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

Abstract

ObjectivesTo study the efficacy and safety of fasinumab in moderate-to-severe, chronic low back pain (CLBP).MethodsIn 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.ResultsSignificant 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.ConclusionsFasinumab 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.

Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis

“…ADA reflects the cell mediated immunity and also involved in maturation of lymphocytes and their function, formation of macrophages from monocytes 9 . RA is associated with increased levels of ADA in the serum and synovial fluid of joints 10 , 11 . ADA has been suggested as a marker to evaluate disease activity in RA by previous studies 12 , 13 .…”

Is Targeting Nerve Growth Factor Antagonist a New Option for Pharmacologic Treatment of Low Back Pain? A Supplemental Network Meta-Analysis of the American College of Physicians Guidelines

“…Thirty studies ( Berry and Hutchinson, 1988 ; Stein et al, 1996 ; Birbara et al, 2003 ; Ruoff et al, 2003 ; Coats et al, 2004 ; Pallay et al, 2004 ; Peloso et al, 2004 ; Kanayama et al, 2005 ; Perrot et al, 2006 ; Pareek et al, 2009 ; Skljarevski et al, 2009 ; Skljarevski et al, 2010a ; Skljarevski et al, 2010b ; Buynak et al, 2010 ; Hale et al, 2010 ; Katz et al, 2011 ; Biondi et al, 2013 ; Kivitz et al, 2013 ; Rauck et al, 2014 ; Tiseo et al, 2014 ; Friedman et al, 2015 ; Rauck et al, 2015 ; Baron et al, 2016 ; Bedaiwi et al, 2016 ; Gottlieb and Njie, 2016 ; Konno et al, 2016 ; Sanga et al, 2016 ; Miki et al, 2018 ; Dakin et al, 2020 ; Markman et al, 2020 ) were included in this NMA ( Supplementary Figure S1 ). Nine groups were included in the main network analysis: placebo (Pla), antidepressant (ADP), anti-NGF (ANGF), acetanilide antipyretic analgesics (AP), nonsteroidal anti-inflammatory drugs (NSAIDs), weak opioids (WO), strong opioids (SO), a combination of AP and WO (cAPWO), and a combination of NSAIDs and skeletal muscle relaxants (cNSMRs).…”

Localization of Nerve Growth Factor Expression to Structurally Damaged Cartilaginous Tissues in Human Lumbar Facet Joint Osteoarthritis

“…The contrasting NGF tissue distribution between facet joint and knee OA might provide insight into the frequency of RPOA as adverse events in NGFi treatment. Recent studies have demonstrated a dose-dependent increase of RPOA in patients with knee OA or CLBP treated with NGFi ( 10 , 11 ), yet this rarely occurred in CLBP patients without peripheral OA. NGF has been described as a regulator of osteogenesis and bone turnover ( 16 ), however, scarce expression in bone marrow would argue against a significant contribution of NGF signalling to FJOA bone remodelling.…”

“…Recent studies revealed efficacy of NGFi in improving pain and physical function in knee OA, while RPOA remained a serious adverse event in 1-3% of the treated patients ( 10 ). In a cohort of chronic CLBP patients NGFi demonstrated efficacious in reducing CLBP intensity and RPOA was almost exclusively observed in individuals with additional peripheral OA ( 11 ).…”