Tanezumab in the treatment of chronic musculoskeletal conditions

Abstract

Introduction:

The management of pain associated with chronic musculoskeletal conditions represents a significant challenge for the clinician. There remains a need for novel medications that have a significant analgesic benefit and are also safe and well tolerated. Both pre-clinical and clinical data have provided evidence of the role of nerve growth factor (NGF) in a multitude of pain eliciting conditions. Therefore, the development of monoclonal antibodies to NGF for chronic painful musculoskeletal conditions has generated interest.

Areas covered:

This manuscript is a review that examines both the pharmacological properties and clinical studies of tanezumab, the most widely studied antibody to NGF, for management of osteoarthritis (OA) and low back pain. In addition, the safety and tolerability profile and development history of tanezumab are also discussed.

Expert opinion:

Most studies provide strong support for the ability of tanezumab to provide clinically meaningful pain relief in individuals with these conditions, with longer-term studies suggesting durability of effect. The adverse event profile appears favorable, assuming the risk mitigation strategies are effective at reducing the incidence of joint-related side effects. Further data are being collected to define the optimal dose and dosing strategy in both OA and chronic low back pain.

1. Introduction

It has been estimated that 126.6 million Americans are affected by chronic painful musculoskeletal diseases resulting in a significant burden on quality of life, function, and associated healthcare costs [1]. The annual treatment and lost wages stemming from these disorders has both direct and indirect costs in excess of $213 billion representing 1.4% of the gross domestic product of the United States [1]. Osteoarthritis (OA) is the most prevalent musculoskeletal disease, commonly involving the large joints of the lower extremities, the hands, and the spine; nonspecific low back pain (LBP) affects up to 80% of people throughout their lifetime [2]. Both conditions can be structurally and clinically progressive resulting in the development of chronic, debilitating pain, and loss of function. There are currently no treatments available that prevent the progression of cartilage degradation associated with OA, and therefore, most nonoperative treatment strategies focus on symptom management [3]. Due to the relative lack of efficacy of these nonoperative analgesic treatments, particularly over the longer term, joint replacement surgery continues to remain a primary focus of both practitioners and their patients for management of chronic, painful hip, and knee disease.

2. Overview of the market

Current pharmacological options and recommendations for the management of degenerative musculoskeletal conditions include acetaminophen, topical or oral nonsteroidal anti-inflammatory medications (NSAIDs), opiate medications, serotonin–norepinephrine reuptake inhibitors such as duloxetine, topical analgesics such as capsaicin, and intra-articular corticosteroid injections [4]. These medications often have an inadequate analgesic effect, are limited in the magnitude and/or the durability of pain relief and in the case of NSAIDs and opioids in particular, can have significant side effects when used in the long term. Therefore, a need remains for the development of medications that have a greater analgesic effect and/or are safer than currently available therapies. However, the majority of novel analgesic pharmacological treatments developed over the past several decades have been derived from current commonly used medications [5]. Efforts to modulate novel mechanistic targets, specifically in the sensory nervous system pathways, have become a focus of recent attention of drug development [6]. Nerve growth factor (NGF) has received recent attention as an important regulator of nociceptive pain and appears to be a potential target molecule for the development of more effective analgesic medications [7–9].

2.1. Nerve growth factor

NGF is a 13-kDa polypeptide, initially synthesized as a precursor pro-NGF which is cleaved to release its C-terminal mature form of a dimer and acts on sensory and sympathetic neurons [10]. During development, NGF is a trophic factor for these neurons; in adults, it assumes the role of modulating pain arising from noxious stimuli inducing sensitization [11,12]. Elevated levels of NGF in the blood and synovial fluid have been found in a number of acute and chronic pain states including OA, rheumatoid arthritis, spondylarthropathies, and lumbar degenerative disk disease [7,13]. Separately, the relationship between pain and increased levels of NGF has been demonstrated in studies in which local administration of NGF resulted in eliciting pain, for example, intramuscular injection of NGF into the masseter muscle resulted in mechanical allodynia and hyperalgesia in one early study [14] and in a randomized double-blind placebo controlled trial caused an increase in subjective pain scores and sensitivity to pressure pain in the injected muscle compared to baseline [15]. Additional evidence of the importance of the NGF in the pain pathway is provided by the fact that genetic mutations in the NGF polypeptide or its tropomysin kinase A (TrkA) receptor have been shown to result in a condition (CIPA, congenital insensitivity to pain with anhidrosis) in which individuals have a decreased ability to perceive pain [16].

