ATCvet code: QN02BG93
Pharmacodynamics
Mechanism of action:
Izenivetmab is a canine monoclonal antibody (mAb) targeting nerve growth factor (NGF). NGF binds to TrkA receptors located on immune cells to elicit the release of additional proinflammatory mediators, including NGF itself. These inflammatory mediators lead to further peripheral sensitisation involved in pain perception. The inhibition of NGF has demonstrated to provide relief from pain associated with osteoarthritis.
Clinical trials:
In clinical trials lasting up to 9 months, treatment of dogs with osteoarthritis was demonstrated to have a favourable effect on the reduction of pain assessed by the Canine Brief Pain Inventory (CBPI). CBPI is an assessment by the animal owner of an individual dog’s response to pain treatment as assessed by pain severity (scale of 0 to 10, where 0 = no pain and 10 = extreme pain), interference of pain with the dog’s typical activities (scale of 0 to 10, where 0 = no interference and 10 = completely interferes) and quality of life (assessed as ‘poor’, ‘fair’, ‘good’, ‘very good’ or ‘excellent’). In the pivotal EU multicentre clinical trial, 37.3% (95/255) of the izenivetmab-treated dogs and 22.6% (58/257) of the placebo-treated dogs demonstrated treatment success, defined as a reduction of ≥ 1 in pain severity score (PSS) and ≥ 2 in pain interference score (PIS), on Day 90 after the first dose. An onset of efficacy was demonstrated at 7 days post administration, with treatment success demonstrated in 23.5% (63/268) of the izenivetmab-treated dogs and 11.9% (32/269) of the placebo-treated dogs.
Pharmacokinetics
In a pre-clinical pharmacokinetic study in healthy adult beagle dogs administered izenivetmab at the approved label dose (0.05 – 0.1 mg/kg), maximum serum drug concentration (Cmax) following subcutaneous use was 0.414 mcg/ml and occurred at an average of 3 days post-dose. In pre-clinical trials in dogs, bioavailability by the subcutaneous use was 100% and the elimination half-life was approximately 10 days.
In a 9-month repeat-dose clinical trial for safety and efficacy of izenivetmab in dogs with OA, the elimination half-life measured in non-immunogenic dogs was approximately 13 days.
Izenivetmab, like endogenous proteins, is expected to be degraded into small peptides and amino acids via normal catabolic pathways. Izenivetmab is not metabolised by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
Immunogenicity:
In a 9-month repeat-dose clinical trial for safety and efficacy at the approved labelled dose (0.05 – 0.1 mg/kg) in adult dogs with OA, a total of 283 dogs in the placebo group and 289 dogs in the izenivetmab-treated group were evaluated for immunogenicity (anti-drug antibodies). Immunogenicity was observed in 3.46% (10/289) of the izenivetmab-treated dogs and in 2.83% (8/283) of the placebo dogs. In izenivetmab treated dogs, neutralising antibodies were detected in 8 out of the 10 animals with immunogenicity, which was generally associated with lower serum izenivetmab concentrations and in some dogs, lack of effectiveness. There were no adverse events (AEs) related to the immunogenicity findings.