Nerve Growth Factor Inhibitor Compounds Cartilage Loss in Osteoarthritis Save

Nerve growth factor (NGF) is a key modulator of pain perception,  Inhibitors of NGF are being studied in several chronic pain conditions, including osteoarthritis (OA).

While investigational NGF inhibition exhibits excellent pain relief in knee OA, adverse events reports of osteonecrosis or subchondral insufficiency leading to total joint replacement during the phase III clinical OA studies led the US Food and Drug Administration to put trials of all NGF inhibitors on partial clinical hold.  The FDA subsequently lifted the moratorium when the consensus expert opinion was that these specific events were likely related to the OA severity of patients enrolled and the loss of proprioception protection with NGF inhibition.

To further investigate this, an animal study was conducted to characterize the impact of NGF inhibition with tanezumab on voluntary weight-bearing and subsequent articular cartilage damage in MMT (medial meniscal tear) rats to see if this model would be useful for investigating potential mechanisms underlying the clinical findings of increased rapidly progressing OA (RPOA) in patients treated with tanezumab.

Male Lewis rat underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg) isotype control or vehicle for 7,14 or 28 days, A second arm, delayed onset of treatment (starting 2-8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A 3rd arm was treated with mid-tibial amputation, evaluated the dependence of the model on weight-bearing.

Tanezumab-treated MMT rats had significantly greater cartilage degeneration width than MMT controls due to increased weight bearing after the surgery. Delaying treatment until weight-bearing fully returned to normal (ie, day 57 after the surgery instead of day 23) resulted in complete protection from worsening of joint damage when compared with control treatments

This study suggests that increased joint damage seen in tanezumab-treated MMT rats was due to an increase in voluntary weight-bearing early in the disease process and not due to direct toxic effect of tanezumab on cartilage or bone.

Results from this study may help guide future clinical trial design by suggesting exclusion criteria (ie, patients deemed sensitive to mechanical overloading/radiographic evidence of bone or joint insufficiency).