Prevalence of preexisting articular bone pathology in patients with osteoarthritis screened for fasinumab clinical trials identified by X-ray or magnetic resonance imaging.

OBJECTIVE: To examine the prevalence of preexisting articular bone pathology in patients with hip or knee pain due to osteoarthritis (OA) screened for fasinumab clinical trials. METHOD: This post-hoc analysis included patients with OA screened for three phase 3 fasinumab studies (NCT02683239, NCT03161093, NCT03304379). During screening, participants who met other clinical inclusion/exclusion criteria underwent radiography of knees, hips, and shoulders. Those with Kellgren-Lawrence grade (KLG) ≥2 for index joint and without an exclusionary finding proceeded to magnetic resonance imaging (MRI) of index, contralateral, and KLG ≥3 joints. Exclusionary findings included bone fragmentation/collapse, bone loss/resorption, osteonecrosis, and fracture, by either X-ray or MRI. Participants with extensive subchondral cysts were also excluded. Prevalence of abnormalities on radiographs and MRIs are reported. RESULTS: Of 27,633 participants screened, 21,997 proceeded to imaging. Of these, 1203 (5.5%) were excluded due to the presence of ≥1 joint with severe articular bone pathology (X-ray or MRI): bone fragmentation/collapse (2.61%), subchondral insufficiency fracture (SIF; 1.67%), osteonecrosis (1.11%), and significant bone loss (0.32%). Additionally, 3.14% screen-failed due to extensive subchondral cysts. More than half of the exclusions due to bone fragmentation/collapse (386/572), osteonecrosis (141/245) and significant bone loss (59/71), and approximately one third of SIF (133/367) and extensive subchondral cysts (229/689) were evident on X-rays. CONCLUSIONS: Approximately one in 20 participants with OA who met the clinical screening criteria for fasinumab phase 3 trials were later excluded due to preexisting severe articular bone pathology findings by X-ray or MRI.

Efficacy and safety of fasinumab in patients with chronic low back pain: a phase II/III randomised clinical trial.

OBJECTIVES: To study the efficacy and safety of fasinumab in moderate-to-severe, chronic low back pain (CLBP). METHODS: In this phase II/III, double-blind, placebo-controlled study, patients with CLBP aged ≥35 years with inadequate pain relief/intolerance to acetaminophen, non-steroidal anti-inflammatory drugs and opioids were randomised to fasinumab 6 or 9 mg subcutaneous every 4 weeks (Q4W), 9 mg intravenous every 8 weeks (Q8W) or placebo. Primary endpoint was change from baseline to week 16 in average daily low back pain intensity (LBPI) numeric rating score. Key secondary efficacy variables included Roland-Morris Disability Questionnaire (RMDQ) and Patient Global Assessment (PGA). The results are based on a modified intent-to-treat analysis of 563/800 planned patients when enrolment was stopped early given emerging signals of joint risk in other osteoarthritis (OA) studies at doses being tested here. RESULTS: Significant placebo-adjusted LBPI reductions at week 16 were observed for fasinumab 9 mg Q4W and Q8W (least squares mean (standard error) -0.7 (0.3); both nominal p<0.05), but not 6 mg (-0.3 (0.3); p=0.39). RMDQ and PGA improvements to week 16 were greatest for fasinumab 9 mg intravenous. Numerically greater efficacy occurred in patients with, versus those without, peripheral OA (pOA) over 16 weeks. Treatment-emergent adverse events (AEs) occurred in 274/418 (65.6%) patients in the combined fasinumab groups and 94/140 (67.1%) placebo patients. Joint AEs, mostly rapid progressive OA type 1, were more frequent in the combined fasinumab groups (19 events in 16 patients (3.8%) vs 1 event in 1 patient (0.7%) for placebo); all except one occurred in pOA patients. CONCLUSIONS: Fasinumab highest doses, but not lower dose, improved both CLBP pain and function. Most joint AEs occurred in pOA patients, consistent with earlier findings in symptomatic OA. Further study is needed of patients with CLBP with and without pOA to determine optimal benefit-risk.

Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension.

Denosumab is a fully human monoclonal antibody against receptor activator of NF-κB ligand (RANKL) that decreases osteoclast formation, function and survival, and is approved for the treatment of postmenopausal women with osteoporosis at increased or high risk for fracture, among other indications. During the pivotal 3-year fracture trial FREEDOM, denosumab 60 mg subcutaneously every 6 months significantly reduced new vertebral (68%), hip (40%), and nonvertebral (20%) fractures; increased bone mineral density (BMD); and reduced bone turnover markers compared with placebo in postmenopausal women with osteoporosis. Questions have arisen regarding imbalances of certain low-frequency adverse events (AEs) observed in FREEDOM, as well as the top 5 most frequent adverse reactions listed in the United States prescribing information (USPI; back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis). We examined the incidences of these AEs in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). This provided a unique opportunity for comparison with the original 3-year denosumab FREEDOM observations. We also examined the incidences of these AEs over 6 years of denosumab treatment (Long-term Group; ie, comparing a second 3 years of treatment with findings in the first 3 years). There was no indication of increasing trends regarding the imbalances of either low-frequency AEs or common AEs observed in FREEDOM. © 2017 American Society for Bone and Mineral Research.