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BIOLOGICS |
From Centocor Research and Development, Inc, Malvern, Pennsylvania (Dr Bouman-Thio, Dr Miller, Dr Getsy, Dr Bai, Dr Yohrling, Mr Frederick, Mr Marciniak, Ms Jiao, Dr Jang, Dr Davis) and Centre for Human Drug Research, Leiden, The Netherlands (Dr Franson, Dr Cohen, Dr Burggraaf).
Address for reprints: Esther Bouman-Thio, MD, Centocor Research and Development, Inc, 200 Great Valley Parkway, Malvern, PA 19355; e-mail: ethio2{at}its.jnj.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1 g/dL above baseline) was achieved 9 to 10 days after administration, with a maximum effect between 19 and 26 days. Two subjects in the 0.9-mg/kg dose group had elevated Hgb concentrations requiring phlebotomy. In this first-in-human study, CNTO 528 was well tolerated and effective in elevating and maintaining Hgb by at least 1 g/dL following a single intravenous administration, which suggests that an erythropoietin mimetic molecule, such as CNTO 528, may be an effective therapy for patients with anemia.
Key Words: erythropoietin • anemia • antibody
CNTO 528 includes an erythropoietin mimetic peptide (EMP1) and portions of an antibody heavy chain and human IgG1 antibody, including the Fc region.7-9 CNTO 528 binds to EPO receptors and triggers erythropoiesis similar to the native hormone EPO (data on file). Preclinical studies in normal rats showed that single subcutaneous injections of CNTO 528 resulted in a sustained increase in reticulocytes and hemoglobin (Hgb). In addition, CNTO 528 was efficacious in rat models of anemia and in a rat model of pure red cell aplasia.10 In contrast, studies in cynomolgus monkeys showed that a single dose of CNTO 528 resulted in a reticulocyte response without a subsequent rise in Hgb concentration. Instead, a fractionated dosing scheme was required to fully express the pharmacology of CNTO 528 in primates (data on file).
The objectives of this first-in-human study were to assess safety, pharmacokinetics, pharmacodynamics, and immunogenicity of single and fractionated intravenous (IV) doses of CNTO 528 in healthy male subjects.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design and Treatment
This was a phase I, first-in-human, single-center, randomized, single-blind, placebo-controlled study of CNTO 528 in healthy male subjects. CNTO 528 is an EPO MIMETIBODY molecule, produced using conventional recombinant DNA and mammalian cell expression techniques.7 The EPO MIMETIBODY construct, by virtue of the Fc domain, was expected to have a prolonged serum half-life compared with the free peptide. It was also designed to enhance the activity of EMP1 by restricting its conformation to an active, dimeric form while still allowing sufficient flexibility for the molecule to penetrate the cleft between the dimerized EPO receptors. EMP1 has no amino acid sequence homology with EPO and is thus unlikely to induce a cross-reactive immune response against endogenous EPO.8,11
In stage 1, subjects were randomized to receive either a single dose of CNTO 528 (0.03, 0.09, 0.3, or 0.9 mg/kg) or placebo via a 15-minute IV infusion. In stage 2, subjects (excluding subjects enrolled in stage 1) were randomized to receive fractionated IV doses of either 0.09 mg/kg CNTO 528 or placebo on days 1, 3, and 5 (1 dose per day), each via a single 15-minute IV infusion. Stage 2 was initiated after 3 of 6 subjects within a stage 1 dose cohort achieved a meaningful reticulocyte response. A meaningful reticulocyte response was defined as a minimum reticulocyte response of at least 3% (absolute value) after the administration of study agent.12 The starting dose in stage 2 was equal to the dose that resulted in the defined meaningful reticulocyte response in stage 1, fractionated into 3 equal administrations. The pharmacologically effective dose was defined as the dose where 4 of 6 CNTO 528-treated subjects achieved an increase in Hgb 1 g/dL within 28 days. Cohorts were enrolled sequentially unless an interruption rule was met (ie, subjects within a dose cohort achieving a very robust rise in Hgb [defined as 1-g/dL increase in 2 weeks] or an Hgb level 17.8 g/dL requiring phlebotomy). All subjects received daily oral iron supplementation (equivalent to 210 mg of elemental iron) through day 29 (stage 1) or day 50 (stage 2). Participants were monitored at the clinical research facility (Centre for Human Drug Research, Leiden, the Netherlands) for 48 hours after the last administration of study agent.
Safety Assessments
All subjects were observed for 48 hours after the infusion and underwent follow-up observations on days 5, 8, 10, 12, 15, 19, 22, 26, 29, and 84 for stage 1 and on days 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 33, 36, 40, 43, 47, 50, and 89 for stage 2. Safety evaluations were performed for all subjects who received a study infusion (CNTO 528 or placebo) and included a summary of the subjects experiencing adverse events (AEs), clinically noteworthy changes in laboratory parameters, vital signs, and ECG measurements.
