Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Dose Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BIIB023 (Anti-TWEAK) in Subjects with Rheumatoid Arthritis.

Wisniacki1,  Nicolas, Chindalore2,  Vishala L., Codding3,  Christine E., Greenwald4,  Maria W., Shaw5,  Marianne L., Fitilev6,  Sergey, Ershova7,  Olga

Biogen Idec, Maidenhead, United Kingdom
Anniston Medical Clinic PC, Anniston, AL
Health Research of Oklahoma, Oklahoma City, OK
Desert Medical Advances, Palm Desert, CA
Duncansville, PA
M. Sechenov Moscow Medical Academy, Moscow, Russia
Clinical Hospital for Emergency Care, Moscow, Russia
Biogen Idec, Cambridge, MA
Biogen Idec Inc, Cambridge, MA

Background/Purpose:

TNF-like weak inducer of apoptosis (TWEAK) and its sole signaling receptor FGF-inducible molecule 14 (Fn14) are highly upregulated locally in the end organ targets of inflammatory and autoimmune diseases. Inhibition of the TWEAK/Fn14 pathway has proved to be efficacious in multiple experimental models of these diseases by reducing inflammatory responses and pathological tissue remodelling. BIIB023 is a humanised anti-TWEAK monoclonal antibody currently in development for the treatment of lupus nephritis.

The objectives of this first in man study were to evaluate the safety, tolerability, PK and immunogenicity of single administration of BIIB023 in subjects with rheumatoid arthritis (RA). Exploratory objectives included the analysis of biomarkers for the assessment of target engagement and pharmacologic effect.

Methods:

This was a multicenter, randomized double-blind, placebo-controlled, dose escalation study in subjects with RA. Fifty three subjects on stable regime of methotrexate received a single intravenous dose of BIIB023 of 0.03 to 20 mg/kg (n=38) or placebo (n=15) and were followed up for 70 days. Safety assessment included adverse events (AEs), serious adverse events (SAE), physical examination and laboratory analysis. Serum samples were collected for PK, immunogenicity and exploratory biomarker assessments.

Results:

Single dose IV administration of BIIB023 demonstrated a favourable safety and tolerability profile with no dose-dependent safety finding observed in any of the dose groups. There were no severe or serious AEs or any subject discontinuation or withdrawal and no difference in infection rate between groups. No notable laboratory or physical exam/ECG findings were observed. The PK profile of BIIB023 revealed a t1/2 of approximately 24 days in the high doses of 10 and 20 mg/kg. A single subject (3%) tested positive for anti-drug antibody.

Serum soluble TWEAK concentrations, an indicator of target engagement, were suppressed to below the level of quantitation at the first timepoint assessed (6 hours after dosing) and returned to baseline levels at 3 to 4 weeks following a single dose of 10 mg/kg or 20 mg/kg BIIB023. Multiplex analysis of biomarkers revealed a trend toward down modulation in MCP-1, ICAM-1, A-SAA, BAFF, E-Selectin, IL-6, and IP-10 in the high dose cohorts (3 to 20 mg/kg) and was consistent with dose dependent activity of BIIB023 upon administration of a single dose.

Conclusion:

Single dose administration of BIIB023 (Anti-TWEAK) showed a favourable safety and tolerability profile in subjects with RA and suppressed serum soluble TWEAK, a biomarker of target engagement, for up to 4 weeks. The PK profile of BIIB023 supports further development in inflammatory and autoimmune diseases and is currently being pursued for the treatment of Lupus Nephritis.

To cite this abstract, please use the following information:
Wisniacki, Nicolas, Chindalore, Vishala L., Codding, Christine E., Greenwald, Maria W., Shaw, Marianne L., Fitilev, Sergey, et al; A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Dose Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BIIB023 (Anti-TWEAK) in Subjects with Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2201
DOI:

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