A new class of pain relievers that targets musculoskeletal pain receptors, instead of more general pain pathways, could alleviate osteoarthritis pain better than any drug now on the market, but hurdles remain before it’s approved by the U.S. Food and Drug Administration. Research on the new therapy was published yesterday in the New England Journal of Medicine.
Osteoarthritis occurs when joint cartilage wears down, with the worst cases requiring joint replacement surgery. The pain can be unrelenting, and there’s no real cure. Patients often get through the day by relying on pain relievers, typically starting with over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. As the pain intensifies and people become inured to the drugs’ effects, they gradually work their way up to opioids such as oxycodone.
The new treatment, called tanezumab, acts on a completely different pathway. While NSAIDs inhibit an enzyme that produces inflammation, and opioids target specific receptors in the central nervous system, tanezumab homes in on musculoskeletal pain receptors. This approach promises fewer side effects, such as internal bleeding, liver damage, and the danger of addiction, which can accompany the alternatives.
Tanezumab, which was developed by Pfizer, is the first in a new class of pain relievers that inhibit sensory neurons, preventing them from transmitting pain signals to the brain. In a clinical trial to assess the intravenous medicine’s efficacy, patients on tanezumab experienced as much as a 62 percent reduction in pain–as much as 40 percent better than the placebo.
“Nothing out there works like this–this is a game-changing molecule,” says Nancy Lane, director of the Center for Healthy Aging at the University of California, Davis, and the study’s lead researcher. NSAIDs and opiates show about half the efficacy of tanezumab (although the current study only compared different tanezumab doses to a placebo rather than to currently available medications). Still, Lane says, “The efficacy was beyond belief.”
Tanezumab works by preventing a protein called nerve growth factor from attaching to sensory neurons, thereby stopping the neurons from transmitting pain signals to the brain. It’s a pathway specifically related to muscle and bone pain, and therefore provides an opportunity for targeted pain relief.
“This really represents a new class of drugs, and it’s been many decades since we’ve introduced a new class of agents for treating osteoarthritis,” says Patrick Mantyh, a professor of pharmacology at the University of Arizona. “It’s an outstanding paper, very thorough, and a beautiful case of coming up with a really novel approach for treating pain and showing a clinically significant result.”
The Centers for Disease Control and Prevention conservatively estimates that about 27 million people in the U.S. suffer from osteoarthritis–a number that represents a huge opportunity for any company that can improve upon existing pain relief. At least four American pharmaceutical companies have therapies in development that inhibit either nerve growth factor or the receptor to which it binds; all are intensely watching Pfizer’s progress.
The study’s results come with a word of caution. Lane and her colleagues completed the trial in 2007. In the years since, Pfizer started a number of phase II and III trials, but has since been ordered by the FDA to suspend them: Ensuing osteoarthritis trials caused a small number of participants to experience so much tissue degeneration that they required joint replacement surgery, and not necessarily on the joint they were undergoing treatment for.
More studies need to be done to determine whether the joint damage occurred because tanezumab was somehow affecting bone or because it was just so effective that the subjects were more active than they should have been and didn’t feel pain to warn them of serious injury. Lane believes it’s the latter. “It works so well that people are going to need to be counseled. Just because they don’t feel pain doesn’t mean their disease is gone,” she says. “Pain is good; it keeps us from doing too much. And this medication is very good, so good that it allows people to do more than they should.”
Getting pain relievers approved by the FDA has always been difficult, since there are so many drugs with a proven safety record and relatively good efficacy already commercially available. In the post-Vioxx era (the drug was approved then taken off the market after it was shown to increase risk of stroke and heart attack), the FDA sets the bar even higher.
Even if it turns out that tanezumab is acting on bone and doesn’t make it through the approval process, Mantyh says, the research is no less important: It proves nerve growth factor has an important role in driving skeletal pain and is thus a good target for pain relief. “In the end, if the drug doesn’t get approved for whatever reason, they have provided clinical data to show that [nerve growth factor] is a major player in driving the pain of osteoarthritis.”
Kevin Koch, the chief scientific officer and president of Boulder, Colorado-based Array Biopharma, says Pfizer should be congratulated on moving this aggressively. “Being the first is always the hardest,” he says. Array is working on its own type of nerve-growth-factor inhibitor, an orally administered version that lasts only 12 hours, rather than eight weeks. So he’s particularly interested in the outcome of tanezumab trials and the FDA’s approval process. “This is a very exciting mechanism,” Koch says. “This is by far the most effective new pain therapy I’ve seen.”