Treatment with the anti–nerve growth factor tanezumab was associated with significant improvements over placebo in pain, physical function, and Patient’s Global Assessment of osteoarthritis results, after 16 weeks in a phase III study of patients with osteoarthritis of the hip.
In the randomized, double-blind, placebo-controlled study of 621 patients with painful hip OA, treatment with the anti–nerve growth factor (anti-NGF) was also well tolerated, according to Dr. Mark Brown and his associates. The study was funded by Pfizer, the manufacturer of tanezumab, and Dr. Brown and three of the five other authors are full-time employees of the company.
Dr. Roy D Altman
Tanezumab "may eventually be useful in OA patients who are intolerant of or nonresponsive to nonopioid treatment," the authors concluded. The study was published online (Arthritis Rheum. 2013 April 1 [doi:10.1002/art.37950]).
Anti-NGFs are monoclonal antibodies directed against nerve growth factor, which "modulates pain processing and sensitivity via nociceptor sensitization," and increased NGF levels are associated with injury, inflammation, and chronic pain, according to the authors.
Tanezumab is one of several anti-NGFs being studied for OA and other chronic pain conditions and is the furthest along in development. In 2010, the Food and Drug Administration placed a partial hold on anti-NGF clinical trials after cases of osteonecrosis and avascular necrosis were reported in patients treated with tanezumab and in those treated with another anti-NGF, including cases in nonindex joints and people with no history of OA. Dr. Brown and his coauthors wrote that some of these cases were reported in phase III hip and knee OA studies, after their study was completed.
In March 2012, an FDA advisory panel of outside experts agreed that the anti-NGFs showed promise as analgesics in studies and unanimously recommended that clinical development should continue, with close monitoring of joint-related adverse effects and adequate informed consent. The authors noted that the clinical hold on tanezumab trials was lifted in August 2012. (The FDA could not provide a comment on this issue because it relates to a drug application under review, an agency spokesperson said.)
The development of the anti-NGFs "is an exciting potential addition to our present inadequate control of pain," and research is resuming with a careful review of the risk of bone and joint changes, Dr. Roy Altman said in an interview. In his view, "the known risks would be acceptable to many people with poorly controlled pain." Dr. Altman, professor of medicine, rheumatology, at the University of California, Los Angeles, was not an investigator in the study.
The Pfizer study compared three tanezumab doses (2.5 mg, 5 mg, and 10 mg) administered intravenously at baseline, 8 weeks, and 16 weeks, with placebo, in 621 people with OA of the hip (mean age, 62-63 years) who could not or did not want to take nonopiate pain medications, did not get enough relief from these medications, and/or were candidates for hip surgery or other invasive treatments. Their baseline Western Ontario and McMaster Universities OA Index (WOMAC) pain and physical function subscale scores were at least 5 at baseline and Patient’s Global Assessment of OA (PGA OA) was "fair," "poor," or "very poor." Almost half were candidates for invasive treatment.
At 16 weeks, compared with placebo, treatment with tanezumab, at all three doses, "produced greater, clinically meaningful, and statistically significant improvements" in each of the three primary efficacy endpoints: changes in the WOMAC pain subscale, the WOMAC physical function subscale, and the PGA OA. Differences between placebo and treatment were greatest for the two higher doses.
On the WOMAC pain subscale, mean baseline scores of all groups ranged from 7.2 to 7.3. Placebo patients’ scores improved by a mean of -1.62 points, but in comparison, improvements were significantly better on progressively higher doses of tanezumab: –2.90 for 2.5 mg, –3.31 for 5 mg, and –3.37 for 10 mg. Similar results occurred on the WOMAC physical function subscale scores, with mean improvements of –1.39 for placebo, –2.57 for 2.5 mg, –2.88 mg for 5 mg, and –3.00 mg for 10 mg.
Other findings included a significantly greater proportion of patients on the treatment who achieved at least 30%, 50%, 70%, and 90% reductions in the WOMAC pain subscale, compared with placebo at 16 weeks. About two-thirds of the patients on treatment remained in the study through week 24 (considered the end of the study because of tanezumab’s long half-life), compared with 38% of those on placebo.
Overall, more patients on tanezumab reported adverse effects (55%-58%, vs. 44% on placebo). Serious adverse events occurred in 3%-4.5% of patients in the treatment groups.