Bindu Murthy

Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis

Objectives To evaluate maintenance of response while reducing intravenous abatacept dose from ∼10 mg/kg to ∼5 mg/kg in patients with early rheumatoid arthritis (RA) who achieved disease activity score (DAS)28 (erythrocyte sedimentation rate, ESR) <2.6. Methods This 1-year, multinational, randomised, double-blind substudy evaluated the efficacy and safety of ∼10 mg/kg and ∼5 mg/kg abatacept in patients with early RA with poor prognosis who had reached DAS28 (ESR) <2.6 at year 2 of the AGREE study. The primary outcome was time to disease relapse (defined as additional disease-modifying antirheumatic drugs, ≥2 courses high-dose steroids, return to open-label abatacept ∼10 mg/kg, or DAS28 (C reactive protein) ≥3.2 at two consecutive visits). Results 108 patients were randomised (∼10 mg/kg, n=58; ∼5 mg/kg, n=50). Three and five patients, respectively, discontinued, and four per group returned to open-label abatacept. Relapse over time and the proportion of patients relapsing were similar in both groups (31% (∼10 mg/kg) vs 34% (∼5 mg/kg); HR: 0.87 (95% CI 0.45 to 1.69)). Mean steady-state trough serum concentration for the ∼10 mg/kg group was 20.3–24.1 µg/mL, compared with 8.8–12.0 µg/mL for the ∼5 mg/kg group. Conclusions This exploratory study suggests that abatacept dose reduction may be an option in patients with poor prognosis early RA who achieve DAS28 (ESR) <2.6 after ≥1 year on abatacept (∼10 mg/kg). Trial registration number NCT00989235.

Pharmacokinetic, Pharmacodynamic, and Safety Profile of a Novel Anti‐CD28 Domain Antibody Antagonist in Healthy Subjects

We report pharmacokinetics, pharmacodynamics, and safety of a novel anti‐CD28 domain antibody antagonist (lulizumab pegol) in healthy subjects following single‐ or multiple‐dose administration. A minimal anticipated biological effect level approach was used to select a 0.01 mg starting dose for a single‐ascending‐dose (SAD), double‐blind, first‐in‐human study. Part 1 included 9 intravenous (IV; 0.01‐100 mg) and 3 subcutaneous (SC; 9‐50 mg) doses or placebo. In part 2, a keyhole limpet hemocyanin (KLH) immunization was performed in 16 subjects/panel, who received 1 of 3 IV doses (9‐100 mg) or placebo. In a double‐blind, multiple‐ascending‐dose (MAD) study, subjects received SC lulizumab 6.25 mg every 2 weeks, 12.5 mg weekly, 37.5 mg weekly, or placebo. Among 180 treated subjects, 169 completed the studies. Peak concentrations and areas under the curve from time 0 to infinity increased dose proportionally. Estimated SC bioavailability was 68.2%. Receptor occupancy of approximately ≥80% was maintained for ≥2 weeks at ≥9‐mg doses (SAD) and throughout the dosing interval (MAD). IV doses ≥9 mg inhibited antibody production against KLH for 2 weeks. No significant cytokine or immune cell changes were observed. No immunogenicity responses persisted, and there was no correlation to adverse events. Headache occurred in 21 SAD and 4 MAD subjects receiving lulizumab; in the MAD study 5 lulizumab subjects experienced infections. Lulizumab IV or SC was safe at all doses studied, without evidence of cytokine release.

Use of a cocktail probe to assess potential drug interactions with cytochrome P450 after administration of belatacept, a costimulatory immunomodulator

Aim This open‐label study investigated the effect of belatacept on cytokine levels and on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam, as CYP probe substrates after oral administration of the Inje cocktail in healthy volunteers. Methods Twenty‐two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4. Results Since belatacept caused no major alterations to cytokine levels, there were no major effects on CYP‐substrate pharmacokinetics, except for a slight (16–30%) increase in omeprazole exposure, which was probably due to omeprazole‐mediated, time‐dependent CYP inhibition. Belatacept did not cause major alterations in the pharmacokinetics, as measured by the geometric mean ratios and associated 90% confidence interval for area under the plasma concentration ‐time curve from time zero to infinity on Day 7 comparing administration with and without belatacept for caffeine (1.002 [0.914, 1.098]), dextromethorphan (1.031 [0.885, 1.200]), losartan (1.016 [0.938, 1.101)], midazolam (0.968 [0.892, 1.049]) or their respective metabolites. Conclusions Therefore, no dose adjustments of CYP substrates are indicated with belatacept coadministration.

