There are no effective treatments to prevent or reverse osteoarthritis (OA), a progressive, degenerative condition where joint cartilage, joint structures, and underlying bone come under attack. Nor are there safe and effective analgesics (pain relievers) for many of the patients with OA who live with chronic, disabling pain. This has led to interest in antibodies that target a molecule called nerve growth factor (NGF) as possible pain medications. Now, the latest clinical trial of anti-NGF therapy for pain sings a similar tune as previous trials, raising the question of what the future of these drugs should look like.
Thomas Schnitzer, Northwestern University Feinberg School of Medicine, Chicago, US, and colleagues show, in a small, randomized clinical trial, that subcutaneous injection (i.e., beneath the skin) of tanezumab significantly improved pain and physical function in OA patients who had not responded previously to standard drug treatments, compared to placebo. And yet, as in previous human studies of anti-NGF antibodies, issues of joint safety cropped up, with those taking tanezumab ultimately requiring more total joint replacements.
After a decade of trials testing tanezumab, the new study should be an important step towards US Food and Drug Administration (FDA) approval of anti-NGF drugs, said William Schmidt, NorthStar Consulting, Davis, US, an expert on drug development who was not involved in the study.
“No doubt, anti-NGF approaches have run into a lot of bumps along the road,” said Schmidt. “But I’m glad new research is going forward because there is a real need for a new chemical entity that can help patients who are desperate for non-NSAID [nonsteroidal anti-inflammatory] drugs to help manage what is a very painful condition. This may not be the first option for treatment, or even the second, but it may offer patients who can’t tolerate NSAIDs or other drugs a way to better manage their pain.”
However, considering the issue of joint safety, the key will be a careful consideration of risk factors for adverse events, according to Jeffrey Katz, Brigham and Women’s Hospital, Boston, US, in an editorial that accompanied the new study.
“For those patients at high risk for total joint replacement-related complications and those with strong preferences to avoid total joint replacement at all costs, tanezumab would not be a wise choice. Patients willing to accept the risk of total joint replacement in exchange for a greater probability of pain reduction than afforded by other available therapies would appear to be acceptable candidates for tanezumab,” wrote Katz.
The trial and editorial were published July 2, 2019, in the Journal of the American Medical Association (JAMA).
Putting tanezumab to the test, once again
An estimated 300 million people across the world have OA; in the US alone, 30 million people suffer from this condition. Historically, OA pain has been treated with NSAIDs, opioids, and other analgesics. But a significant portion of OA patients do not experience sufficient pain relief, cannot tolerate the drugs because of side effects, or cannot take them because of contraindications.
So researchers began a search for alternatives, with anti-NGF therapies receiving a significant amount of attention. NGF is a protein that plays a role in the survival and maintenance of sensory neurons (nerve cells that are activated by sensory input from the environment, including cells involved in pain processing). Tanezumab is an antibody that works by inhibiting the binding of NGF to its receptors (which are proteins embedded in the cell membrane).
In 2010, the FDA suspended the bulk of anti-NGF clinical trials because of consistent reports of joint safety issues. But, by 2012, an advisory panel of the FDA voted in favor of restarting clinical trials of anti-NGF therapies for pain (see related news story on the IASP Pain Research Forum).
Schnitzer, who led the new study, said that while past clinical trials found that tanezumab relieved OA pain, the current trial assessed a new subcutaneous form of the drug.
“Previous studies were done with an IV [intravenous] form of the drug, which demonstrated consistent efficacy in terms of pain relief,” he explained. “We wanted to look at this subcutaneous formulation, which is easier for doctors to administer.”
So Schnitzer and colleagues recruited 696 patients, with an average age of approximately 61 years, who had been diagnosed with moderate to severe OA of the hip or knee. To qualify for the trial, patients had to present with a score of 5 or higher on the 11-point Western Ontario and McMaster Universities Osteoarthritis (WOMAC) subscales for pain (zero equals no pain and 10 is extreme pain), and for physical function (where zero means no difficulty and 10 is extreme difficulty), regarding the joint most affected by OA. WOMAC is a standardized measure commonly used by doctors to evaluate OA patients.
The researchers also needed to see a score of fair, poor, or very poor on a different assessment scale for OA, the patient global assessment of osteoarthritis (PGA-OA). Patients were further required to have a documented history of insufficient pain relief from acetaminophen, or an insufficient response to, adverse side effects from, or a medical contraindication to NSAIDs, tramadol or opioid medications.
Study participants were then randomized into two distinct treatment groups and compared to placebo. One-third of patients received 2.5 mg of tanezumab at baseline (the start of the study) and 8 weeks later; one-third received 2.5 mg of tanezumab at baseline and 5 mg at week 8; and one-third received placebo.
The results—and what they mean for patients
At week 16 of the trial, the researchers found that patients who received at least one treatment dose of tanezumab reported a greater and statistically significant decrease in average pain and physical function scores on WOMAC, compared to placebo. For instance, significantly more patients in the treatment groups showed a 50% or more reduction in WOMAC pain scores. Average PGA-OA scores also dropped more in those who received one of the two tanezumab regimens, compared to placebo.
But, despite the modest improvement the study found, 16 (about 7%) of those who received 2.5/5 mg of tanezumab, and 8 (3.5 %) in the 2.5 mg group required joint replacements, with just 4 (1.7%) of patients in the placebo group requiring them; these differences reached statistical significance. Almost all of the joint replacements involved the index joint, which is the joint for which patients sought care.
Schnitzer said the results did not surprise him.
“The results were quite reflective of what’s been seen before in other studies,” he said. “Unfortunately, this study, like many of the others before it, had too small of a sample size to provide any specific answers about potential safety issues. We need a lot more data to understand what might be happening, and to really understand the magnitude of the potential safety concerns and which patients are at highest risk for experiencing them,” he said. Schnitzer added that future trials, including some that are ongoing, should provide that additional insight.
“Assuming tanezumab is approved by the FDA,” Schnitzer continued, “there may well be a group of patients for whom this drug won’t work. But it’s just as likely that there is a group of patients, who can’t take NSAIDs or opioids for whatever reason, for whom this drug will work when there are really no other options available to them.”
Schmidt, for his part, agreed. He said that the response to tanezumab reported in the study is encouraging, and he believes that future trials will advance understanding of which OA patients will respond best to anti-NGF treatments.
“Are there risks with this drug? Yes, there are,” he said. “But, as more trials go forward, we can get the data we need to better understand and manage them. We need to collect the right information so we can better determine which patients will be the best candidates for this drug, so we can offer it to patients who can’t use other drugs to find the relief they need.”
Kayt Sukel is a freelance writer based outside Houston, Texas.
This story first appeared on the IASP Pain Research Forum and has been adapted for RELIEF.