NGF has two cell membrane receptor targets, the TrkA tyrosine kinase receptor and the p75 neurotrophin receptor [17]. TrkA is found on nociceptor nerve endings and is the high affinity NGF receptor; therefore, it is believed to be the primary receptor responsible for initiating a pain response [18]. The NGF–TrkA receptor complex formed following binding is endocytosed and transported to the nucleus where it regulates gene expression of neuropeptides associated with pain such as substance-P and calcitonin gene-related peptide [19] further sensitizing these neurons. Binding of NGF to this receptor also leads to intracellular activation of MAP kinases, phosphatidyl inositol-3 (PI3)-kinase, and Ras-signaling pathways [20]. This subsequently results in post-translational changes in the transient receptor potential vanilloid receptor 1 (TRPV1) ligand-gated cation channel [21,22]. This channel responds to thermal, mechanical, and chemical stimuli and is pivotal to the conduction of nociceptive signals [8]. When activated by a stimulus, the TRPV1 channel opens resulting in the influx of Ca²⁺ necessary for the generation of an action potential and the transmission of pain signals by the neurons. The binding of NGF to the TrkA receptor leads to TRPV1 channel sensitization and decreases the threshold at which it opens. NGF also increases the expression of TRPV1 and its trafficking to the plasma membrane, which also decrease the threshold for action potential generation in nociceptive neurons [21,22].

Targeting and inhibiting the NGF pathway therefore represent a potential treatment strategy for patients affected by chronic painful musculoskeletal conditions. A number of therapeutic approaches have been proposed including blocking the NGF receptors themselves or limiting the release of NGF. Inhibiting the tetrodotoxin-resistant voltage-gated sodium channel role in NGF-induced hyperalgesia has also been investigated [23]. The most immediately promising strategy, however, appears to be inhibiting the effect of NGF through the administration of anti-NGF monoclonal antibodies. A recent study by Xu et al. [24] confirmed the potential of this strategy by examining the effect of the anti-NGF murine precursor antibody MuMAb911 in a monosodium iodoacetate (MIA) rat model of OA. They found that both therapeutic and preventative treatment with MuMAb911 reduced MIA-induced pain behavior as well as reduced the number of subchondral osteoclasts.

While several anti-NGF monoclonal antibodies have entered clinical trials, including fasinumab and fulranumab, tanezumab has been the most extensively studied and will be the focus of the remainder of this article.

2.2. Tanezumab – introduction to the compound

Tanezumab is a humanized monoclonal antibody of the lgG2 class directed against NGF with a molar mass of 145.4 kg/mol [25]. Developed by Pfizer since 2006 when it was acquired from Rinat Neurosciences, tanezumab binds to NGF preventing it from interacting with its receptors, thereby precluding signaling through the sensory nociceptive neurons responsible for the perception of pain. Tanezumab has been shown to bind to NGF with high specificity and affinity [26] with an IC₅₀ of 20 pM [27]. The tanezumab/NGF complex has a half-life of >100 h also suggesting the tight binding of the drug to its target.

Zorbas et al. [28] performed a toxicity and pharmacokinetic (PK) study in cynomolgus monkeys (n = 8) in which the drug was administered intravenously weekly at 30 mg/kg for 23 weeks and 1 or 10 mg/kg for 26 weeks followed by an 8-week recovery period. Gross necropsies of the primates performed at study completion failed to demonstrate any abnormalities, and no histological abnormalities were found in the central nervous system including brain and spinal cord. No abnormalities were found in serum chemistry, hematology, or urinalyses. Plasma samples were taken to measure antidrug antibody levels, reported in 20% of the monkeys, and PK. In animals that were antibody negative, steady state was achieved at approximately 8 weeks after the initial dose with the exposure to tanezumab being dose proportional. One monkey did die during the study with findings suggestive of a hypersensitivity reaction; however, overall, tanezumab was reported to have a favorable toxicity and PK profile.

