Nerve growth factor (NGF) inhibitors have been demonstrated in numerous controlled trials to be effective for neuropathic and nonneuropathic pain, including visceral pain and cancer. This versatility is consistent with preclinical studies demonstrating elevated NGF levels after both tissue and peripheral nerve injury and the critical role NGF-mediated signaling plays in the initiation and maintenance of chronic pain. The best-studied condition for NGF inhibitors is knee osteoarthritis (OA), which represents one of the leading causes of disability worldwide. Although the evidence of the efficacy for NGF inhibitors in knee OA is robust, the incidence of rapidly progressive OA (RPOA) and osteonecrosis, estimated at between 1% and 3%, has posed a major obstacle to regulatory approval. The incidence for these conditions is increased with higher doses, longer exposure, and concomitant use of nonsteroidal anti-inflammatory drugs, a mainstay of treatment in arthritis and spine pain. In 2012, the U.S. Food and Drug Administration (FDA) placed a hold on clinical trials evaluating NGF inhibitors, which was lifted in 2015 with the imposition of stringent monitoring, dose limitations, and enrollment restrictions. On March 2, 2020, the FDA accepted a Biologics License Application for tanezumab 2.5 mg subcutaneous injection for the treatment of moderate-to-severe osteoarthritis, an indication that would include the knee and other sites such as the hip, shoulder, hand, and possibly spine.
Perhaps one factor that led the FDA to rescind the hold and accept regulatory submission for tanezumab is that NGF inhibitors are relatively safer and less expensive than the standard alternative treatment for knee and hip OA: joint replacement (coincidentally, the most common treatment for RPOA). The evidence supporting tanezumab for joint OA makes it an attractive target for other musculoskeletal pain conditions, such as nonradicular low back pain (LBP). However, unlike knee and hip OA, LBP can have myriad causes (eg, arthritis, muscle, or disk pathology), has no widely accepted treatment algorithm, and is characterized by wildly divergent treatment results. It is therefore of considerable interest to investigate whether the promise of tanezumab for joint OA translates to efficacy in LBP.
In the current issue of PAIN, Markman et al. report on the efficacy and safety of tanezumab in treatment-refractory chronic nonradicular LBP. The investigators compared subcutaneous tanezumab 5 or 10 mg administered every 8 weeks to oral tramadol 100 to 300 mg daily and to oral and subcutaneous placebo. Tanezumab 10 mg met the primary study endpoint of a significant decrease in LBP intensity at 16 weeks compared to placebo, whereas neither the 5-mg dose nor tramadol met this endpoint. Joint safety events were also significantly more frequent with tanezumab 10 mg (2.6%) compared to tanezumab 5 mg (1.0%), tramadol (0.2%), or placebo (0%). Seven participants in the 10-mg group (1.4%) underwent total joint replacement, compared to none in any of the other groups. Thus, although tanezumab seems to be effective for chronic LBP, it may come at the cost of increased serious adverse events. As we examine its efficacy and safety in detail, weighing the risks and benefits of tanezumab becomes increasingly complicated.
The reported efficacy of tanezumab is admittedly impressive: 64.8% in the 5-mg group and 65.5% in the 10-mg group achieved ≥30% improvement in LBP intensity at 16 weeks. Yet, the placebo response in this study was also impressive, with 55.9% of placebo recipients reporting ≥30% improvement. The gap becomes even narrower at the ≥ 50% improvement threshold, with 46.3% and 43.3% in the tanezumab 10 and 5 mg groups, respectively, meeting this secondary endpoint, compared to 37.4% in the placebo group. In other words, although there was a clear clinical response to tanezumab, the placebo response was also quite large. Previous studies have also demonstrated a higher response rate for subcutaneous placebo than placebo pills, an effect which is magnified by the need for repeated injections. This finding does not detract from the clinical effectiveness of tanezumab, but it does suggest that much of the observed benefit of tanezumab may derive from the placebo effect. Interpreted another way, the number needed to benefit with tanezumab 10 mg over placebo is 10 for 30% improvement, and 11 for 50% improvement. For comparison, the number needed to benefit for 50% improvement with topical nonsteroidal anti-inflammatory drugs in chronic musculoskeletal pain is 7 to 10.
The observation that only the higher dose of tanezumab 10 mg met the primary efficacy endpoint is consistent with prior studies demonstrating greater efficacy with increased doses. However, higher doses are also associated with more adverse events such as RPOA, prompting Pfizer and Eli Lilly to apply for approval of the low 2.5 mg dose in the Biologics License Application. Numbers needed to harm were not provided in the Markman et al. study, but based on their data, the numbers needed to harm for RPOA was 38 with tanezumab 10 mg, 100 with tanezumab 5 mg, and 500 for tramadol. These adverse events occurred despite the strict exclusion of patients with known knee, hip, or shoulder OA.
Approval of tanezumab would have widespread implications for physicians who treat pain. In addition to using lower doses to treat knee and hip OA, physicians would be allowed to administer the drug in higher doses and off-label for indications other than OA, including LBP. Yet, deviation from FDA-approved drug dosing and treatment indications may alter the fine balance between benefits and harms, particularly in the case of NGF inhibitors.
Osteoarthritis is a clinical, serological, or radiological diagnosis (depending on the diagnostic criteria used), whereas LBP is a symptom with multiple possible etiologies. Some LBP may be from OA (eg, facet arthropathy), but disks and muscles are more common pain generators. Many patients have multiple etiologies for pain, and psychosocial factors probably play a more prominent role in nonspecific LBP than joint pain. Although this does not necessarily mean that patients with diskogenic or myofascial LBP would not benefit from NGF inhibitors, it does suggest that their role in the treatment of LBP will be different from their role in joint OA. For joint OA, NGF inhibitors would likely be recommended after more conservative treatments and before surgery. In other words, patients who fail NGF inhibitors would be candidates for joint replacement, so that many patients who develop RPOA on NGF inhibitors would be on the road to joint replacement anyway. By contrast, it is more challenging to identify a specific place for NGF inhibitors in the treatment pathway for axial LBP because there are several different algorithms. There is enormous variability in the responses to medications and surgery, and the latter is widely acknowledged to be less effective for LBP (eg, fusion) than for joint OA (ie, joint replacement). Not only would the higher doses required for efficacy increase the risk for RPOA, but it would do so in a population that does not typically require joint replacement.
The introduction of an entirely novel class of analgesics is an exciting development in the treatment of pain, but it also presents new challenges. Considering the current evidence and treatment options, it seems that NGF inhibitors offer less potential benefit and greater potential harms for LBP than for joint OA. However, until studies consider the heterogeneity of LBP etiologies and treatment responses, the tipping point between the risks and benefits of NGF inhibitors for LBP remains unclear.
Pain. 2020;161(9):1941-1942. © 2020 Lippincott Williams & Wilkins