Despite a rocky past, it looks like the investigational anti-nerve growth factor (anti-NGF) drug class will continue to be developed to treat pain.
In March, an FDA advisory committee voted unanimously (21-0) to move forward with anti-NGF drug trials despite concerns that the drugs caused severe joint-related adverse events. Although it is not required to, the FDA often follows the recommendations of its advisory panels.
Currently no anti-NGF drugs have been approved, but initial data showed promise for this new class of drugs. “By inhibiting NGF, we really get a dramatic reduction in pain in patients who have pretty severe osteoarthritis,” Nancy Lane, MD, director of the Aging Center, Medicine and Rheumatology, at the University of California, Davis, said in a statement.
Dr. Lane has authored several recent studies examining the efficacy of tanezumab (Pfizer), one of the humanized monoclonal anti-NGF antibodies being developed to treat pain. In a proof-of-concept study, Dr. Lane reported that “treatment with tanezumab was associated with a reduction in joint pain and improvement in function, with mild and moderate adverse events, among patients with moderate to severe osteoarthritis of the knee” (N Engl J Med 2010;363:1521-1531).
The trouble began when researchers identified 16 of 6,800 patients who experienced progressively worsening hip and knee damage, including osteonecrosis and avascular necrosis, after receiving tanezumab in Phase III studies; all patients required total joint replacements. These 16 events led the FDA on June 22, 2010, to suspend Phase III clinical trials with tanezumab until more information was available on the effects of the drugs and the causes of these events.
To evaluate the safety of anti-NGF drugs, the FDA formed an advisory committee to review the data; it found that the drugs did appear to cause rapid joint destruction. The FDA presented 355 cases where patients receiving anti-NGF drugs underwent joint replacement surgery. Of those cases, 83 (21%) were rapidly progressing osteoarthritis and 30 (7%) were osteonecrosis.
The researchers also found that, in patients who already had osteoarthritis, joint deterioration was more severe than if their disease had progressed naturally, and that higher doses of anti-NGF drugs as well as the use of nonsteroidal anti-inflammatory drugs were linked to rapidly progressing osteoarthritis and osteonecrosis.
The FDA panelists called for testing anti-NGF drugs in patients with no other options for analgesics, including those with interstitial cystitis and chronic pancreatitis.
There is an “enormous need” for new types of analgesics with novel mechanisms of action, said Bob Rappaport, MD, director of the FDA’s Division of Anesthesia, Analgesia and Addiction Products, Beltsville, Md.
“Based on the assessments of risk and benefit, we conclude that further clinical investigation of tanezumab in osteoarthritis and other forms of chronic pain is warranted with the protection of additional risk management and surveillance measures,” Pfizer said in an FDA briefing document.
Janssen and Regeneron will continue testing the safety and efficacy of their drugs, fulranumab and REGN475, respectively, to treat a variety of chronic painful conditions, including chronic low back pain, diabetic peripheral neuropathy, postherpetic neuralgia, chronic prostatitis, vertebral fractures and cancer pain. The market potential of NGF blockers for pain control/analgesia is projected to be $11 billion.
Despite the panel’s ruling, some researchers disagree that the companies should go ahead with further testing. Michael Carome, MD, deputy director of the Public Citizen Health Research Group, Washington D.C., issued a public comment, urging the panel not to recommend development go forward because the risk–benefit profile of the drugs was unacceptable.
Elaine Tozman, MD, associate professor in the Division of Rheumatology and Immunology at the University of Miami Miller School of Medicine, in Florida, agreed, noting she doesn’t think this new painkiller would add much to the treatment of osteoarthritis. “This is really a drug that is for a symptom of osteoarthritis; it’s really for pain,” she said, in a statement. “As rheumatologists, most of us are looking for a drug that works on the underlying disease.”
Dr. Rappaport said the companies must now present a plan on how to move forward with their studies in a way that minimizes the osteoarthritis risk for patients. Panelists suggested performing radiographic scans of patients before administering the drug and during treatment to monitor bone loss. The companies are also proposing to run trials using the drugs at lower doses and without other pain medications.