Population Pharmacokinetics and Exposure‐Response Relationship of Intravenous and Subcutaneous Abatacept in Patients With Rheumatoid Arthritis

Abatacept population pharmacokinetics (PK) and exposure‐response (E‐R) models for selective efficacy end points were developed using phase 2 and 3 study data in patients with rheumatoid arthritis treated with abatacept (intravenous [IV] or subcutaneous [SC]), followed by simulations. Two efficacy end points were assessed in the E‐R analyses: Disease Activity Score in 28 joints (DAS28) and American College of Rheumatology response criteria for 20/50/70% improvement (ACR20/50/70). The analyses were performed with data from 11 clinical studies for the population PK analysis and from 3 clinical studies for the E‐R analyses (DAS28 and ACR20/50/70). The PK of abatacept were time invariant and can be described by a linear 2‐compartment model with first‐order elimination and with zero‐order IV infusion or first‐order absorption for SC abatacept. Baseline body weight was the only clinically meaningful covariate; that is, abatacept clearance and volume of central compartment increased with increasing baseline body weight. Steady‐state trough concentration (Cminss) of abatacept was identified as the best exposure predictor of DAS28 response compared with other exposure measures. In addition, the E‐R relationship was the same for IV and SC abatacept. Similar results were confirmed in the ACR20/50/70 E‐R analyses. Efficacy responses increased with increasing Cminss and a near‐maximal response was associated with Cminss ≥10 μg/mL. The model‐based analyses confirmed that the weight‐tiered ∼10 mg/kg IV and fixed 125 mg SC abatacept dosing regimens are comparable and achieved plateau responses, by delivering Cminss ≥10 μg/mL in RA patients across all body weights.

THU0194 A Novel Reversibile Bruton's Tyrosine Kinase (BTK) Inhibitor (BMS-986142) Provides Favorable Safety, Pharmacokinetic, and Pharmacodynamic Profiles in Healthy Subjects

Background BTK is an attractive, novel therapeutic target for autoimmune disease, based on the established mechanistic data via B cell receptor (BCR)-dependent and Fc receptors (FcR)-dependent pathways (Whang et al. Drug Discov Today, 2014;19:1200–4). BMS-986142, a new small molecule reversible inhibitor of BTK, is being developed for the treatment of rheumatoid arthritis (RA) and auto-immune diseases. To support clinical development of BMS-986142, it is important to demonstrate sufficient pharmacodynamic (PD) activity, acceptable pharmacokinetic (PK) profile, and low drug-drug interaction potential with methotrexate (MTX) prior to testing in patients. Objectives Here we present the outcomes from two phase 1 studies investigating safety, tolerability, PK, PD, and its effect on MTX PK following oral administration of BMS-986142 in healthy subjects. Methods In Study 1, healthy volunteers (18–50 y) were randomized to receive single doses of BMS-986142 (5 to 900 mg or placebo) or multiple doses of BMS-986142 (25 to 350 mg or placebo once daily [QD] for 14 days) to assess the safety, tolerability, PK, and PD (as measured by CD69 inhibition). In Study 2, safety and tolerability was assessed in healthy males (18–50 y) receiving single doses of MTX alone (7.5 mg) and in combination with BMS-986142 (350 mg QD) while assessing the effect of BMS-986142 on the PK of MTX. Results BMS-986142 was well tolerated in both studies. In Study 1, a grade 3 SAE (psychosis, 75 mg BMS-986142) not related to study drug was reported in 1 subject; 1 grade 3 AE (blood creatinine phosphokinase elevation, placebo) was also reported. Three drug related grade 1 AEs (headache-SAD, 900mg; back pain-MAD, 200 mg; cough-MAD, placebo) were reported in Study 1. There were no grade 3 AEs reported in Study 2. AEs reported at least twice among all dosing groups are presented in the table. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 hours and gradually eliminated with a half-life of up to 11 hours, enabling QD dosing in the patient studies. BMS-986142 showed linear PK following either a single- or multiple-dose administration. A dose- and concentration-dependent decrease in CD69 expression was observed following the administration of BMS-986142. Daily administration at 350 mg led to near complete coverage above the IC50 for CD69 inhibition throughout the dosing interval without time-dependent changes. BMS-986142 did not affect the PK of MTX, as the peak concentrations and total exposure were comparable when administered with and without BMS-986142 (adjusted geometric mean ratios [90% CI]: Cmax, 1.046 [0.910, 1.202]; AUC(0-T), 1.041 [0.950, 1.139]). Study 1 Study 2 SAD MAD Placebo BMS-986142 Placebo BMS-986142 BMS-986142 n=12 n=36 n=8 n=24 n=12 Subjects with AEs 2 8 4 8 4 Dizziness 0 1 0 0 2 Headache/tension headache 1 5 1 1 2 Nausea 0 1 0 0 2 Diarrhea 0 1 0 1 0 Cough 0 1 1 1 0 Upper respiratory infection 0 2 0 1 0 Thermal burns 0 1 0 1 0 Conclusions BMS-986142 was found to be safe and well tolerated at the doses tested in two phase 1 studies in healthy subjects. It showed favorable PK/PD profile including lack of interaction with MTX and can be safely administered in RA patients that are on background MTX. Overall, BMS-986142 has the potential to show clinical activity in treating autoimmune diseases. Disclosure of Interest S. K. Lee Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, J. Xing Employee of: Bristol-Myers Squibb Company, I. Catlett Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, R. Adamczyk Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, A. Griffies Employee of: Bristol-Myers Squibb Company, A. Liu Employee of: Bristol-Myers Squibb Company, B. Murthy Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, M. Nowak Employee of: Bristol-Myers Squibb Company

