POS0268 INTRAVENOUS TOCILIZUMAB FOR THE TREATMENT OF GIANT CELL ARTERITIS: A PHASE IB DOSE-RANGING PHARMACOKINETIC BRIDGING STUDY

Abstract

BackgroundSubcutaneous (SC) tocilizumab (TCZ), a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody, is approved globally for the treatment of giant cell arteritis (GCA), with once weekly injections, based on the GiACTA trial.ObjectivesThis Phase Ib study (NCT03923738) investigated the pharmacokinetics (PK), pharmacodynamics (PD), safety and exploratory efficacy of 2 doses of TCZ given intravenously (IV) in patients with GCA. The purpose was to explore an IV dose resulting in a minimum exposure level within the range of effective trough concentrations achieved with TCZ SC dosing in GCA and not exceeding the exposure of the well-tolerated 8 mg/kg IV every 4 weeks (Q4W) in rheumatoid arthritis (RA).MethodsThis study enrolled patients with GCA in Switzerland who had received ≥5 consecutive doses of TCZ IV 8 mg/kg (off label) Q4W and were in remission. Patients received 5 or 6 doses of TCZ IV 7 mg/kg Q4W in period 1 and, if still in remission, then received 5 or 6 doses of 6 mg/kg Q4W in period 2. Glucocorticoid use was at the investigator’s discretion. PK endpoints were maximum concentration (Cmax), minimum (trough) concentration (Ctrough), area under the curve (AUCτ) over a dosing interval (τ) and average concentration (Cmean) calculated as AUCτ/τ of TCZ after the last dose of each period. Other endpoints included PD markers (IL-6, soluble IL-6R [sIL-6R], C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]), safety (adverse events [AEs], serious AEs [SAEs]) and exploratory efficacy (rates of flare and remission).ResultsIn 24 patients enrolled, median (range) age was 65.5 (57-90) years and the majority were female (62.5%). All patients had a history of elevated ESR and/or CRP and evidence of GCA by temporal artery biopsy and/or evidence of large vessel vasculitis at GCA diagnosis. The mean PK profile following TCZ IV 7 mg/kg Q4W in Period 1 was of a similar shape to mean PK profile following TCZ IV 6 mg/kg Q4W in Period 2, with a slightly lower exposure at the 6-mg/kg dose level (Figure 1). Compared with the 7-mg/kg dose, TCZ exposures (Cmax and AUCτ) were on average 11.2% and 20.0% lower at the 6-mg/kg dose (Table 1). Mean IL-6 serum concentrations were elevated at baseline due to previous TCZ treatment and remained elevated throughout the study, with slightly higher concentrations in Period 1 (7 mg/kg) than Period 2 (6 mg/kg). Mean sIL-6R concentrations were elevated at baseline and comparable between the 2 doses at steady state. As expected for patients in remission, CRP levels and most ESRs were within the normal ranges at baseline and throughout the study. Overall, 22 patients (91.7%) had ≥1 AE; infections were the most frequently reported AEs. Two patients (8.3%) experienced a Grade ≥3 AE. The majority of AEs (70.8%) were not TCZ-related. Four patients (16.7%) reported an SAE; 1 (pneumococcal pneumonia) was considered TCZ-related by the investigator and 3 led to treatment interruption. There were no deaths. No patients experienced a GCA flare, and all patients remained in remission throughout the study.Table 1.Steady-State PK Parameters of TCZ IV 7 and 6 mg/kg Q4WPK Parameters, mean, median (range)7 mg/kg IV(Period 1) n=22*6 mg/kg IV(Period 2) n=22Cmax, μg/mL205182197 (118-352)178 (115-320)AUCτ, day•μg/mL215017202130 (1120-4300)1610 (921-3070)Cmean, μg/mL76.961.576.0 (40.1-154)57.5 (32.9-110)Ctrough, μg/mL35.322.737.2 (6.59-69.0)22.7 (3.38-54.5)AUCτ, area under the curve over a dosing interval (τ); Cmax, maximum concentration; Cmean, mean concentration (AUCτ/τ); Ctrough, minimum (trough) concentration; IV, intravenous; PK, pharmacokinetics; Q4W, every 4 weeks; TCZ, tocilizumab.*n=21 for Cmax.ConclusionBoth dose levels of TCZ-IV (6 and 7 mg/kg) Q4W were generally well tolerated in patients with GCA. The Cmax and Cmean achieved with 6 mg/kg IV Q4W in patients with GCA were similar to those seen in patients with RA treated with 8 mg/kg IV Q4W, and Ctrough was within the range observed in patients with GCA treated with once weekly and every 2 weeks SC dosing.AcknowledgementsThis study was sponsored by F. Hoffmann-La Roche Ltd. Third party medical writing assistance, under the direction of the authors, was provided by Health Interactions, Inc, and was funded by F. Hoffmann-La Roche Ltd.Disclosure of InterestsChristophe Schmitt Shareholder of: F. Hoffmann-La Roche Ltd, Employee of: F. Hoffmann-La Roche Ltd, Laura Brockwell Employee of: F. Hoffmann-La Roche Ltd, Mylène Giraudon Employee of: F. Hoffmann-La Roche Ltd, Mauro Zucchetto Employee of: Working for F. Hoffmann-LaRoche Ltd as an employee of Parexel International, Lisa Christ Shareholder of: Gilead Sciences and F. Hoffmann-La Roche Ltd, Consultant of: Bristol-Myers Squibb, Novartis, and Sanofi, Grant/research support from: Gilead Sciences, F. Hoffmann-La Roche Ltd, and Pfizer, Bettina Bannert: None declared, Thomas Daikeler Speakers bureau: Novartis, Consultant of: Advisory fees from Novartis, Grant/research support from: Research support from Novartis, Peter Villiger Speakers bureau: Roche, MSD, AbbVie, Pfizer, Novartis, Grünenthal, Amgen, Sanofi, Chugai, BMS, and Gilead, Consultant of: Advisory fees from Roche, MSD, AbbVie, Pfizer, Novartis, Grünenthal, Amgen, Sanofi, Chugai, BMS, and Gilead, Grant/research support from: Research support from Roche, MSD, AbbVie, and Pfizer