Treating Pain from Osteoarthritis of the Knee with Tanezumab

Healthcare professionals are increasingly recognizing the potential role of nerve growth factor in pain modification through nociceptor sensitization. Increased nerve growth factor is found in tissues of patients with arthritis, pancreatitis, and prostatitis, and according to researchers, levels of nerve growth factor are elevated in animal models of inflammatory pain. Pharmacologic inhibition of the activity of nerve growth factor in the animal models reduces or blocks signs of pain. Patients with painful osteoarthritis of the knee have few treatment options; nonsteroidal antiinflammatory drugs and narcotic analgesics, often used in treatment of knee pain, have gastrointestinal and cardiorenal side effects, and efficacy in some patients is substandard. Analgesic medications with acceptable side effect profiles may help to avoid or delay surgical intervention in patients with osteoarthritis of the knee. Researchers recently conducted a proof-ofconcept study to investigate the safety and analgesic efficacy of tanezumab, a humanized immunoglobulin G2 monoclonal antibody directed against nerve growth factor that blocks the interaction of nerve growth factor with its receptors, TrkA and p75. They reported study results in the New England Journal of Medicine [2010;363(16):1521-1531]. The study cohort included 450 patients with osteoarthritis of the knee who had not had a satisfactory response to nonopiate pain medications or who were considered candidates for invasive intervention. On day 1 of the study, the patients were randomly assigned to receive tanezumab, administered at a dose of 10, 25, 50, 100, or 200 mcg per kilogram of body weight or placebo on days 1 and 56. The main efficacy measures of the study were knee pain while walking and a self-assessment of response to therapy by the patient. The researchers also assessed pain, stiffness, and physical functioning using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); the rate of response using the criteria of the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI); and safety. Tanezumab, at all doses, was associated with an improvement in the primary efficacy measures, as compared with placebo. When averaged over weeks 1 through 16, the mean reduction from baseline in the score on the visual analog scale for knee pain while walking ranged from 31.0 to 45.2 with various doses of tanezumab, compared with 15.5 points with placebo. This translated to a reduction of 45% to 62% with tanezumab versus 22% for placebo, P<.001. The mean increase from baseline in the score on the patients’ global assessment of response to therapy (averaged over weeks 1-16) ranged from 16.3 to 23.7 points with various doses of tanezumab, compared with 9.2 points with placebo. This translated to an increase of 29% to 47% with tanezumab versus 19% with placebo, P≤.001 for comparison of all doses of tanezumab with placebo. Mean reductions from baseline in overall knee pain over the 16 weeks of the study ranged from 43% to 62% with various doses of tanezumab compared with 23% with placebo, P<.001 for comparison of all doses of tanezumab with placebo. Treatment with tanezumab was associated with reductions in the mean WOMAC scores for pain (reductions of 46 to 64% vs 23% with placebo), stiffness (48 to 65% vs 22% with placebo), and physical function (47 to 65% vs 22% with placebo) over the same time period (P<.001 for all comparisons). Percentage of patients who had a response to therapy with tanezumab at various doses, according to OMERACT-OARSI criteria, averaged over weeks 1 through 16, ranged from 74 to 93, compared with 44 with placebo, P<.001 for comparison of all doses of tanezumab with placebo. In the group treated with tanezumab, the rate of adverse events was 68%, compared with 55% in the placebo group. The most common events in the tanezumab group were mild to moderate and included headache (9%), upper respiratory infections (7%), and paresthesia (7%).