.4, 0.64, and 1 mg/kg) during the next PLB treatment scheduled within 4-9 weeks, depending on the participant's adverse event (AE) profile. If the next PLB dose was not required for > 12 weeks, the patient was considered to have achieved a drug effect on top of the PLB, and was considered to have reached end-of-study (EoS). Results: All six patients completed the final dose, and five reached the EoS without requiring PLB for more than 12 weeks. Three patients did not require PLB immediately after the first single dose (0.25 mg/kg). Two patients required periodic PLB at intervals of 4 to 9 weeks until a 0.65 or 1.0 mg/kg dose of respectively. The remaining patient requested a different treatment regimen at week 7 (day 49) after the 1.0 mg/kg dose and is being followed up for adverse events after the default observation and final results after LPO will be reported. No severe adverse events (SAEs) were observed in any patient. Of the 64 adverse events observed with or without a causal relationship to the administered drug, 47 were causally related to the drug. Among the causally related adverse events, seven occurred in more than two cases, including (i) elevated CRP, (ii) lymphopenia, (iii) fatigue, (iv) low-grade fever, (v) neutrophilia, (vi) infusion-related reaction (IRR), and (vii) temporary serum iron. Six AEs that appeared to be IRR-related recovered within one week. Pharmacokinetic results showed that the half-life of the antibody was 15 hours, which was significantly shorter than that of other antibody therapeutics. Conclusions: No SAEs were observed, with mild side effects comparable to those observed in previous HV studies. PPMX-T003 is rapidly consumed by erythrocytes and BFU-C/CFU-C progenitor cells in bone marrow, which express high levels of TfR1, resulting in a very short half-life of less than one day. Efficacy was noted in overall erythrocyte parameters, such as hematocrit and hemoglobin levels, and when effective, a tendency toward microcytic anemia was observed. The clinical effect of PPMX-T003 on human erythroid production is expected to offer an alternative to PLB treatment for patients with PV or erythrocythemia. In the future, it will help further develop its potential for a variety of cancer patients.