FRI0312 Abatacept exposure-response analysis and its impact on dose selection in lupus nephritis

Background Recent post-hoc analyses of patients participating in a trial of abatacept (ABA) vs. placebo, in combination with mycophenolate mofetil and corticosteroids for treatment of active lupus nephritis (IM101075) have provided an evidence-based rationale for choosing among alternative definitions of complete renal response (CRR) used in recent Phase 2/3 clinical trial in lupus nephritis.1 Objectives The objective of this analysis was to characterize the relationship between ABA exposure and CRR using these alternative definitions to guide the dose selection for a follow-on Phase 3 study. Methods In IM101075, patients with biopsy-proven active, proliferative lupus nephritis were randomized to receive placebo (n=100) or one of two intravenous ABA regimens: 30 mg/kg on Days 1, 15, 29 and 57 followed by ~10 mg/kg every 4 weeks (30/10; n=99), or ~10 mg/kg for the entire 12 months (10/10; n=99). Pharmacokinetic (PK) data collected in the study were analyzed by population PK analysis, and were used to determine various summary measures of exposure (Cavg and Cmin over Month 1and 3, Cmin at Month 12 based on clearance observed at Month 1) in each subject. We assessed rates of CRR at 12 months according to 3 sets of criteria, from 1) an ongoing National Institutes of Health trial of ABA (Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study [NCT00774852]), 2) the Aspreva Lupus Management Study trial of mycophenolate mofetil (NCT00377637), and 3) the Lupus Nephritis Assessment with Rituximab (LUNAR) trial of rituximab2. The probability of achieving a CRR at 12 months was described by a logistic regression exposure-response (E-R) model. Age, weight, sex and baseline urine protein creatinine ratio (UPCR) were assessed as covariates in the model. LUNAR criteria were selected for further model evaluation based on largest observed difference (CRR of ~ 6% in placebo group, compared to ~20-24% in ABA group). The final model using CRR (assessed by the LUNAR criteria) was applied to predict efficacy in a proposed Phase III trial. Results The average model-predicted minimum concentration of ABA over the first month (Cmin (1 month)) was a significant predictor of CRR at Month 12. Higher baseline UPCR was also identified as a positive predictor of CRR at Month 12. There was a strong relationship between Cmin (0–1 month) and the probability of achieving CRR in nephrotic (UPCR >339 mg/mmol) and non-nephrotic (UPCR ≤339 mg/mmol) pts. An association was identified between proteinuria and exposure suggesting that ABA is cleared more rapidly in nephrotic subjects and that ABA exposure increased over time in some nephrotic subjects suggesting that reduction in proteinuria may reduce clearance over time. Model evaluation shows reasonable agreement between model-predicted and observed response rates predicting that there may be incremental benefit from induction with 30 mg/kg of ABA for 57 days. This regimen provides the most benefit compared to placebo over time. Conclusions CRR based on LUNAR criteria shows a positive E-R relationship for ABA in the treatment of lupus nephritis and identifies proteinuria as a confounder in dose selection and a target of treatment effect. This supports further evaluation of ABA and dose selection for the treatment of lupus nephritis in an ongoing Phase III study. References Wofsy D, et al. Arthritis Rheum 2012;64:3660–65. Rovin B, et al. Arthritis Rheum 2012;64:1215–26. Disclosure of Interest: S. Suryawanshi Employee of: Bristol-Myers Squibb, M. Tagen Employee of: Bristol-Myers Squibb, B. Murthy Employee of: Bristol-Myers Squibb, J. Hillson Employee of: Bristol-Myers Squibb, A. Roy Employee of: Bristol-Myers Squibb