Background & Aims

Osteoarthritis (OA) is chronic degenerative disease of the joint that is characterized by structural changes to the synovium, articular cartilage and subchondral bone. The pathogenesis of OA is a slow and heterogeneous disease process which ultimately results in clinical symptoms such as pain and loss of joint function. Currently, there is an urgent need to develop treatments that are safer and more efficacious than presently marketed analgesics. Nerve growth factor (NGF) has been well documented in both human and veterinary medicine as a promising new target for the treatment of OA-associated pain. Consequently, bedinvetmad (ZTS-00508841, Librela) has been developed as a fully canine monoclonal antibody (mAb) that binds to NGF, reduces NGF binding to TrkA receptor, and decreases TrkA signal transduction in cell types involved in pain. Developing bedinvetmab into an analgesic designed to treat pain associated with OA required the use of multiple animals models of OA.

Methods

One model of OA that has been utilized extensively to study OA pain is the rat monoiodoacetate (MIA) model. For these studies, rats (n=10-12/treatment group) were induced with 2 mg MIA to create a chronic state of joint pain. At 21 days post-MIA induction, bedinvetmab (0.5-2 mg/kg, SC) or placebo was administered. In addition to the rat MIA model, the efficacy of bedinvetmab was examined in the target species by utilizing a canine synovitis model. In this synovitis model, beagle dogs (n=13/treatment group) were treated with LPS inta-articularly which resulted in lameness that was scored by a trained observer on a visual analog scale. Seven days prior to LPS-induction, dogs were treated with bedinvetmab (5 mg/kg, IV) or placebo.

Results

In the rat MIA model, MIA induced statistically significant (P<0.05) decreases in weight bearing on the affected joint as compared to pre-MIA weight bearing measures. Bedinvetmab produced statistically significant (P<0.05) increases in weight bearing compared to placebo by 7 days after dose administration and this effect lasted for the 28 day duration post-administration. In the canine synovitis model, LPS induced a measurable lameness in dogs. Similar to the rat MIA model, bedinvetmab produced a statistically significant (P<0.5) reduction in LPS-induced lameness as compared to placebo-treated animals.

Conclusions

These results demonstrate that bedinvetmab produces significant reductions in weight bearing deficits in animal models of OA pain. Additionally, these studies demonstrate the need for multiple animal models to assess the effects of any putative analgesic agents, while also supporting a strong translatability for the rat MIA as a model of OA in dogs. Finally, and most importantly, this describes the preclinical in vivo development of bedinvetmab, a highly effective treatment for canine OA.

References

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Presenting Author

Jason Ross

Poster Authors

Jason Ross

Zoetis Animal Health

Lead Author

Topics

  • Treatment/Management: Pharmacology: Monoclonal Antibodies, Biologics, and Biosimilars