Background CD19+ B cells may play a role in the pathogenesis of SSc. MEDI-551 is a humanized afucosylated IgG1κ monoclonal antibody that binds to CD19 and depletes B cells. Therefore, MEDI-551 may show activity in patients with SSc.
Objectives Safety and tolerability of escalating single IV doses of MEDI-551 in adults with SSc who have moderate skin thickening. PK, PD, immunogenicity, and disease activity are also assessed.
Methods A phase 1, randomized, placebo-controlled study in adults with SSc with moderate skin thickening (modified Rodnan Skin Score [mRSS] ≥2) in an area suitable for repeat biopsy. Subjects received 1 of 5 single IV doses of MEDI-551 (0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo (PBO). Cohort 1 (0.1 mg/kg; n=1) received MEDI-551 in an open-label manner; cohort 2 (0.3 mg/kg; n=5) was randomized 4:1 to receive MEDI-551 or PBO; cohorts 3 and 4 (1.0, 3.0 mg/kg; n=7) were randomized 6:1; and cohort 5 (10 mg/kg; n=8) was randomized 7:1. AEs were monitored. Blood was collected for PK, PD, and anti-drug antibodies (ADAs). All subjects were followed until the B-cell count in peripheral blood returned to baseline (BL).
Results All subjects (MEDI-551 n=24; PBO n=4) completed primary follow up period (Day 85) of the study; there were no discontinuations for any reason. Most subjects were white (86%) and female (68%); median age 48.5y and median disease duration 4.65y from first non-Raynaud's symptoms. 86% subjects had diffuse cutaneous SSc; median mRSS was 22 (range 9–43). Follow-up is ongoing. As of 31Dec13, median duration in study ranged from 401d–1364d for MEDI-551 subjects and was 622d for PBO. Related AEs occurred only with MEDI-551; most were single events except infusion-related reaction (n=4; only observed in subjects without pre-medication) and cough (n=2). No serious AEs occurred in the PBO group. 15 SAEs occurred in 6 subjects in the MEDI-551 group; 2 (supraventricular tachycardia, subclavian vein thrombosis) were considered possibly related to MEDI-551. 1 subject in the 3.0 mg/kg group died due to worsening of scleroderma renal disease (not considered MEDI-551 related). PK was nonlinear after MEDI-551 administration (0.1–10.0 mg/kg). The t1/2 were similar (11.2–13.5d) for doses ≥1.0 and shorter for doses <1.0 mg/kg (6.8–7.1d). ADAs were detected in 4 subjects who received MEDI-551; all had reduced serum MEDI-551 levels compared to those without ADAs in the same dose group. Following MEDI-551 infusion, B-cell counts were depleted ∼90% from BL in all dose groups by Day 57. B-cell depletion was maintained for ≥6mos in 1 (17%) subject in the 1.0 mg/kg group, 3 (50%) in the 3.0 mg/kg group, and 6 (86%) in the 10 mg/kg group. Median mRSS decreased from BL (-5; range -14 to 2) with MEDI-551 by Day 85 but increased with PBO (2.5; range -4 to 8) suggesting clinical activity on skin thickness by MEDI-551.
Conclusions The safety profile of MEDI-551 at single IV doses ranging from 0.1 to 10.0 mg/kg supports further clinical development. Rapid sustained B-cell depletion was observed following single IV infusion with 3.0 and 10.0 mg/kg MEDI-551. Clinical activity was suggested by decreased mRSS with MEDI-551.
Acknowledgements This study was sponsored by MedImmune.
Disclosure of Interest E. Schiopu Grant/research support: Actelion, InterMune, MedImmune, Pfizer, United Therapeutics, Consultant for: Sobi, Inc., Paid instructor for: United Therapeutics, Speakers bureau: United Therapeutics, Actelion, S. Chatterjee Grant/research support: MedImmune, V. Hsu Grant/research support: MedImmune, A. Flor Shareholder of: AstraZeneca, Employee of: MedImmune, D. Pavlovic Shareholder of: AstraZeneca, Employee of: MedImmune, K. Patra Shareholder of: AstraZeneca, Employee of: MedImmune, J. Li Shareholder of: AstraZeneca, Employee of: MedImmune, K. McKeever Shareholder of: AstraZeneca, Employee of: MedImmune, R. Herbst Shareholder of: AstraZeneca, Employee of: MedImmune