Human studies have demonstrated that tanezumab is subject to both linear and nonlinear PK of drug elimination. Population modeling across wide dose ranges indicates a two-compartment model (central and peripheral compartment) with linear elimination being the more important mechanism, particularly at doses ≥2.5 mg [27,29]. The linear elimination of monoclonal antibodies is nonspecific due to the fact that it occurs via catabolism following endocytosis by the reticuloendothelial system [30]. This process is relatively slow with a half-life estimated at 21 days. PK/Pharmacodynamic studies evaluating the role of gender and weight on interindividual variability have shown a negligible effect leading to the majority of phase III clinical studies incorporating a fixed dose regimen [26].

2.3. Clinical trails of tanezumab

The primary focus of this article is the use of tanezumab in OA and nonspecific LBP, which are both chronic musculoskeletal pain states, as these studies represent the majority of research performed on the drug. Clinical trials have also been performed in neuropathic pain states such as peripheral diabetic neuropathy and postherpetic neuralgia [31], interstitial cystitis [32,33], and metastatic bone pain [34], but these studies have been limited in scope and are not the focus of this article.

2.3.1. Osteoarthritis

2.3.1.1. Phase I/II clinical trails.

There have been 4 major phase I/II clinical trials of tanezumab for OA. In the first phase I/phase II trial in patients with moderate-to-severe knee OA, Hefti et al. [7] investigated the effect of one dose of tanezumab IV compared to placebo (n = 79, 27 in 100 μg/kg dosing group, 26 in 300 μg/kg, and 26 in the placebo group) and followed these patients for 181 days. They reported a significant reduction in pain and improved function in both treatment groups compared to placebo.

In a phase II proof of concept study, Lane et al. [35] investigated 450 patients with moderate-to-severe knee OA randomly assigned to receive intravenous (IV) administration of tanezumab at 10, 25, 50, 100, and 200 μg/kg or placebo 8 weeks apart (i.e. subjects received the drug on day 1 and day 56). Pain was measured using a visual-analog scale. Tanezumab treatment led to a substantial, significant improvement in the primary efficacy measures of knee pain during walking and the patient’s assessment of responses to therapy. For the former, there was a 45–62% decrease in pain from baseline averaged over the 16-week period in the different tanezumab dose groups compared to a 22% reduction in the placebo group, and a similar significant benefit was reported in the latter in favor of the tanezumab groups. The standardized effect sizes for the tanezumab doses investigated were 0.33 (10 μg/kg), 0.52 (25 μg/kg), 0.38 (50 μg/kg), 0.75 (100 μg/kg), and 0.77 (200 μg/kg). Treatment with the drug was not associated with a statistically significantly increase in the proportion of adverse events (AEs) compared to placebo (68% with tanezumab compared to 55% with placebo). However, the number of treatment-related AEs was increased with the highest doses of the drug (59% in those receiving 50 μg/kg compared to 78% receiving 200 μg/kg), with a higher rate of abnormalities of peripheral sensation at the two highest doses. The most common AEs that were reported were headache, upper respiratory tract infections, and paresthesias.

In an open-label extension of this initial phase II tanezumab trial, Schnitzer et al. [36] investigated the longer term (56 weeks) safety and effectiveness of repeated doses of tanezumab in 281 participants with painful knee OA. All subjects received an IV infusion of tanezumab at a dose of 50 μg/kg at entry into the study and at day 56, with following doses administered at 8-week intervals (each patient therefore received up to eight total infusions). Compared to their baseline pain prior to receiving tanezumab in the initial study, individuals in the extension study demonstrated decreased pain and improved function at 56 weeks. Treatment-related AEs were reported in 7.5% of subjects, with 1.4% of subjects discontinuing due to AEs. The most common AEs were arthralgia, back pain, and headache; abnormal peripheral sensation was reported in less than 5% of subjects, with most events rated mild and resolving prior to study completion. This study was important in demonstrating that the efficacy of treatment with tanezumab could be sustained over a long time course.

