(SACRAMENTO, Calif.) -- Just months after a pharmaceutical company halted studies of tanezumab, a drug used in reducing pain and improving function in people with moderate-to-severe osteoarthritis of the knee, the results of a small, phase II clinical trial found only a few minor side effects and substantial improvement in patient conditions. The results of the 16-week study are published in the Sept. 30 issue of The New England Journal of Medicine. Other, longer-term studies have indicated that tanezumab may accelerate osteoarthritis, and the company that manufactures the drug has withdrawn it from further study until the U.S. Food and Drug Administration (FDA) reviews the data and determines whether it is safe.
Although many currently available medications -- especially the non-steroidal anti-inflammatory inhibitors (NSAIDS) -- can help alleviate osteoarthritis symptoms, their long-term use can lead to serious problems, including gastrointestinal bleeding, ulcers, kidney dysfunction, heart attacks and strokes. NSAIDs include aspirin, ibuprofen, naproxen and COX-2 inhibitors such as Vioxx and Celebrex.
"The need to find new drugs to treat osteoarthritis is critical," said Nancy E. Lane, professor of internal medicine and director of the UC Davis Center for Healthy Aging, who was a principal investigator and co-lead author of the new study along with Thomas J. Schnitzer of Northwestern Medicine in Chicago. "We really don't have anything that slows its course, and most people with severe disease end up dependent on narcotic analgesics while waiting to have a joint replaced."
Tanezumab is a humanized monoclonal antibody that binds and inhibits nerve growth factor, a small protein that occurs naturally in the body and is important for the growth, maintenance and survival of sympathetic and sensory neurons. The growth factor is found at high levels in inflamed tissues of patients with osteoarthritis. In animal experiments, inhibiting the growth factor seemed to reduce signs of pain and as a result, investigators developed a novel drug to block it.
"The bottom line is this is a very effective drug for relieving pain," said Schnitzer, a rheumatologist and professor of physical medicine and rehabilitation. "Unfortunately, it appears some people go on to have their osteoarthritis progress more quickly. The long-term safety of tanezumab needs to be better understood."
The study, a phase II trial, is typically performed on a few hundred patients and is designed to assess how well a drug works and whether it is safe. Before a drug is marketed, it usually undergoes a Phase III study, which may involve a few thousand patients and compares the new drug to the current best medication for the condition.
Several Phase III trials were under way for tanezumab when reports emerged that a small number of study subjects developed accelerated osteoarthritis in the hips and shoulders. At the request of the FDA, the pharmaceutical company Pfizer withdrew the drug from all ongoing clinical trials in late June of this year.
"I believe that the apparent worsening of certain patients' condition may be due to the fact that tanezumab works so well," said Lane. "People feel so much better that they become more active, putting increased stress on their already badly diseased joints."
Careful identification of appropriate candidates to use the drug is crucial for its safe and appropriate use, she added. "Giving tanezumab to people with the most severe disease is probably not a wise choice.
Increasing the activity level of a patient who already needs a joint replaced may not be in their best interest."
The study randomized 450 patients who experienced knee pain from walking to receive one of various dosages of tanezumab or a placebo, given by injection at the start of the study and then again eight weeks later. The participants regularly rated their pain and other aspects of physical functioning on a scale of 1 to 100. On average over the 16 weeks of the study, walking knee pain was reduced from baseline by up to 62 percent in subjects given tanezumab vs. 22 percent in those taking the placebo. Tanezumab treatment also was found to be superior to placebo in relieving stiffness, improving physical function and helping patients live with the degenerative joint disease.
"The effects of tanezumab were remarkable," said Lane. "People on the drug went from having very limited activity to practically being on the dance floor. No medication available today has such dramatic results."
Side effects of the drug were temporary and considered to be minor. Rates of side effects were 68 percent in the tanezumab group vs. 55 percent of subjects given a placebo, and those given higher doses of tanezumab were more likely to develop side effects than those given lower doses. Patients taking tanezumab most commonly developed headache (9 percent), cold-like symptoms (7 percent) and paresthesias (7 percent). Paresthesias are abnormal sensations, such as a tingling, itchiness, numbness or hypersensitivity. Some patients given tanezumab also experienced diminished deep tendon reflexes, which are tested when a physician taps a patient's knee or ankle with a medical hammer.
Osteoarthritis is the most common joint disorder, affecting more than 20 million people in the United States. Caused by the breakdown and eventual loss of cartilage of the joints, it characteristically causes pain of the hips, knees, hands, feet and spine. The pain tends to worsen in humid weather and is often accompanied by joint swelling and stiffness. While initially pain occurs mainly with movement, the disease may become so advanced that a patient experiences severe pain even at rest.
According to Lane, the reporting of apparent problems with the experimental drug has been exemplary, with transparent communications between the study authors, the FDA and the drug company.
"This is how drug development should be carried out," she said. "As with any potentially great new drug, you expect challenges, but the important thing is to carry out investigations in a responsible and open manner."
Along with Lane and Schnitzer, other study authors were Charles A. Birbara of the University of Massachusetts School of Medicine; Masoud Mokhtarani of Bay Biopharma Development LLC; Hyperion Therapeutics; David L. Shelton of Rinat Neurosciences Corporation (now a subsidiary of Pfizer Inc.); and Mike D. Smith and Mark T. Brown, both of Pfizer Inc.
The research was funded by Rinat Neuroscience Corporation, now a subsidiary of Pfizer Inc. Lane receives consulting fees from Pfizer Inc, Zosano-Pharma, Merck, UCB Pharma and Eli Lily; performs clinical research for Proctor and Gamble, Pfizer and NordicBiosciences/Novartis; and is on the speaker's bureau for Eli Lily, Roche/GSK, Amgen, Novartis, and Genentech.
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