Immunogenicity
The development of anti-CNTO 528 antibodies was evaluated in all subjects. In stage 1, serum samples were collected at baseline and on days 15, 29, and 84. In stage 2, serum samples were collected at baseline and on days 19, 29, 50, and 89. Antibodies to CNTO 528 were determined using a validated, quantitative antigen bridging immunoassay. The limit of detection was 240 to 1120 ng/mL, the false-positive rate was 5.15%, and the assay was tolerant of up to 100 ng/mL CNTO 528. Samples with detectable antibodies to CNTO 528 were classified as positive regardless of the presence or absence of detectable CNTO 528 in the sample. For the overall immune response status to CNTO 528, subjects were designated as positive when a positive immune response was detected at any time point after CNTO 528 administration.
Pharmacokinetic Assessments
Blood samples for the determination of the serum concentration of CNTO 528 were collected at various time points, up to day 84 and day 89 for stage 1 and stage 2, respectively. CNTO 528 serum concentrations were determined using a validated electrochemiluminescent immunoassay that used a monoclonal antibody specific for EMP1 and a monoclonal antibody specific for human Fc. The lower limit of quantification (LLOQ) was 0.08 µg/mL, the mean accuracy was 103.97%, the intra-assay precision was 5.22%, and the interassay precision was 18.62%. Pharmacokinetic parameters, including maximum observed concentration (Cmax), area under the concentration versus time curve (AUC), AUC from time 0 to the last collected and/or measurable concentration (AUC0-tz), half-life (t1/2), clearance (CL), and volume of distribution (Vz), were estimated for each individual using the WinNonlin pharmacokinetic program (Version 4.0.1, Pharsight Corporation, Mountain View, California).
Pharmacodynamic Assessments
Blood samples for the determination of the pharmacodynamic markers were collected at various time points up to day 29 and day 50 for stage 1 and stage 2, respectively. The following pharmacodynamic assessments were performed: reticulocyte count and Hgb, ferritin, soluble transferrin receptor (sTfR), and EPO concentrations. Additional measurements of reticulocytes, Hgb, and ferritin were performed at later time points at the discretion of the investigator. Assays to assess sTfR and EPO serum concentrations were performed according to the manufacturer's protocol (R&D Systems, catalog numbers DTFR1 and DEP00, respectively). Percent changes in pharmacodynamic measurements from baseline were summarized for each dose cohort. In addition, the AUCT (area under the response [minus the predose baseline value] vs time curve from time 0 to some specified time after dosing) for reticulocyte response and Hgb, sTfR, and serum ferritin concentrations through day 29 were determined for each dose cohort.
Statistical Analyses
Descriptive statistics were used to summarize the endpoints and baseline characteristics. Summary statistics included the mean, standard deviation (SD), median, and range for continuous variables, as well as frequency and proportion for categorical variables.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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17.8 g/dL) without any accompanying untoward signs and symptoms and had 500 mL of whole blood removed (1 subject on day 17 and 1 subject on day 19). The baseline levels of Hgb of 1 of these 2 subjects were relatively high (16.1 g/dL). These AEs are considered to be extensions of the pharmacological activity of CNTO 528. Due to the increase in Hgb concentration at the 0.9-mg/kg dose level requiring phlebotomy, no further dose progression of CNTO 528 was performed. There were no other clinically significant changes in laboratory, vital signs, or ECG measurements reported. None of the 30 subjects who received CNTO 528 were positive for anti-CNTO 528 antibodies.
Pharmacokinetics
The median serum concentration-time profiles following IV administration of CNTO 528 for stages 1 and 2 are shown in Figure 1. The single-dose profiles (Figure 1A) suggest that for the 0.09-, 0.3-, and 0.9-mg/kg doses, CNTO 528 conforms to a 2-compartment model, with an initial distribution phase that lasts for 2 to 3 days followed by a terminal elimination phase. There were insufficient quantitative data for the 0.03-mg/kg dose to make the same inference. The pharmacokinetic parameters generated from these profiles are summarized in Table II. Both the Cmax and AUC values increased in approximately a dose-proportional manner between the 0.09- and 0.9-mg/kg CNTO 528 dose levels. The CL values, as well as the mean Vz values for the 0.09-, 0.3-, and 0.9-mg/kg dose groups, remained relatively constant. The mean t1/2 for CNTO 528 increased with the dose, with the largest increase occurring between the 0.03- and 0.09-mg/kg doses (from 1.55 to 3.85 days). Between the 0.09- and 0.9-mg/kg dose groups, the increase in the mean t1/2 for CNTO 528 was more gradual, occurring from 3.85 to 7.60 days. For stage 2, the median Cmax and tmax were 2.33 µg/mL and 4.0 days, respectively (Table II). The median Cmax value in the stage 2 dose group was slightly higher than that observed at the single 0.09-mg/kg dose in stage 1. This difference was not unexpected based on the cumulative effects of the fractionated dosing scheme in stage 2. The total median AUC for the 3 x 0.09-mg/kg cohort (10.72 µg·day/mL) was comparable to that observed with a single dose of 0.3 mg/kg in stage 1 (12.24 µg·day/mL), after adjusting for the 11% higher dose given in stage 1. The remaining pharmacokinetic parameters, CL, Vz, and terminal t1/2, for the 3 x 0.09-mg/kg cohort in stage 2 were comparable to those observed for the 0.3-mg/kg cohort in stage 1.