Another early phase I/II study, this time in a Japanese population of patients with moderate-to-severe knee OA pain, by Nagashima et al. [37] assessed the preliminary efficacy, safety, and PK profile of tanezumab in a dose-escalation study. Subjects (n = 83) received a single dose of 10, 25, or 50 μg/kg and were followed for 92 days or separately 100, 200 μg/kg and were followed for 120 days, with comparison made to placebo. The outcome measures included the incidence of AEs, change in pain intensity from baseline to week 8 and the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) subscales. At week 8, the 25, 100, 200-μg/kg doses (but not the 10- or 50-μg/kg) resulted in significant improvement in the pain indices and WOMAC subscales. The standardized effect sizes on WOMAC pain in this study for the tanezumab doses investigated were −0.31 (10 μg/kg), 0.42 (25 μg/kg), −0.09 (50 μg/kg), 0.34 (100 μg/kg), and 0.94 (200 μg/kg). Seven patients reported AEs, which included abnormal peripheral sensation, allodynia, paresthesia, dysesthesia, and thermohypoesthesia, the majority of which were in the 200-μg/kg group. Overall, the drug appeared to be well tolerated and improved OA symptoms in this Japanese cohort.

2.3.1.2. Phase III clinical trials.

The majority of published phase III clinical trials have either investigated tanezumab as monotherapy in placebo-controlled trials or as coadministration with other classes of analgesic medications such as NSAIDs. Most studies also used the WOMAC pain and physical function subscales (with a numeric rating scale [NRS] of 0–10) and the patient’s global assessment of OA (PGA, with a Likert scale of 1–5) as outcome measures.

2.3.1.2.1. Tanezumab as monotherapy.

Brown et al. [38] compared the efficacy of tanezumab versus placebo (n = 621) for reducing pain and improving physical function in patients with hip OA. Patients were randomized to treatment with IV tanezumab 2.5 mg, 5 mg, 10 mg, or placebo at 8-week intervals for 16 weeks with follow-up at 32 weeks. Baseline WOMAC pain scores for these subjects ranged from 7.2 to 7.3 and PGA scores of 3.5–3.6. They found that tanezumab treatment was superior to placebo at all doses for the three primary outcome measures (WOMAC pain, WOMAC physical function and patient’s global assessment of their OA). The magnitude of the effect was similar for tanezumab at the 5 and 10-mg dose levels (average reduction in WOMAC pain score of −3.31 and −3.37, respectively) versus placebo (−1.62) and somewhat higher than that for tanezumab at 2.5 mg (−2.90), but all doses were effective. With regard to safety, compared with placebo, the incidence of adverse effects was greater overall in the tanezumab groups. Patients who received 10 mg dosing had the largest proportion of AEs, which included abnormalities of peripheral sensation, specifically paresthesia (2–5%) and hypoesthesia (1–4%). Total joint replacement was reported in eight patients, three in the placebo group (three index hips), and a total of five among the tanezumab groups (four index hips and one shoulder). In a corresponding study in patients with knee OA (n = 690), the same research team investigated the analgesic effect of tanezumab versus placebo with similar findings [39]. The mean baseline WOMAC pain scores for subjects were 7.0–7.2 and mean baseline PGA scores ranged from 3.4 to 3.5. All tanezumab doses were significantly superior to placebo for the primary efficacy end points, with a very similar effect size to the prior hip study (average reduction in WOMAC pain score ranged from 3 to 4 irrespective of dose compared to 2–2.5 for placebo).

A long-term non-controlled, randomized, double-blind safety study of tanezumab at doses of 2.5 mg, 5 mg, and 10 mg administered subcutaneously every 8 weeks for 16 weeks in patients with hip or knee OA (n = 679) [40] demonstrated improvements in WOMAC pain, physical function, and patient global assessment of OA that were higher in the 5- and 10-mg groups compared to the group that received the lower dose of 2.5 mg. The incidence of AEs was also somewhat higher in the two highest doses groups compared to the 2.5-mg group.

