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.

Takakuwa:Pfizer Japan Inc.: Research Funding; Bristol-Myers Squibb K.K.: Research Funding; Incyte Biosciences Japan GK: Research Funding; GlaxoSmithKline K.K.: Research Funding; Sanofi K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Hino:Kyowa Kirin Co., Ltd: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Labcorp Drug Development: Honoraria; Japan Blood Products Organization: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; PharmaEssentia Corporation: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria, Research Funding; Genmab K.K.: Honoraria; Amgen K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; MOCHIDA PHARMACEUTICAL CO.,LTD.: Honoraria; Novartis: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Nippon Kayaku Co.,Ltd.: Honoraria, Research Funding; Sanofi K.K.: Honoraria; Gilead Sciences, Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Eisai Co., Ltd: Honoraria; argenx Japan K.K.: Honoraria; AbbVie GK: Honoraria; AstraZeneca K.K.: Honoraria; Astellas Pharma Inc.: Honoraria; Asahi Kasei Corporation: Honoraria, Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; TEIJIN PHARMA LIMITED.: Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding; MSD K.K.: Honoraria; Sumitomo Pharma Co., Ltd.: Research Funding. Nakamae:Parexel International Inc.: Honoraria; NIPPON SHINYAKU CO., LTD.: Honoraria; Bristol Myers Squibb Company: Honoraria; AbbVie GK: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; KISSEI PHARMACEUTICAL CO., LTD.: Honoraria; AstraZeneca K.K.: Honoraria; Sanofi K.K.: Honoraria; Incyte Biosciences Japan G.K.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; the Japan Cancer Society: Research Funding; the Japan Society of Hematology: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Cmic Co., Ltd.: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Amgen K.K.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Novartis: Honoraria. Shimoda:Daiichi Sankyo Co Ltd: Research Funding; Eisai Co Ltd: Research Funding; Kyowa Kirin Co Ltd: Research Funding; Mochida Pharmaceutical Co Ltd: Research Funding; Nippon Kayaku Co Ltd: Research Funding; Otsuka Pharmaceutical Co Ltd: Research Funding; PharmaEssentia Japan KK: Research Funding; Shinogi & Co Ltd: Research Funding; Sumitomo Dainippon Pharma Co Ltd: Research Funding; Taisho Pharmaceutical Co: Research Funding; Takeda: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co Ltd: Research Funding; AbbVie GK: Honoraria, Research Funding; Sierra Oncology: Consultancy. Kumagai:Perseus Proteomics inc: Consultancy, Honoraria. Yamamoto:Perseus Proteomics inc: Consultancy, Honoraria. Matsuura:Perseus Proteomics inc: Current Employment, Patents & Royalties: I'm one of inventor of patents for this Ab therapeutics.