Safety, Pharmacokinetics, and Activity of Pateclizumab
Safety, Pharmacokinetics, and Activity of Pateclizumab
We designed this randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary evidence of biologic activity of pateclizumab in patients with RA. Study participants were recruited from 26 centers in the United States and Hungary. The institutional review boards at each study site approved the protocol, and all subjects provided their written informed consent. The trial was registered under US National Institutes of Health ClinicalTrials.gov identifier NCT00888745.
Patients 18 to 75 years of age with a diagnosis of RA according to the American College of Rheumatology (ACR) 1987 revised criteria for RA for at least 6 months were eligible for inclusion. Prior to randomization, patients must have been maintained on a stable disease-modifying antirheumatic drug (DMARD) regimen. Methotrexate up to 25 mg/week for 4 weeks, leflunomide up to 20 mg/day for 8 weeks, sulfasalazine up to 3 g/day for 6 weeks, hydroxychloroquine up to 400 mg/day for 8 weeks, or oral prednisone (or its equivalent) up to 10 mg/day at a stable dose for 4 weeks, were permitted.
Patients enrolled in the single ascending dose (SAD) stage had RA and were being treated with a stable DMARD regimen without prespecified disease activity. Patients enrolled in the multiple ascending dose (MAD) stage were being treated with a stable DMARD regimen, had received previous treatment with no more than one biologic agent and were also required to have moderate RA disease as defined by a swollen joint count (SJC) ≥ 5 (of 66), a tender joint count (TJC) ≥ 5 (of 68), and C-reactive protein (CRP) ≥ 1.0 mg/dl.
In the SAD phase of the study, 30 patients (n = 5/cohort) were enrolled sequentially into six cohorts of five patients each (treatment allocation 4:1 pateclizumab:placebo) with four intravenous (IV) dose levels (0.3, 1.0, 3.0, and 5.0 mg/kg with 1-hour IV infusion; cohorts A, B, D and F, respectively) and two subcutaneous (SC) dose levels (1.0 and 3.0 mg/kg; cohorts C and E) (Table 1). Patients were enrolled into the next dose cohort 14 days after administration of the study drug from the last patient in the previous dose cohort. All patients in the SAD phase were followed for 12 weeks after the last dose of the study drug, with follow-up visits at Weeks 2, 4, 6, 8, and 12.
In the MAD phase of the study, 35 patients were enrolled sequentially into three cohorts with the same treatment allocation of 4:1 active:placebo (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; and 5.0 mg/kg 1-hour IV infusion, n = 5; cohorts G, H, and I, respectively). Prior to enrollment of the MAD dose cohorts, all available safety data were reviewed for all patients from the SAD phase of the study through at least 14 days of follow-up. Patients in the MAD cohorts received three doses of the study drug at 2-week intervals (0, 2, and 4 weeks). To enable detection of early clinical activity, 20 patients were enrolled in the target dose cohort 3.0 mg/kg SC (16 patients received active drug and 4 received placebo). All patients were followed for 12 weeks after the last dose of the study drug, with follow-up visits at Weeks 6, 8, 10, 12, and 16.
Safety Safety data were collected at each visit and graded according to the National Cancer Institute Common Toxicity Criteria Adverse Event version 3.0 (National Cancer Institute, Frederick, MD, USA).
In the SAD phase of the study, PK serum samples were obtained at predose, 1 hour (IV only) and 4 hours after dosing on study day 1, then on study Days 2, 4, 8, 15, 22, 29, 43, and 57. In the MAD phase of the study, PK serum samples were obtained on Day 1 (predose, 1 hour postdose IV only); Days 4, 8, and 15 (predose, 1 hour after the end of the IV infusion only); Days 18 and 29 (predose 1 and 4 hours after the end of the IV infusion only); and Days 30, 32, 36, 43, 57, 71, and 85. PK samples were analyzed using a validated ELISA with a lower limit of quantification of 100 ng/ml.
For anti-therapeutic antibody measurement, serum samples were collected at Day 1 (predose), 29 (predose), and 57 in the SAD stage. For the MAD stage, samples were collected at Day 1 (predose), 29 (predose), 57, and 85. On the basis of the assay validation data, the measured anti-pateclizumab responses are not likely to be enhanced by soluble LTα cross-reactivity, and the assay is formatted appropriately to reduce drug interference (data not shown).