Phase III studies comparing tanezumab to other analgesic medications have also been performed. Two randomized controlled studies (n = 828 and n = 840) [41] evaluated the efficacy and safety of tanezumab versus naproxen for the treatment of knee or hip OA. These studies compared the effect of IV tanezumab (5 or 10 mg) every 8 weeks for 16 weeks to placebo and naproxen (500 mg twice daily). Baseline WOMAC pain scores for these subjects ranged from 7.2 to 7.5. Tanezumab reduced pain versus placebo and improved function (WOMAC) and PGA scores. Both the 5- and 10-mg dosing regimens of tanezumab did result in statistically significant improvements compared to naproxen in all outcome measures, except for WOMAC pain which was statistically significant with the 5-mg tanezumab group (mean change −2.95 for the 5-mg tanezumab dose, −2.26 for naproxen, and −1.81 for the placebo) but not with the 10-mg tanezumab dose (−2.62). Functional outcome scores with both the 5- and 10-mg tanezumab dose groups were superior to NSAIDs (mean change in WOMAC physical function, −2.68 with the 5-mg tanezumab dose, −2.45 with the 10-mg tanezumab dose, and −1.91 with naproxen). There was a greater incidence of peripheral sensory AEs in the tanezumab groups compared to the placebo and naproxen groups although the frequency of discontinuations as a result of AEs was similar between study groups (rates of discontinuation for tanezumab ranged from 6.7–77% compared to 6.3–7.6% for naproxen and 3.4–4.8% for placebo across the two studies incorporated in this report).

Spierings et al. [42] compared the effect of two doses of tanezumab (5 or 10 mg in 8-week intervals) to controlled release oral oxycodone (10–40 mg every 12 h) or placebo in people with OA of the hip or knee (n = 610). The average baseline WOMAC pain scores ranged from 7.63 to 7.85. They found that at 8 weeks, the WOMAC pain score for both tanezumab groups was significantly improved from baseline compared to placebo and oxycodone (mean change in pain score −2.62 for the placebo group, −2.59 for the oxycodone group, −3.58 for the 5-mg tanezumab group, and −3.58 for the 10-mg tanezumab group. Tanezumab also provided significant improvements versus placebo and oxycodone for WOMAC physical function and stiffness scores and patient global assessment of OA at week 8.

2.3.1.2.2. Coadministration with other analgesic medications.

Adjunctive trials were undertaken to determine if tanezumab would provide additional benefit to individuals receiving NSAID therapy for OA. Schnitzer et al. [43] examined the efficacy and safety of tanezumab administered as either monotherapy or in combination with NSAIDs in a large cohort (n = 2700) of patients with knee or hip OA-related pain. WOMAC pain scores averaged from 6.3 to 6.5 in enrolled subjects. Patients received IV tanezumab (5 or 10 mg) every 8 weeks for 16 weeks with or without oral naproxen 500 mg twice daily or celecoxib 100 mg twice daily and this was compared to the same doses of naproxen or celecoxib alone. All tanezumab treatment groups (monotherapy and combination therapy) had statistically significant improvements in WOMAC pain (mean change in pain score for 10 mg tanezumab alone was −2.02 compared to −2.36 in combination with naproxen and −2.41 in combination with celecoxib) and compared to both NSAID alone groups (−1.44 naproxen, −1.47 celecoxib). Combination therapy (tanezumab + NSAID) did not cause a substantial improvement in pain or function over tanezumab monotherapy. With regard to the PGA scores, both of the 5-mg tanezumab monotherapy groups failed to show statistical superiority to NSAIDs alone, although the combination 10 mg tanezumab + NSAID groups did (−0.72 change in PGA score with 10 mg tanezumab + naproxen compared to −0.54 with naproxen alone and −0.75 change in PGA score with 10-mg tanezumab + celecoxib compared to −0.54 with celecoxib alone) meeting the prespecified definition of superiority. The frequency of AEs was similar in all treatment groups. There was a higher incidence of paresthesia, hypoesthesia, arthralgias, and peripheral edema in all groups treated with tanezumab compared to NSAIDs alone, with the combination tanezumab + NSAID groups generally having the highest frequencies. The incidence of rapidly progressive OA (RPOA) was greater in the treatment groups that included tanezumab compared to the NSAID alone treatment groups (0.2% NSAID alone, 0.7% 5 mg tanezumab, 1.3% 10 mg tanezumab, 1.7% tanezumab 5 mg + NSAID, 2.4% tanezumab 10 mg + NSAID), but only in the tanezumab + NSAID treatment groups did this increase reach statistical significance. Further discussion of this issue follows in the subsequent section on safety and tolerability issues of the drug.