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1 g/dL above baseline was achieved on day 10 for the 0.3-mg/kg and 0.9-mg/kg groups in stage 1. The maximum effect occurred at day 19 for the 0.3-mg/kg group and at day 26 for the 0.9-mg/kg group. Based on the duration of Hgb response seen in healthy volunteers following a single administration of CNTO 528, a decision was made to amend the protocol for additional hematology measurements (past day 29 for stage 1 and past day 50 for stage 2) to capture the return to baseline values for Hgb (data not shown). These additional observations indicated that in the 0.3-mg/kg dose group, the median Hgb remained 0.16 g/dL (range, –0.6 to 1.6 g/dL) above baseline through days 78 to 80. In the 0.9-mg/kg dose group, the median Hgb remained 2.09 g/dL (range, 0-2.9 g/dL) above baseline through days 58 to 71. Three subjects in the 0.9-mg/kg dose cohort maintained markedly elevated Hgb levels over baseline at day 65 (2.42, 2.09, and 2.90 g/dL; data not shown). The maintenance of elevated Hgb concentrations over a long follow-up period suggests that a single infusion of CNTO 528 resulted in a sustained effect on Hgb.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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17.8 g/dL) without any accompanying untoward signs and symptoms. It is important to note that one of these subjects had a relatively high baseline Hgb level. These subjects had 500 mL of whole blood removed to return Hgb levels to within the normal range. These AEs are considered to be extensions of the pharmacological activity of CNTO 528. No subjects were positive for anti-CNTO 528 antibodies. This safety profile is consistent with that of other erythropoiesis-stimulating agents (ESAs) administered to healthy volunteers.13,14 It was hypothesized that CNTO 528 would have a more prolonged serum t1/2 in humans than that of recombinant human EPO (rHuEPO) (4-13 hours) by virtue of its Fc domain.15-17 The study results supported this hypothesis with an observed mean terminal t1/2 ranging from 3.85 to 7.60 days after single IV doses of 0.09 to 0.9 mg/kg CNTO 528 and 4.47 days after the 3 x 0.09-mg/kg fractionated IV dose regimen. This is the longest terminal t1/2 reported to date for an ESA, including continuous erythropoietin receptor activator (CERA), which has a reported t1/2 of approximately 130 hours (5.5 days) in healthy volunteers.18,19 The relatively short t1/2 (1.55 days) that was observed with the lowest single dose of CNTO 528 (0.03 mg/kg) was attributed to the lack of quantifiable concentrations that could be measured beyond 2 days postdosing. Therefore, the actual t1/2 measured represented the initial distribution phase seen at the higher doses, rather than the elimination phase. The data, however, do not rule out the possible presence of a process involved in the clearance of CNTO 528 that becomes saturated at higher doses, resulting in a decrease in clearance with increasing doses (ie, nonlinear kinetics). However, the fact that both Cmax and AUC increased in roughly a dose-proportional manner between the 0.09- and 0.9-mg/kg doses suggested that, within this dose range, the pharmacokinetics of CNTO 528 were linear. Such apparent linear pharmacokinetics of CNTO 528 were observed in both stages of this study because the total exposure following the three 0.09-mg/kg doses was nearly the same as that following the single 0.3-mg/kg dose, after correcting for the small difference in the total dose between the 2 dose groups.
