When Is Osteonecrosis Not Osteonecrosis?: Adjudication of Reported Serious Adverse Joint Events in the Tanezumab Clinical Development Program

Abstract

Objective. Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated jointrelated AEs in the tanezumab clinical program.Methods. The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis.Results. The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus.Conclusion. Despite initial reports, tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of tanezumab, tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.Tanezumab, a humanized monoclonal antibody, specifically targets and inhibits, with high affinity, interaction of nerve growth factor (NGF) with its receptors, TrkA (neurotrophic tyrosine kinase receptor type 1) and p75 (a low-affinity NGF receptor) (1-11). Tanezumab has been shown to reduce pain and improve function and patient's global assessment in patients with osteoarthritis (OA) of the knee and hip and those with chronic low back pain in phase II and III randomized controlled cliniClinicalTrials.gov identifiers:

Breaking barriers to novel analgesic drug development

“…For example, Anti-NGF antibodies (tanezumab, fulranumab and fasinumab) have proven in a very unusual twist to be more efficacious in patients with osteoarthritis (OA) than the preclinical data would have expected 258 , with greater signals than gold standard NSAIDs and opioids for chronic low back pain – sometimes thought of as the graveyard of analgesic trials – as well as in OA and diabetic neuropathy 259–261 . Conversely, tenezumab has been found to produce rapid progression of OA particularly when administered at high doses and with NSAIDs 262 . While the cause of this is uncertain, one possibility is that overuse of damaged joints because of high analgesia coverage may lead to accelerating joint destruction – pain is after all a protective mechanism as well as a disease burden.…”

Nerve growth factor blockade for the management of osteoarthritis pain: what can we learn from clinical trials and preclinical models?

“…The adjudication committee could demonstrate unambiguous osteonecrosis in only two of the 86 reported osteonecrosis cases (although eight of those had insufficient information to distinguish primary osteonecrosis and the committee failed to reach consensus on another five) (20). …”

Is the atrophic phenotype of tibiofemoral osteoarthritis associated with faster progression of disease? The MOST study

“…Several pharmaceutical programs evaluating anti-nerve growth factor (a-NGF) compounds at present defined the atrophic OA phenotype as a potential risk factor for potential joint adverse events such as rapid progression or osteonecrosis 19,20 . Our data does not support this assumption, but it needs to be clearly acknowledged that subjects in the MOST study were not under a-NGF treatment and are thus not comparable to a-NGF cohorts.…”