In a randomized double-blind trial, Balanescu et al. [44] evaluated the efficacy and safety of tanezumab added to oral diclofenac sustained release (DSR) in patients with hip or knee OA pain (n = 604). Mean baseline WOMAC pain scores were 5.76–6.06. Patients were randomized to receive DSR 75 mg twice daily with IV tanezumab (2.5, 5, or 10 mg) or IV placebo at weeks 0, 8, or 16 with final assessment at 16 weeks. The co-primary end points included WOMAC pain and physical function subscales and patient’s global assessment of OA. WOMAC pain score, which was their primary outcome, improved significantly in the tanezumab + DSR groups (mean change in pain −2.09 2.5 mg tanezumab + DSR, −2.19 5 mg tanezumab + DSR, and −2.25 10 mg tanezumab + DSR) compared to placebo + DSR (−1.68). The overall incidence of AEs was higher with the tanezumab + DSR groups (45.2–49.7%) than with the placebo + DSR groups (34.9%), though serious AEs were similar between treatments (5.3–7.6%).

2.3.2. Low back pain

In comparison to OA, there are a limited number of comparative studies that have examined the long-term efficacy of tanezumab for the treatment of chronic LBP. The management of this condition is challenging since the etiology may be multifactorial and the treatment can involve a number of modalities; hence, the development of medications for this indication can be challenging.

In a recent randomized, double-blind, placebo controlled trial, tanezumab was given to patients with at least 3 months of non-radiculopathic back pain that required regular analgesic medication [45]. These patients also had to have an average LBP intensity (aLBPI) score of >4 using an 11-point NRS. The subjects received a single IV dose of 200 μg/kg tanezumab, naproxen (500 mg twice a daily for 12 weeks), or a placebo and were observed over a 12-week period. At both the 6 and 12-week time points, the subjects receiving tanezumab had a significantly greater reduction in aLBPI score (−3.37 change at week 6) compared to the naproxen (−2.54 change at week 6) and placebo groups (−1.96 at week 6). In addition, tanezumab resulted in a greater decline in disability scoring from the Roland Morris disability questionnaire (RMDQ) at 12 weeks. Treatment-related AEs were higher with tanezumab treatment, the most common of which were headache, arthralgia, myalgia, and hyperesthesia that was dose dependent.

The other much larger phase II study was in patients with chronic LBP (n = 1347) [46]. Participants were randomized to receive IV tanezumab 5, 10, or 20 mg every 8 weeks or naproxen 500 mg twice daily and were compared to a placebo group. The overall efficacy was similar between the 10- and 20-mg dose groups and both showed significantly greater improvement in physical function, PGA, and pain (−2.18 change in aLBPI score for 20 mg tanezumab and −2.08 for 10 mg tanezumab) than either the placebo (−1.25) or the naproxen groups (−1.66) at week 16. The 5-mg dose did not have a statistically significant improvement in these outcome measures compared to placebo. The most common AEs that were reported were paresthesia (4.7–12.9% in the tanezumab groups versus 1.7% in the naproxen group and 2.2% in the placebo group). There were no cases of osteonecrosis or need for total joint replacement. In a long-term extension of this study [47] at a mean duration of follow-up of 194 and 202 days with tanezumab 10 and 20 mg, respectively, both tanezumab doses provided similar and sustained improvements in brief pain inventory short-form scores, RMDQ scores, and the patient’s global assessment of LBP. In this extension study, six participants reported AEs that were initially classified as osteonecrosis with an additional nine participants (tanezumab 10 mg n = 7, 20 mg n = 2) requiring total joint replacement. A blinded adjudication committee (as outlined in section on safety) reviewed all the cases of osteonecrosis and individuals having total joint replacement and subsequently decided that none of the cases initially classified as osteonecrosis could be confirmed.

