Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis

Background: Inflammation is an essential component of arthritis pain. Nerve growth factor (NGF) plays a key role in acute and chronic pain states especially those associated with inflammation. NGF acts through tropomyosin-receptor-kinase A (TrkA). NGF blockade has reduced arthritis pain in clinical trials. We explored the mechanisms within the joint which may contribute to the analgesic effects of NGF by selectively inhibiting TrkA in carrageenan-induced or collagen-induced joint pain behaviour. The goal of the current study was to elucidate whether inflammation is central to the efficacy for NGF blockade. Methods: Rats were injected in their left knees with 2 % carrageenan or saline. Collagen-induced arthritis (CIA) was induced by intradermal injections of a mixture of bovine type II collagen (0.2 mg) and incomplete Freund’s adjuvant (0.2 mg). Oral doses (30 mg/kg) of AR786 or vehicle control were given twice daily after arthritis induction. Ibuprofen-treated (35 mg/kg, orally, once daily) rats with CIA were used as positive analgesic controls. Pain behaviour was measured as hind-limb weight-bearing asymmetry and hind-paw withdrawal thresholds to von Frey hair stimulation (carrageenan synovitis), or withdrawal to joint compression using a Randall Selitto device (CIA). Inflammation was measured as increased knee joint diameter and by histopathological analysis. Results: Intra-articular injections of carrageenan or induction of CIA was each associated with pain behaviour and synovial inflammation. Systemic administration of the TrkA inhibitor AR786 reduced carrageenan-induced or CIA-induced pain behaviour to control values, and inhibited joint swelling and histological evidence of synovial inflammation and joint damage. Conclusions: By using two models of varying inflammation we demonstrate for the first time that selective inhibition of TrkA may reduce carrageenan-induced or CIA-induced pain behaviour in rats, in part through potentially inhibiting synovial inflammation, although direct effects on sensory nerves are also likely. Our observations suggest that inflammatory arthritis causes pain and the presence of inflammation is fundamental to the beneficial effects (reduction in pain and pathology) of NGF blockade. Further research should determine whether TrkA inhibition may ameliorate human inflammatory arthritis

Fasinumab (REGN475), an antinerve growth factor monoclonal antibody, for the treatment of acute sciatic pain: results of a proof-of-concept study

Paul J Tiseo,1 Haobo Ren,2 Scott Mellis3 1Pharmacovigilance Operations and Risk Management, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 2Biostatitics, Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA; 3Translational Medicine and Predictive Medicine, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA Objective: To evaluate the efficacy and safety of subcutaneously administered fasinumab (REGN475), a nerve growth factor-neutralizing antibody, in patients with acute sciatic pain receiving standard of care therapy. Methods: This was a double-blind, parallel-group, proof-of-concept study. Patients with unilateral, moderate-to-severe sciatic pain of 2–16 weeks' duration were randomized to a subcutaneous dose of placebo (n=51), fasinumab 0.1 mg/kg (n=53), or 0.3 mg/kg (n=53); follow-up was 12 weeks. Pain was assessed in a daily diary using a numerical rating scale (NRS) (0= no pain, 10= worst pain) for average and worst leg and back pain. The primary efficacy end point was the area under the curve of NRS scores for average leg pain from baseline to week 4. Key secondary end points included changes in average and worst leg and back pain from baseline to the end of week 4 and to each weekly study visit. Patient functioning (Oswestry Disability Index) and concomitant analgesic use were also assessed. Safety and tolerability were evaluated by treatment-emergent adverse events (TEAEs). Results: Demographic and clinical characteristics were similar among the treatment groups; 141 (88.7%) patients completed the study. For the primary end point, mean ± standard deviation area under the curve values from baseline to week 4 were not significantly different between placebo (96.8±6.0) and fasinumab 0.1 mg/kg (112.7±58.3; P=0.0610) or fasinumab 0.3 mg/kg (112.4±55.8; P=0.0923). All secondary efficacy end points of changes in pain and function demonstrated responses that were similar between placebo and fasinumab groups. Incidence of TEAEs was 45.1%, 50.9%, and 64.8% in the placebo, fasinumab 0.1mg/kg, and fasinumab 0.3 mg/kg groups, respectively. The most commonly reported TEAEs included paresthesia, arthralgia, pain in extremity, and headache. Conclusion: Administration of fasinumab provided no significant clinical benefit compared with placebo for the pain or functional limitations associated with acute sciatica. Fasinumab was generally well tolerated and incidence of TEAEs appeared to be dose related. Keywords: fasinumab, monoclonal antibody, nerve growth factor, sciatica, lumbar radiculopath

The safety and tolerability of donepezil in patients with Alzheimer's disease

Cholinesterase (ChE) inhibitors, which prevent the hydrolysis of acetylcholine, have been approved for the symptomatic treatment of Alzheimer's disease (AD) for over a decade. However, the first ChE inhibitors were associated with a high incidence of side-effects and general tolerability concerns, including hepatotoxicity. Side-effects associated with increased cholinergic activity, particularly in the gastrointestinal (GI) system, can prevent patients from achieving effective doses of drug. In addition, the advanced age and frail nature of patients with AD mean that poor tolerability is a serious concern. The potential for drug–drug interactions is also an important consideration, due to the high prevalence of comorbid disease in these patients