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FRI0482 Safety and Tolerability of MEDI-551 in Subjects with Systemic Sclerosis (SSC): Results from A Phase 1 Randomized, Placebo-Controlled Escalating Single-Dose Study
  1. E. Schiopu1,
  2. S. Chatterjee2,
  3. V. Hsu3,
  4. A. Flor4,
  5. D. Pavlovic4,
  6. K. Patra4,
  7. J. Li5,
  8. K. McKeever4,
  9. R. Herbst4
  1. 1University of Michigan, Ann Arbor
  2. 2Cleveland Clinic, Cleveland
  3. 3Robert Wood Johnson Medical School Clinical Research Center, New Brunswick
  4. 4MedImmune, Gaithersburg
  5. 5MedImmune, Mountain View, United States

Abstract

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

DOI 10.1136/annrheumdis-2014-eular.5908

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