In the SAD phase of the study, PD serum samples were obtained at screening, Day 1 (predose) and Days 2, 4, 8, 15, 22, 29, 43, and 57. In the MAD phase of the study, serum samples were obtained at screening, Day 1 (predose) and Days 8, 15, 29, 36, 43, 57, 71, and 85. In all cohorts, levels of CXCL13 and total soluble LTα (free and drug bound LTα, which may include all trimeric forms) were assessed by ELISA with lower limits of quantification of 15.6 pg/ml and 100 pg/ml, respectively.
Exploratory analyses were conducted for the MAD stage to evaluate the effect of pateclizumab on the clinical response variables, including ACR20 and ACR50 (20% and 50% improvement, respectively, in tender or SJCs, as well as 20% and 50% improvement, respectively, in three of the other five American College of Rheumatology criteria for RA), Disease Activity Score in 28 joints (DAS28) responses and C-reactive protein (CRP) These analyses were performed at week 6, two weeks after the last dose of study drug.
All patients who received at least one dose of the study drug were included in the safety, PK, and PD analyses. Adverse events (AEs), vital signs, laboratory tests, PK, and evidence of biologic activity were descriptively compared across the various treatment groups with no formal statistical testing.
For disease activity measurements, data were censored for patients who received a new or increased dose of a DMARD or who withdrew from the study. For all patients who received pateclizumab, censored data were imputed as the highest disease activity score in the corresponding cohort at the corresponding time point for active patients (or lowest activity for that patient, whichever was lower). For patients who received placebo, censored data were imputed as the last observation recorded for that patient.
PK was assessed by noncompartmental analysis using WinNonlin Professional version 5.2.1 software (Pharsight, Mountain View, CA, USA). Preliminary population PK modeling was conducted to estimate the bioavailability following SC dosing using all the available SAD and MAD PK data (NONMEM 7.2, ICON Development Solutions, Ellicott City, MD, USA).
Materials and Methods
We designed this randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary evidence of biologic activity of pateclizumab in patients with RA. Study participants were recruited from 26 centers in the United States and Hungary. The institutional review boards at each study site approved the protocol, and all subjects provided their written informed consent. The trial was registered under US National Institutes of Health ClinicalTrials.gov identifier NCT00888745.
Patients
Patients 18 to 75 years of age with a diagnosis of RA according to the American College of Rheumatology (ACR) 1987 revised criteria for RA for at least 6 months were eligible for inclusion. Prior to randomization, patients must have been maintained on a stable disease-modifying antirheumatic drug (DMARD) regimen. Methotrexate up to 25 mg/week for 4 weeks, leflunomide up to 20 mg/day for 8 weeks, sulfasalazine up to 3 g/day for 6 weeks, hydroxychloroquine up to 400 mg/day for 8 weeks, or oral prednisone (or its equivalent) up to 10 mg/day at a stable dose for 4 weeks, were permitted.
Patients enrolled in the single ascending dose (SAD) stage had RA and were being treated with a stable DMARD regimen without prespecified disease activity. Patients enrolled in the multiple ascending dose (MAD) stage were being treated with a stable DMARD regimen, had received previous treatment with no more than one biologic agent and were also required to have moderate RA disease as defined by a swollen joint count (SJC) ≥ 5 (of 66), a tender joint count (TJC) ≥ 5 (of 68), and C-reactive protein (CRP) ≥ 1.0 mg/dl.
Study Design
In the SAD phase of the study, 30 patients (n = 5/cohort) were enrolled sequentially into six cohorts of five patients each (treatment allocation 4:1 pateclizumab:placebo) with four intravenous (IV) dose levels (0.3, 1.0, 3.0, and 5.0 mg/kg with 1-hour IV infusion; cohorts A, B, D and F, respectively) and two subcutaneous (SC) dose levels (1.0 and 3.0 mg/kg; cohorts C and E) (Table 1). Patients were enrolled into the next dose cohort 14 days after administration of the study drug from the last patient in the previous dose cohort. All patients in the SAD phase were followed for 12 weeks after the last dose of the study drug, with follow-up visits at Weeks 2, 4, 6, 8, and 12.
