ATLANTA – as part of a recent randomized, double-blind, active-controlled, phase 3 study.
Jeff Craven/MDedge News
Dr. Marc C. Hochberg
Although patients who switched from NSAIDs to 5 mg subcutaneous tanezumab every 8 weeks reported significantly improved Western Ontario and McMaster Universities (WOMAC) index pain and function scores at 16 weeks, the difference was no longer statistically significant at 56 weeks; there was an increase in the number of joint safety events in both low- and high-dose tanezumab groups when compared with patients who continued on NSAIDs, Marc C. Hochberg, MD, of the University of Maryland, Baltimore, said in his presentation at the annual meeting of the American College of Rheumatology.
“Despite prior stable doses of NSAIDs, tanezumab subcutaneously administered every 8 weeks was associated with significantly more joint safety events than NSAIDs in a dose-dependent fashion,” he said.
Dr. Hochberg and colleagues conducted a phase 3 study of tanezumab in response to a Food and Drug Administration hold on the drug in 2010 in response to reports of osteonecrosis in patients taking tanezumab. “An adjudication committee was set up at that time to review all the records of individuals who participated in those studies who had been reported to have adverse joint related events, including osteonecrosis, as well as all the elected total joint replacements,” Dr. Hochberg explained. Only 4-month safety and efficacy data for tanezumab had been reported prior to these new data with at least 1 year of follow-up.
The study comprised 2,996 patients with hip or knee osteoarthritis (OA) from 446 centers in 18 countries, where patients were randomized to receive 2.5 mg of subcutaneous tanezumab (1,002 patients), tanezumab at 5 mg (998 patients) or NSAIDs (996 patients) for up to 80 weeks. Approximately two-thirds of the patients were women, and about 70% were white. About 85% of all patients had knee OA. The most common NSAIDs were celecoxib, diclofenac, and naproxen.
Less than 1% had Kellgren-Lawrence grade 0-1 at baseline, while about 30% had grade 2, 47% grade 3, and 22% grade 4. Patients had a mean 7.0 or 7.1 score on the WOMAC pain and function subscales, and a mean Patient’s Global Assessment of OA (PGA-OA) score of 7.4 or 7.5. Baseline radiographs were taken, as well as at safety follow-ups at 24 weeks, 56 weeks, and 80 weeks.
The researchers examined rapidly progressive OA (RPOA) type 1, classified as loss of 2 mm or more of joint space width within 1 year, and type 2, which was defined as abnormal bone loss or destruction, including limited or total collapse of at least one subchondral surface. Other primary joint safety endpoints examined were primary osteonecrosis, subchondral insufficiency fracture, and pathologic fracture. Each of these was reported individually in addition to the rate of total joint replacement. If an event was discovered, it was sent to an adjudication committee, Dr. Hochberg said. “You have either investigator-reported joint safety events, possible joint safety events or identified from the central raters’ assessment of imaging, or the reported total joint replacement reviewed blindly by the adjudication committee, blinded to treatment allocation, and then the adjudication results are those that are used for the analysis,” he said.
Overall, 447 patients who received tanezumab at 2.5 mg, 419 patients who received tanezumab at 5 mg, and 446 patients who continued receive NSAIDs completed treatment. There were 71 joint safety events in the tanezumab 5-mg group (7.1%) per 1,000 person-years, compared with 39 events per 1,000 person-years in the 2.5-mg group (3.9%), and 15 events per 1,000 person-years in the NSAIDs group (1.5%). The rate of joint safety events was significantly higher in both tanezumab groups, compared with the NSAIDs group (both P less than or equal to .001). Among patients with RPOA type 1, 4.9% of patients in the 5-mg group and 2.9% of patients in the 2.5-mg tanezumab group experienced joint safety events, compared with 1.1% of patients in the NSAIDs group. While RPOA type 2, primary osteonecrosis, and subchondral insufficiency fractures were uncommon in the study, Dr. Hochberg noted there was a statistically significant difference in joint safety events between the 5-mg tanezumab group and the NSAID group for patients with RPOA type 2 (1.4% vs. 0.1%; P less than or equal to .001).
The relationship between total joint replacement and tanezumab was dose-dependent: In the 5-mg group, 8.0% of patients underwent total joint replacement, while 5.3% of patients underwent total joint replacement in the 2.5-mg group, compared with 2.6% of patients in the NSAID group. “Most of the total joint replacements were due to normal progression of osteoarthritis,” Dr. Hochberg said.
When asked if he believed there is a role for tanezumab in the management of patients with OA, Dr. Hochberg said moderate to severe symptomatic hip or knee OA, including polyarticular OA, are potential areas where tanezumab and other nerve growth factor inhibitors could be beneficial.
“There is a tremendous unmet need in this population, and these are patients who have either had an inadequate response to, are intolerant of, or have contraindications to nonsteroidal anti-inflammatory drugs, have not responded well to intra-articular therapy, or have multiple joint involvement,” he said. There is also a role for tanezumab in OA patients who don’t want to take weaker opioid analgesics such as tramadol, he added.
This study was funded by Pfizer and Lilly, and the companies sponsored the summarization of the study. The authors reported various ties with these and other companies.
SOURCE: Hochberg MC et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1302 and Abstract 2756.