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1-g/dL increase of Hgb above baseline was seen as early as 10 days after administration of CNTO 528 (Figure 3A). Of equal interest, the Hgb concentrations remained markedly elevated by 2.09 to 2.90 g/dL over baseline in 3 of the 6 subjects in the 0.9-mg/kg cohort up to 69 days after dosing. The magnitude and duration of the erythropoietic response in Hgb levels after a single administration are remarkable compared with rHuEPO12,20 but have been documented with a pegylated erythropoietin mimetic peptide.13 The mean time-integrated response for the reticulocyte count for the 3 x 0.09-mg fractionated doses of CNTO 528 was higher than that observed following the 0.3-mg/kg single dose (Table III), suggesting that the time-integrated effect of the reticulocyte response with the fractionated dosing scheme is additive to that of a single dose. This is similar to the results observed in animal studies (data on file). In contrast, the maximal increases in Hgb concentrations seen in stage 2 subjects (Figure 3B) were not as dramatic as those seen in stage 1. Caution should be exercised in this interpretation because only one fractionated dose-level scheme was evaluated in this study. However, it also has been described with rHuEPO that the time interval between repeated administrations of rHuEPO has an important influence on its pharmacodynamics. Administration of rHuEPO within an interval of 72 hours was more effective in stimulating erythropoiesis than when administration was given within a 24-hour interval for the same total dose.23,24
The observed decrease in serum ferritin levels following CNTO 528 administration was expected because iron stores are consumed for the production of reticulocytes, resulting in a functional iron deficiency.24-26 For both stages 1 and 2, the time course in the drop and recovery of ferritin levels paralleled the increase and return to baseline in reticulocyte counts (Figure 4A,B). This effect also appeared to be dose-dependent. The recovery toward baseline levels of ferritin at day 29 suggests a restoration of iron stores.20
The transferrin receptor is expressed on most cells and serves as the gatekeeper in regulating cellular uptake of iron from transferrin, a plasma protein that transports iron in circulation. It also has been demonstrated that erythroid progenitor cells shed transferrin receptors during the maturation to erythrocytes.27 Similarly, sTfR serum concentrations are known to correlate with an increase in immature erythroid cells.28 Therefore, the observation of a dose-related increase of sTfR concentration at days 5 to 7 correlates with the erythropoietic stimulation in response to CNTO 528 treatment.
EPO production is associated with certain forms of anemia and is the principal factor regulating RBC proliferation. Serum EPO concentrations are primarily regulated by oxygen availability but also have been found to be modulated through pathways regulating the GATA-2, NF
B, and protein kinase A transcription factors.29-31 The effect of EMP1 on these pathways is unclear, making it difficult to interpret the observed initial increase in serum EPO concentrations 6 hours following a single administration of CNTO 528, followed by a decrease in serum EPO concentrations from days 9 to 29. One hypothesis to explain the early increase in EPO levels following CNTO 528 administration could be a displacement mechanism of EPO from the EPO receptor by CNTO 528. In addition, it appears that the Hgb response-time profile for the 0.9-mg/kg cohort is biphasic. The early rise in the Hgb response from day 1 through day 8 could be the result of the total effect of circulating endogenous EPO and exogenous CNTO 528 on Hgb levels. Perhaps this causes a release of RBCs into circulation from an unidentified compartment, whereas the second Hgb increase, starting around day 8, coincides with the maximum increase in the reticulocyte response (J. J. Perez-Ruixo et al, unpublished data, 2008). Endogenous EPO levels are likely suppressed after day 8 as a result of a normal feedback mechanism, which also has been observed with other ESAs.13,20 It is believed that EPO receptors in the bone marrow are primarily responsible for EPO clearance in humans.32 It is further hypothesized that the decrease in EPO levels is due to an expansion of the erythroid precursor pool in the bone marrow after erythropoiesis stimulation.32 However, because there does not seem to be a deleterious effect of lower serum EPO levels on Hgb or hematocrit values in these subjects, these findings do not appear to have a clinically meaningful impact on the data.
In summary, the results of this first-in-human study demonstrated that CNTO 528 was well tolerated in healthy male subjects who received either single or fractionated IV infusions of CNTO 528. By virtue of the Fc domain, the CNTO 528 fusion protein had a prolonged serum t1/2 compared with that of rHuEPO. Dose-dependent increases in reticulocytes and Hgb were seen with single IV doses of CNTO 528 in the 0.09- to 0.9-mg/kg dose range, and the elevated Hgb levels were maintained through day 65 for several of the subjects in the 0.9-mg/kg group. The results of this study suggest that an EPO mimetic molecule, such as CNTO 528, may be a new effective therapy for anemia, but its benefit/risk profile ought to be studied further in those patient populations.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was funded by Centocor Research and Development, Inc. Authors E B-T, BM, JG, SAB, JY, BF, SM, QJ, HJ, and HD are or were employees of Centocor Research and Development, Inc at the time this study was performed and own stock in Johnson & Johnson, of which Centocor Research and Development, Inc is a wholly owned subsidiary. BM is currently employed by GlaxoSmithKline, SAB is currently employed by Endo Pharmaceuticals, and JG is currently employed by Promedior, Inc.
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REFERENCES |
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  P. Sathyanarayana, E. Houde, D. Marshall, A. Volk, D. Makropoulos, C. Emerson, A. Pradeep, P. J. Bugelski, and D. M. Wojchowski CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools Blood, May 14, 2009; 113(20): 4955 - 4962. [Abstract] [Full Text] [PDF]
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