Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomised, placebo- and active-controlled trial

Abstract

Aims:The efficacy and safety of monotherapy with fulranumab, a monoclonal antibody that neutralises human nerve growth factor (NGF), was evaluated compared with placebo and an active comparator, controlled-release (CR) oxycodone, in patients with moderate to severe chronic knee pain of primary osteoarthritis (OA). Methods: In this phase-2, double-blind (DB), double-dummy, placebo-and active-controlled study, patients (40-80 years) were randomised (1:1:1:1) to placebo, fulranumab 3 or 9mg every 4 weeks (Q4 wk), or oxycodone CR twice-daily. Primary efficacy end-point: responder rates based on percent improvement in average osteoarthritis-related pain intensity (OAPI) scores from baseline to week-12 or when Food and Drug Administration (FDA) put a clinical hold on all anti-NGF trials, whichever was earlier. Secondary efficacy end-points: average OAPI score (week-16), Western Ontario and McMaster Osteoarthritis Index Global Score and subscales (pain, physical function, stiffness), and Patient Global Assessment. Results: As of an FDA clinical hold on all anti-NGF trials, only 196/300 patients were randomised and 33% (65/196) had completed 12 weeks of the 16-week DB phase. Responders were patients who did not withdraw and whose pain improved. Responder rates were not significantly different between fulranumab treatment groups (3mgQ4wk: 71%, p = 0.739; 9mgQ4wk: 80%, p = 0.843) and placebo (77%), whereas, oxycodone CR (56%) had significantly lower responder rates in comparison to both fulranumab (3mgQ4wk: p = 0.008; 9mgQ4wk: p = 0.012) and placebo (p = 0.0021). Secondary efficacy results were consistent with primary. None of the joint replacements (four in three patients) were adjudicated as rapidly progressing OA/osteonecrosis. Conclusion: Low sample size because of early termination make interpretation of this study difficult, but fulranumab monotherapy resulted in significantly better pain relief and function compared with oxycodone CR (but not against placebo) and was generally well-tolerated. Trial registration: ClinicalTrials.gov: NCT01094262.

Nerve growth factor antibody for the treatment of osteoarthritis pain and chronic low-back pain: mechanism of action in the context of efficacy and safety

“…A single phase 2 study demonstrated statistically significant improvement in WOMAC Pain and Physical Function scores with IV fulranumab (3 or 9 mg administered at baseline, week 4, and week 8) at week 12 compared with oral oxycodone-controlled release (20-50 mg twice daily). 73 Surprisingly, there was no difference between placebo and either fulranumab regimen in this study, complicating interpretation of the oxycodone vs fulranumab comparison. The study was also limited by low sample size due to early termination.…”

Effects of carrageenan induced synovitis on joint damage and pain in a rat model of knee osteoarthritis

“…The mechanisms that drive OA pain are likely to include peripheral and central sensitisation, and recent data in rats 44e46 and humans 47,48 using NGF-blocking pharmaceutical agents emphasise the key contribution of peripheral sensitisation. Peripheral sensitisation in OA has been associated with synovitis 49 .…”

The Efficacy of Nerve Growth Factor Antibody for the Treatment of Osteoarthritis Pain and Chronic Low-Back Pain: A Meta-Analysis

“…Furthermore, hyperalgesia and pain were reduced by the application of anti-NGF antibodies or IgG fusion proteins, both of which have the potential to inhibit NGF activities ( Lane et al., 2010 ; Schnitzer et al., 2011 ; Kivitz et al., 2013 ). Recent clinical studies presented promising outcomes for anti-NGF drugs in the treatment of OA and chronic LBP in human beings ( Nagashima et al., 2010 ; Katz et al., 2011 ; Brown et al., 2012 ; Brown et al., 2013 ; Kivitz et al., 2013 ; Sanga et al., 2013 ; Spierings et al., 2013 ; Balanescu et al., 2014 ; Ekman et al., 2014 ; Tiseo et al., 2014 ; Gow et al., 2015 ; Schnitzer et al., 2015 ; Mayorga et al., 2016 ; Sanga et al., 2016 ; Slatkin et al., 2019 ). Fasinumab, fulranumab, and tanezumab are three NGF-Abs undergoing clinical trials ( Schmelz et al., 2019 ).…”