Fasinumab in the treatment of hip and knee osteoarthritic pain: Efficacy and safety in a 36-week randomized, double-blind placebo-controlled clinical trial

Abstract

Purpose: Chronic pain in older adults is often due to osteoarthritis (OA). Fasinumab is a fully-human, high-affinity monoclonal antibody directed against nerve growth factor (NGF). By selectively blocking NGF, fasinumab has the potential to effectively modulate NGF-associated pain without some of the well-known adverse side effects of other analgesic medications, such as opioids and NSAIDS. Method(s): For inclusion into this study patients were required to have a clinical diagnosis of OA of the knee or hip based on ACR criteria, an inadequate response to or be intolerant of standard-of-care pain medications, and a Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score of >=4 and a Kellgren-Lawrence Xray grading of >=2 in at least one hip or knee. Eligible patients were randomized to either 1 mg, 3 mg, 6 mg, or 9 mg of fasinumab SC or matching placebo every 4 weeks throughWeek 12. The primary efficacy outcome was change from baseline to week 16 for the WOMAC pain subscale; WOMAC physical function and Patient Global Assessment (PGA) were secondary endpoints. Safety follow-up continued for 24 weeks after the last dose. The study incorporated extensive imaging of index and non-index joints at baseline and over the course of the study, with a focus on arthropathies including subchondral insufficiency fractures (SIF), osteonecrosis (ON) and rapidly progressive osteoarthritis (RPOA). The primary efficacy variable, change from baseline to week 16 in the WOMAC pain subscale score, was analyzed using a mixed-effect model repeated measure (MMRM) approach. Result(s): 419 subjects received at least one dose of study medication. At week 16, LS mean changes from baseline in the WOMAC pain subscale in patients were -2.25 for placebo and -3.03 to -3.65 for the fasinumab groups; all fasinumab groups showed significant improvement vs placebo (p=<0.05). Improvements were also observed for WOMAC physical function and PGA. Symptoms scores returned toward baseline after treatment was discontinued. Over the entire 36-week treatment and follow-up period, fasinumab was generally well tolerated. As previously reported for the class of NGF antibodies, certain neuromuscular events, including arthralgia, paraesthesia, hypoaesthesia, and peripheral edema, occurred more commonly in fasinumab treated patients compared to the placebo-treated group. Over the 36-week period, the incidence of adjudicated arthropathies was found to be dose-related, with a higher rate of patients experiencing arthropathies in the higher dose groups [12 percent (9mg), 7 percent (6mg), 5 percent (3mg), 2 percent (1mg) and 1 percent (placebo)]. Conclusion(s): In this 36-week clinical trial, fasinumab provided significant improvement compared to placebo in both pain and function in patients with moderate to severe OA. All doses provided efficacy, with the 9 mg dose providing the best effect. Fasinumab was generally well tolerated, with an apparent dose relationship for some adverse events, including adjudicated arthropathies. The efficacy and safety of lower doses of fasinumab, shown here, provide the basis for selection of the optimal treatment regimen for OA pain.