2.3.3. Safety, tolerability, and regulatory affairs

During the development of tanezumab, unexpected AEs identified initially by site investigators as osteonecrosis led the Division of Analgesia, Anesthetic and Addiction Products of the US Food and Drug Administration (FDA) to place a clinical hold in 2010 on studies involving the medication for all indications other than cancer pain. This hold was subsequently extended to all anti-NGF monoclonal antibodies in clinical development based on similar reports in other development programs. There was also concern regarding progression of OA disease in some patients and subsequent expedited need for total joint replacement [48,49]. This initial partial clinical hold specific to tanezumab was lifted in 2013; however, later that year, the FDA placed the anti-NGF class of medications on a second partial clinical hold due to changes that had been reported in the sympathetic nervous systems of mature rats and monkeys in histologic studies [50]. After further data were presented to the FDA, the partial clinical hold placed on the use of tanezumab was lifted in 2015.

The joint safety concerns in the tanezumab studies were raised by the reports of osteonecrosis by site investigators in a total of 87 subjects; 81 of them were enrolled in phase III OA studies and the other 6 cases were from phase II studies in patients with chronic LBP [48]. The number of cases and rate were higher in participants randomized to tanezumab plus NSAIDs than in those treated with tanezumab monotherapy or NSAIDs. Within the groups containing tanezumab, there was also a dose–response relationship with more risk seen at higher compared to lower doses.

To evaluate these reports of osteonecrosis and joint damage further, Pfizer convened an Adjudication Committee composed of a multispecialty group of physicians and scientists that reviewed all the cases reported as osteonecrosis as well as all participants having joint replacement surgery during and immediately after being involved in tanezumab studies [49]. Of the 87 subjects who had initially been reported as having potential suspected osteonecrosis by the site investigators, only 2 were confirmed to have the disorder by the Adjudication Committee (1 patient had received 10 mg of tanezumab and the other 5 mg; the latter patient had no symptoms related to this joint finding, the event only being found on a scheduled end of study X-ray [48].

In 51 cases, the committee made the adjudicated diagnosis of worsening OA, with two-thirds of these cases classified as RPOA [48]. This was diagnosed by the presence of bone destruction out of proportion to that normally seen in progressive OA (type 2 RPOA). The rate of RPOA in participants who received the tanezumab + NSAID combination was increased compared to the rate in those receiving tanezumab monotherapy by greater than threefold. In a further 21 cases originally reported as osteonecrosis, the committee diagnosed another condition, with the most common being a subchondral insufficiency fracture of the knee. In eight cases, there were not enough imaging studies to provide a definitive diagnosis, and in five cases, the committee did not reach a consensus although none of these was felt to have osteonecrosis.

The mechanisms involved in RPOA remain poorly understood. Occurrence of this complication has been reported with NSAIDs during their initial development with a proposed mechanism of increased joint loading due to reduced pain in an already damaged joint [51,52]. It has been shown that decreased pain with NSAID administration alone can increase the load placed on the degenerative portion of an osteoarthritic joint [53]. However, this effect has never been conclusively shown to lead to RPOA in a cause–effect relationship and therefore does not necessarily explain the occurrence with concurrent tanezumab and NSAID use. There was also an initial suggestion that the basis for the development of RPOA was analogous to a neurogenic arthropathy (Charcot joint). However, a major difference is the lack of evidence for the development of a severe neuropathy and loss of protective sensation in weight bearing joints, which is present in a Charcot joint. Another potential reason could be based on the role of the NGF pathway for bone formation and bone repair. A recent study using transgenic mice with a significantly altered NGF–TrkA-signaling pathway found that inhibition of TrkA activity in bone prevented loading-induced expansion of osteoblasts, and in a separate fracture model experiment found a reduction in bone callus formation in these mice [54]. Thus, NGF may have an important role in bone repair, and the coupling in bone of the inhibition of the TrkA pathway using an anti-NGF medication with inhibition of prostaglandin-dependent bone repair and remodeling, seen with NSAIDs [55], could be expected have a major impact on the anabolic/repair response of bone to load-induced micro-fractures. These effects could ultimately be expressed clinically as an increase in the risk of RPOA.

