Tanezumab, a humanized monoclonal antibody that binds and inhibits nerve growth factor (NGF), was found to be effective in reducing joint pain and improving function in patients with knee osteoarthritis (OA), according to new research.
Nancy E. Lane, MD, from the University of California–Davis Medical School, in Sacramento, and colleagues, reported the findings online today in the New England Journal of Medicine.
Tanezumab May Work "Too Well"
According to Dr. Lane, the blocking of the NGF protein significantly reduces knee pain more than is observed with any other medication. "Tanezumab works so well that patients may need to be warned not to use or overuse their joints...they may forget they have knee OA, and it is important to remember that pain does serve as a reminder to take it easy on joints," Dr. Lane told Medscape Medical News.
As a result of the progressively worsening OA, which occurred in 16 patients out of many hundreds participating in 1 of 13 phase 3 studies for OA of the hip or knee and was associated with radiograpich bone necrosis, the US Food and Drug Administration put the phase 3 study and 2 other studies of tanezumab on hold as of June 22, 2010.
According to the researchers, increased NGF expression is found in inflamed tissues caused by diseases such as arthritis, pancreatitis, and prostatitis. "Pharmacologic inhibition of the activity of nerve growth factor in these models reduces or blocks signs of pain."
Dr. Lane and colleagues conducted a phase 2 proof-of-concept study in 450 patients with moderate to severe OA of the knee. On days 1 and 56, patients received placebo or tanezumab at doses of 10, 25, 50, 100, or 200 μg/kg body weight.
Pain, stiffness, and physical function were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index, as were efficacy measures (knee pain while walking and patient's global assessment of response to therapy). The rate of response was measured using the Outcome Measures in Rheumatoid Arthritis Clinical Trials/Osteoarthritis Research Society International response criteria.
Significant Improvements in Pain and Response Scores
From week 1 to week 16 of treatment, pain reduction averaged from 45% to 62% compared with 22% with placebo (P < .001). Tanezumab was also associated with improved response to therapy, with global assessment score increases of 29% to 47% vs 19% with placebo (P ≤ .001). The rate of response was 74% to 93% vs 44% with placebo (P < .001).
Adverse events associated with tanezumab occurred in 68% of patients compared with 55% for placebo. The most common adverse event in tanezumab-treated patients were headache (9%), upper respiratory tract infection (7%), and paresthesia (7%).
According to Dr. Lane, further studies are needed to understand how long tanezumab remains effective and to find a dose that is efficacious, safe, and tolerable.
"This type of pain medication may be a major step forward in improving the pain and quality of life with individuals with chronic pain from OA and possibly other diseases. The future looks bright," she said.
In a related editorial, John N. Wood, DSc, from the University of London, United Kingdom, notes that the use of neutralizing antibodies to NGF seems to provide an "effective analgesic therapy," but he adds that the "most problematic issue is joint failure...most likely caused by excessive wear and tear in the absence of joint pain," Dr. Wood writes.
"The study by Lane et al. suggests that a complete quenching of pain in patients with [OA] may not necessarily be a good thing," he added.
Mechanism of Joint Deterioration Unclear
Independent commentator Patrick Mantyh, PhD, JD, from the University of Arizona, in Tucson, who researches mechanisms of skeletal pain, noted that NGF is released in response to tissue injury and then binds to receptors called TrkA, expressed by nociceptors, causing pain. "By blocking the NGF, pain can be blocked," he toldMedscape Medical News.
According to Dr. Mantyh, 2 possible explanations for the observation of joint deterioration may be overuse by the patients — the pain relief caused them to use the affected joint more — and anti-NGF having an effect on bone itself (ie, NGF release and TrkA expression may be involved in normal bone maintenance). "I don't think we know what the answer is," he said.
"However, this is a very elegant paper, and really shows that NGF does play a pivotal role in driving [OA] pain. That, in and of itself, I think is a major advance and still a very definitive observation."
The research was supported in part by Pfizer and Rinat Neuroscience, now a subsidiary of Pfizer. The authors report receiving funding and other financial support from Pfizer as well as Annenberg CME Foundation and many other pharmaceutical companies including, but not limited to, Novartis, Roche, Nordic Bioscience, Stryker, Genentech Amgen, and Eli Lilly. Dr. Wood reports receiving consultancy fees from Pfizer, Dr. Mantyh has disclosed no relevant financial relationships.
NEJM. Published online September 29, 2010.
Emma Hitt, PhD • Medscape Medical News © 2010 WebMD, LLC