FDA Advisory Panel Gives the Green Light to Restart NGF Antibody Trials
An advisory panel of the U.S. Food and Drug Administration (FDA) has voted unanimously that antibodies against nerve growth factor (NGF) should re-enter clinical trials for pain. The 21-person Arthritis Advisory Committee made its recommendation to the FDA in a meeting held yesterday at the FDA’s campus in Silver Spring, Maryland, US.
NGF antibodies showed great promise in Phase 3 trials for osteoarthritis, and in Phase 2 testing for other conditions, but have been sitting on the shelf since 2010, when the FDA suspended almost all trials due to reports of unexplained joint damage. At yesterday’s meeting, the FDA advisors, along with drug makers Pfizer, Janssen Research & Development (part of Johnson & Johnson), and Regeneron, agreed that NGF antibodies are, in fact, associated with joint problems, especially when administered at higher doses and in combination with non-steroidal anti-inflammatory drugs (NSAIDs). They concluded that new restrictions on future trials are needed—but that additional trials are, indeed, warranted.
The Advisory Committee, which included clinicians, researchers, and industry and patient representatives, expressed clear concern about the damage the antibodies did to some patients’ joints. Although the antibodies by themselves did not significantly increase the total number of joint replacements among study subjects, some patients exhibited rare and particularly serious forms of joint damage. Despite those drawbacks, none of the Committee members were ready to close the door on what could be an entirely new, and very effective, class of pain therapeutics.
The Committee evaluated whether NGF antibodies merit continued testing in osteoarthritis and other conditions for which treatments already exist, and separately considered whether the pain relievers deserve study in other, more intractable pain conditions. All panelists agreed on both counts, with the exception of David Blumenthal of Case Western Reserve University and the Cleveland Veterans Affairs Medical Center, US, who voted against the plan to reopen testing beyond the osteoarthritis setting. Importantly, the antibodies may cause damage even in patients whose joints are not already compromised by osteoarthritis, because some cases of unexpected joint damage cropped up in trials for other ailments and in patients without a known history of osteoarthritis. Blumenthal said that patients with osteoarthritis who are already at risk for joint replacement surgery will make the best study subjects for now. But only after learning more about how to mitigate joint damage risk should testing continue beyond this group. “I see this as a two-stage process,” he said during the meeting.
Indeed, one theme that emerged during the discussion was the dearth of information about treatment-related joint damage, and how to design the next round of NGF antibody testing to fill in the gaps. Most notably, clinical reviewers who examined cases of serious joint damage in the trials had difficulty pinning specific diagnoses on the incidents, largely because of spotty imaging and pathology data. So committee members discussed monitoring protocols—imaging joints before patients enter a study, for example—that could help researchers discover the mechanisms and risk factors for treatment-induced joint damage.
Despite all of the questions about the negative effects on joints, one clear finding is that the risk of joint damage rises significantly when patients take NSAIDs and NGF antibodies together. So drug makers and panelists also discussed restricting chronic NSAID use in patients in future trials, though, as with the monitoring protocols, the Committee made no official decision on this matter at the meeting.
Thomas Schnitzer, of Northwestern University Feinberg School of Medicine, Chicago, US, was pleased that researchers will have a chance to track down the cause of the joint problems and explore NGF antibodies’ potential. “This was a vote for responsible research in pain,” he told PRF after the meeting. Schnitzer has led some trials of Pfizer’s NGF antibody, tanezumab, and is a paid consultant for Pfizer who spoke at the Advisory Committee meeting on behalf of the drug makers.
Restrictions on future trials may limit the potential uses of NGF inhibitors in clinical practice, but researchers involved in anti-NGF studies are hopeful, given the outcome of the advisory meeting. “I’m guardedly optimistic,” said Patrick Mantyh, who studies NGF inhibition in preclinical models, and serves as a paid advisor to Pfizer on tanezumab development. Mantyh, from the University of Arizona, Tucson, US, emphasized the importance of investigating the pain-relieving powers of NGF antibodies in a range of painful conditions in people. “We have shown that they work in animals in non-malignant and malignant models of skeletal pain,” he told PRF. “But now the critical issue is to more fully understand their clinical efficacy and side effect profile in patients with specific types of chronic pain.”
Image: X-ray of a knee with osteoarthritis. Credit: James Heilman, MD, Wikimedia Commons.
Correction: The title of this article was changed from the original to reflect that it was an advisory committee, not the FDA, that voted in favor of continuing antibody trials. The FDA often but not always follows the recommendations of its advisory committees.
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