CHICAGO – The nerve growth factor antibody tanezumab met its primary efficacy endpoints for improving pain and physical function in patients with knee or hip OA while also showing a low incidence of the drug’s most concerning adverse effect in the first results from a phase 3 study of a drug in this new class.
The placebo-controlled, multicenter study enrolled 696 U.S. OA patients with moderate to severe knee or hip pain and showed that two subcutaneous injections of the humanized antibody tanezumab spaced 8 weeks apart led to statistically significant improvements relative to placebo for pain, physical function, and patient global assessment of OA,, said at the annual meeting of the American College of Rheumatology.
The primary efficacy measurements occurred 8 weeks following the second subcutaneous injection. The study included two active treatment arms, and all the efficacy measures responses showed consistent, “modest” improvements in the patients who received a 2.5 mg injection followed by a 5 mg injection, compared with those who received two 2.5 mg injections.
For the safety analysis the researchers followed patients out to 24 weeks after they received their final injection. The main adverse event of interest was rapidly progressive OA (RPOA), which occurred in five patients who received two 2.5-mg dosages and in one patient who received the 2.5 mg followed by 5 mg regimen; no RPOA occurred among placebo patients. The 1.3% incidence of RPOA among all 494 patients who received tanezumab “aligned with expectations based on the risk mitigation procedures used,” said Dr. Schnitzer, a rheumatologist and professor of medicine, anesthesiology, and physical medicine and rehabilitation at Northwestern University, Chicago. No patient developed primary osteonecrosis.
Two patients who developed RPOA then underwent total joint replacement. The overall rate of total joint replacement was 4 among placebo patients, all involving knees, and 24 among patients treated with tanezumab, including 12 knee replacements and 12 hip replacements. Blinded adjudication determined that 26 of the total 28 joint replacements resulted from “normal” OA progression.
The rates of all adverse events, serious adverse events, and adverse events leading to treatment discontinuation were low and similar in the three treatment arms.
Earlier clinical studies of tanezumab had signaled a problem with RPOA (Arthritis Rheumatol. 2016 Feb;6), which led the Food and Drug Administration to order a temporary halt to clinical testing of all nerve growth factor antagonists in 2010 that the agency then lifted in 2015 (Clin Exp Rheumatol. 2017 Sept-Oct;3). In 2017, the FDA gave clinical development of tanezumab “ ” status. The results that Dr. Schnitzer reported represent the first outcomes from several phase 3 studies that the companies developing tanezumab are now running and that collectively include about 7,000 total patients, according to a written from the developing companies. The companies released an initial about the current results in July 2018.
Thereported by Dr. Schnitzer enrolled patients with OA of the knee or hip at several U.S. sites. For the primary endpoint of mean change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index ( ) pain score, the results at 16 weeks were –2.6 units in the placebo patients and –3.4 units among patients who received the higher dosage. For the primary outcome of mean change in WOMAC physical function score, the results were –2.6 in the placebo arm and –3.5 in patients on the higher dosage. For the primary outcome of change in patient’s global assessment of their OA, the results were –0.65 in the placebo patients and –0.90 in those on the highest dosage. All three between-group differences were statistically significant.
A key secondary outcome was the percentage of patients having at least a 50% reduction in their WOMAC pain score, which occurred in 38% of the placebo patients and in 57% on the higher tanezumab dosage, a statistically significant difference, Dr. Schnitzer reported. A final efficacy finding was the percentage of patients who had a 50% or greater pain reduction at week 16 who did not have a pain response at week 8, a parameter that could reflect incremental benefit from the larger, second tanezumab dose. This outcome occurred in 19% of placebo patients and in 22% of patients who received two 2.5-mg doses of tanezumab; among those who received a 5-mg dose after the first 2.5-mg dose, the rate was 33%.
The study was sponsored by Eli Lilly and Pfizer, the companies jointly developing tanezumab. Dr. Schnitzer has been a consultant to and has received research support from Eli Lilly and Pfizer. He has also been a consultant to AbbVie, Aptinyx, Genzyme, Regeneron, and Vertex Pharmaceuticals, and has received research support from Grünenthal and Radius Health.
SOURCE: Schnitzer TJ et al. Arthritis Rheumatol. 2018;70(Suppl 10) .