Abstract
Osteoarthritis and other degenerative joint diseases are common causes of chronic pain in cats. Frunevetmab is a felinized monoclonal antibody that binds to nerve growth factor (NGF) and provides relief from pain by blocking the receptor-mediated signaling cascade induced by NGF. Results from three studies were combined to provide an overview of frunevetmab pharmacokinetics (PK) and immunogenicity. The objective of the first study was to establish the pharmacokinetic parameters resulting from intravenous (IV) and subcutaneous (SC) administration of frunevetmab to the feline patient population at 3 mg/kg. Ten adult cats with naturally-occurring osteoarthritis were administered frunevetmab in a crossover design at 28 day intervals. Non-compartmental pharmacokinetic analysis of the plasma concentration-time data showed that the half-life was 10.1 ± 1.9 days after IV dosing and the SC bioavailability was 60.3 ± 15.8% with maximum drug levels observed at 3–7 days after dosing. Plasma samples were collected at ~28 days after dosing during two field safety and effectiveness studies of cats with degenerative joint disease. The doses ranged from 1.0 to 2.8 mg/kg; 2 or 3 doses were administered either SC/IV, SC/SC, or SC/SC/SC. The data from these studies along with the data from the laboratory pharmacokinetic study were analyzed using non-linear mixed-effects (NLME) modeling. The model closely predicted the trough concentrations from the two field studies, including the IV treatment in the pilot field study. The trough concentrations were predicted to be close to steady-state after 2 doses. A second objective was to determine the incidence and clinical relevance of frunevetmab immunogenicity. A three-tier anti-drug antibody assay (screen, confirm, titer) was developed and validated. Immunogenicity was assessed in 259 frunevetmab-treated animals enrolled in the two field studies. Only 4 of these animals (1.5%) appeared to develop immunogenicity to frunevetmab. None of the four exhibited adverse events attributed to immunogenicity and no impact on drug levels or efficacy was observed in three of the animals. In the placebo animals, 2.3% (3/131) appeared to develop treatment-emergent immunogenicity. Overall, frunevetmab administration resulted in a very low incidence of treatment-emergent immunogenicity with no safety findings and minimal effect on drug exposure and efficacy.
Highlights
Osteoarthritis (OA) and other degenerative joint diseases (DJD) are prevalent in cats [1]
It is important to note that since the assay was based on the capture of frunevetmab by the drug target, nerve growth factor (NGF), the assay was a “free” drug assay, meaning that only frunevetmab that was still capable of binding NGF would be detected [26]
Frunevetmab bound to NGF or to neutralizing anti-drug antibodies (ADAs) would not be detected in the assay
Summary
Osteoarthritis (OA) and other degenerative joint diseases (DJD) are prevalent in cats [1]. The important role of the neurotrophin beta nerve growth factor (NGF) in chronic pain states, including DJD pain, has been demonstrated in animals and humans [2]. NGF binds to its two receptors, tyrosine kinase receptor type 1 (TrkA) and p75, to activate a signaling cascade that triggers neurite outgrowth and sensitization in neurons [3]. Several anti-NGF monoclonal antibodies have been tested in human to antagonize NGF activity and provide relief from pain [4–6]. In dogs diagnosed with clinical OA, a 0.2 mg/kg intravenous (IV) injection demonstrated some analgesic effect for 4–6 weeks post-injection [7]. A proof-of-concept study and multicenter, placebo-controlled, randomized, double-blind pilot and pivotal field studies demonstrated efficacy of frunevetmab, a felinized anti-NGF mAb ( called NV-02), for the treatment of DJD-associated pain [8–10]. Assay of plasma samples collected up to 42 days after dosing showed that peak drug levels were achieved at ∼3 days after dosing and the plasma elimination half-life averaged 9 days
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