In the MAD phase of the study, 35 patients were enrolled sequentially into three cohorts with the same treatment allocation of 4:1 active:placebo (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; and 5.0 mg/kg 1-hour IV infusion, n = 5; cohorts G, H, and I, respectively). Prior to enrollment of the MAD dose cohorts, all available safety data were reviewed for all patients from the SAD phase of the study through at least 14 days of follow-up. Patients in the MAD cohorts received three doses of the study drug at 2-week intervals (0, 2, and 4 weeks). To enable detection of early clinical activity, 20 patients were enrolled in the target dose cohort 3.0 mg/kg SC (16 patients received active drug and 4 received placebo). All patients were followed for 12 weeks after the last dose of the study drug, with follow-up visits at Weeks 6, 8, 10, 12, and 16.
Assessments
Safety Safety data were collected at each visit and graded according to the National Cancer Institute Common Toxicity Criteria Adverse Event version 3.0 (National Cancer Institute, Frederick, MD, USA).
Pharmacokinetic Assessments
In the SAD phase of the study, PK serum samples were obtained at predose, 1 hour (IV only) and 4 hours after dosing on study day 1, then on study Days 2, 4, 8, 15, 22, 29, 43, and 57. In the MAD phase of the study, PK serum samples were obtained on Day 1 (predose, 1 hour postdose IV only); Days 4, 8, and 15 (predose, 1 hour after the end of the IV infusion only); Days 18 and 29 (predose 1 and 4 hours after the end of the IV infusion only); and Days 30, 32, 36, 43, 57, 71, and 85. PK samples were analyzed using a validated ELISA with a lower limit of quantification of 100 ng/ml.
For anti-therapeutic antibody measurement, serum samples were collected at Day 1 (predose), 29 (predose), and 57 in the SAD stage. For the MAD stage, samples were collected at Day 1 (predose), 29 (predose), 57, and 85. On the basis of the assay validation data, the measured anti-pateclizumab responses are not likely to be enhanced by soluble LTα cross-reactivity, and the assay is formatted appropriately to reduce drug interference (data not shown).
Pharmacodynamic Biomarker Assessments
In the SAD phase of the study, PD serum samples were obtained at screening, Day 1 (predose) and Days 2, 4, 8, 15, 22, 29, 43, and 57. In the MAD phase of the study, serum samples were obtained at screening, Day 1 (predose) and Days 8, 15, 29, 36, 43, 57, 71, and 85. In all cohorts, levels of CXCL13 and total soluble LTα (free and drug bound LTα, which may include all trimeric forms) were assessed by ELISA with lower limits of quantification of 15.6 pg/ml and 100 pg/ml, respectively.
Clinical Activity Assessments
Exploratory analyses were conducted for the MAD stage to evaluate the effect of pateclizumab on the clinical response variables, including ACR20 and ACR50 (20% and 50% improvement, respectively, in tender or SJCs, as well as 20% and 50% improvement, respectively, in three of the other five American College of Rheumatology criteria for RA), Disease Activity Score in 28 joints (DAS28) responses and C-reactive protein (CRP) These analyses were performed at week 6, two weeks after the last dose of study drug.
Statistical Analysis
All patients who received at least one dose of the study drug were included in the safety, PK, and PD analyses. Adverse events (AEs), vital signs, laboratory tests, PK, and evidence of biologic activity were descriptively compared across the various treatment groups with no formal statistical testing.
For disease activity measurements, data were censored for patients who received a new or increased dose of a DMARD or who withdrew from the study. For all patients who received pateclizumab, censored data were imputed as the highest disease activity score in the corresponding cohort at the corresponding time point for active patients (or lowest activity for that patient, whichever was lower). For patients who received placebo, censored data were imputed as the last observation recorded for that patient.
PK was assessed by noncompartmental analysis using WinNonlin Professional version 5.2.1 software (Pharsight, Mountain View, CA, USA). Preliminary population PK modeling was conducted to estimate the bioavailability following SC dosing using all the available SAD and MAD PK data (NONMEM 7.2, ICON Development Solutions, Ellicott City, MD, USA).
Source...