Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


REGN475/SAR164877, a Nerve Growth Factor Inhibitor, in Osteoarthritis Patients with Moderate to Severe Knee Pain: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled Study.

Tiseo4,  Paul, Kivitz1,  Alan J., Ervin2,  John E., Mellis3,  Scott J., Ren4,  Haobo, Skific4,  Damir, Wu4,  Richard

Altoona Arthritis & Osteo Ctr, Duncansville, PA
Center for Pharmaceutical Res, Kansas City, MO
Regeneron Pharmaceuticals, Inc., Tarrytown, NY
Regeneron Pharmaceuticals, Inc.

Purpose:

To evaluate the safety and efficacy of REGN475/SAR164877 (R/S), a fully human monoclonal antibody with highly selective binding affinity for nerve growth factor (NGF), in the treatment of osteoarthritis (OA) pain.

Methods:

This phase 2, double-blind, placebo-controlled, parallel-group, repeat-dose study enrolled patients aged 40–75 y with physician-confirmed diagnosis of active, moderate to severe OA (ACR criteria + subjective pain + Kellgren-Lawrence G2-G3 radiographic severity). Other eligibility requirements included walking knee pain (WKP) levels >= 4 at baseline [11-pt numerical rating scale (NRS)] and washout of any current pain medications prior to baseline visit (Day 1). Rescue medication with acetaminophen (up to 4g per day; no more than 4 consecutive days) was permitted. Patients (N=217) were randomized to receive intravenous (IV) R/S 0.03, 0.1, or 0.3 mg/kg or IV placebo (Pbo) on Day 1 and Day 57, with a 16-wk follow-up period after the second dose. Safety/tolerability [frequency of treatment emergent adverse events (TEAEs)] was the primary endpoint. Key efficacy variables included change from baseline on WKP and Western Ontario and McMaster Osteoarthritis (WOMAC) Index.

Results:

Baseline characteristics were similar among treatment groups: mean (SD) age 59.3±8.7 yrs; 31.2% male; and 78.1% white. After 24 weeks, the incidence of TEAEs ranged from 66.1–75.0% in the R/S groups vs 63.6% for placebo. The most common TEAEs included headache (R/S range 7.1–7.7% vs Pbo 7.3%), hypoaesthesia (3.8–7.7% vs 0%), musculoskeletal pain (3.6–19.2% vs 5.5%), paraesthesia (0–5.8% vs 5.5%), peripheral edema/joint swelling (3.6–9.6% vs 0–1.8%), and respiratory infections (1.9–8.9% vs 1.8–7.3%). 5.6% of R/S patients and 3.7% of Pbo patients withdrew due to TEAEs; serious TEAEs were infrequent and the incidence was similar between active treatment groups and Pbo. Evidence of treatment effect was reported in the individual R/S dosing groups vs Pbo; results of the key efficacy evaluations are summarized in the table below. At Week 16, a consistent dose-response relationship was demonstrated in the WOMAC pain and function subscales.

Treatment Differences from Baseline at Weeks 8 and 16

Key Efficacy VariablesPlaceboREGN475/SAR164877
 (n = 55)0.03 mg/kg (n = 53)0.1 mg/kg (n = 53)0.3 mg/kg (n = 54)
Walking Knee Pain (NRS)    
Mean Change (SD) from Baseline at Wk 8-2.01 (2.08)-2.8 (2.29)-3.3 (2.61)*-3.6 (2.48)*
Mean Change (SD) from Baseline at Wk 16-2.5 (2.15)-3.4 (2.24)*-3.4 (2.58)*-3.3 (2.55)
WOMAC Pain Score    
Mean Change (SD) from Baseline at Wk 8-1.9 (1.74)-2.6 (2.01)*-3.4 (2.54)*-3.5 (2.42)
Mean Change (SD) from Baseline at Wk 16-2.4 (2.18)-2.7 (1.89)-3.4 (2.53)*-3.2 (2.24)*
WOMAC Function Score    
Mean Change (SD) from Baseline at Wk 8-1.8 (1.95)-2.8 (2.07)*-3.4 (2.32)*-3.4 (2.57)
Mean Change (SD) from Baseline at Wk 16-2.3 (2.30)-2.9 (1.78)-3.4 (2.28)*-3.1 (2.18)*
*P <= 0.05 (difference vs Pbo).

Conclusions:

REGN475/SAR164877 was generally well-tolerated; incidence and type of TEAEs were similar to those previously reported with NGF inhibition. Preliminary data suggest that neurosensory TEAEs were more frequent at higher doses. Efficacy assessments indicate that anti-NGF therapy may be associated with a significant reduction in OA knee pain for up to 8 weeks, with dropouts at the highest dose possibly accounting for the reduced efficacy at 16 weeks.

To cite this abstract, please use the following information:
Tiseo, Paul, Kivitz, Alan J., Ervin, John E., Mellis, Scott J., Ren, Haobo, Skific, Damir, et al; REGN475/SAR164877, a Nerve Growth Factor Inhibitor, in Osteoarthritis Patients with Moderate to Severe Knee Pain: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled Study. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :710
DOI: 10.1002/art.28478

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