A commonly reported adverse effect of tanezumab has been the development of abnormalities of peripheral sensations (e.g. allodynia, hypoalgesia, and paresthesias) [35,37,47]. In most studies to date, these symptoms have generally been short-lived but some have persisted beyond the end of the study follow-up and long-term neurologic safety warrants further study. Carpal tunnel syndrome in a small number of individuals has been a surprising finding, as a more diffuse polyneuropathy would be a more likely presentation of an agent that has a general neurotoxic effect, and this finding has been infrequently seen [38]. The reason for the higher incidence of reports of carpal tunnel symptoms with tanezumab therapy is not known. No evidence of an elevated incidence of autonomic dysfunction was reported in the tanezumab studies.

2.3.4. Risk mitigation

In an attempt to minimize the potential risks of tanezumab therapy in future studies, a number of proposed strategies were suggested by the adjudication committee for future study design with the goal of limiting these AEs [49]. These included eliminating or significantly limiting the concomitant use of NSAIDs, comprehensive evaluation of OA medical history and joint anatomic status prior to study entry to exclude individuals at increased risk of OA progression, increased patient monitoring for subjects who complain of severe persistent joint pain, and the use of the lowest effective doses of tanezumab for OA treatment (e.g. 2.5 or 5 mg every 8 weeks). Finally, NGF administration was suggested to be discontinued if a participant had not shown a positive response early after treatment in order to limit longer term exposure to nonresponders [49].

3. Conclusions

The finding that NGF is an important mediator of pain has led to the development of a novel class of analgesic medications that target this pain pathway. Tanezumab, a monoclonal antibody directed against NGF, has been shown in a large number of studies to reduce pain and improve function in individuals with painful degenerative musculoskeletal conditions [Box 1]. Joint-related safety concerns reported in these studies have led to risk mitigation strategies that are being evaluated in ongoing studies focusing on providing a better definition of joint-related and overall safety of tanezumab. These studies will allow for a more complete understanding of the risks and benefits of tanezumab in the treatment of patients with musculoskeletal pain.

Box 1. Drug Summary.

Drug name	Tanezumab
Phase	III
Indication	Musculoskeletal pain and osteoarthritis
Pharmacology description	Nerve growth factor antagonist/monoclonal antibody
Route of administration	Injectable
Pivotal trial(s)	[35,43]

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4. Expert Opinion

An extensive dataset (reviewed above) exists that supports the efficacy of tanezumab in the management of OA. Multiple studies in diverse populations of individuals with OA have demonstrated efficacy compared to placebo for all the prespecified and well-validated standard end points. A smaller dataset exists in LBP, but studies to date likewise have demonstrated efficacy when evaluated by standard, validated end points. Taken together, these studies provide strong support for the ability of tanezumab to provide relief of pain and improvement in function and well-being for individuals with the two leading causesof chronic musculoskeletal pain. Longer term studies in OA provide evidence for durability of effect.

Additional data are needed to define the optimal dose and dosing strategy in both OA and chronic back pain. Using the lowest effective dose is an integral part of any risk mitigation approach; so, better definition of this issue will be helpful. Also, important to gauge is how tanezumab monotherapy compares with existing therapies. This has been at least partially answered at doses of 5 and 10 mg (a dose that will likely not be carried forward in OA) administered intravenously every 8 weeks (see above). Similar studies utilizing the 2.5-mg dose would also be informative, as will data from current studies using a more patient-friendly subcutaneous rather than IV route of administration.

Considerations regarding safety of treatment are paramount in the management of chronic pain. Although existing drugs such as NSAIDs and opioids provide inconsistent and often suboptimal efficacy, concerns regarding their safety, particularly in the setting of long-term therapy, are what makes the development of novel agents so critical. In that regard, tanezumab offers the potential of significant advances but also has raised new issues that need to be further addressed. Tanezumab treatment has not been associated with the most common and limiting side effects of NSAIDs or opioids: no gastrointestinal or cardiovascular safety issues have been identified at this point and no central nervous system effects of the drug reported or expected. As a highly specific targeted monoclonal antibody, such effects were not expected. However, a different set of safety events have been identified, including those that may be more mechanism based, including dysesthesias and other abnormalities of peripheral sensation, as well as those whose mechanism is not well understood, such as cases of RPOA. The peripheral nervous system-based AEs appear to be not severe and largely transient in nature. The joint-related events, which precipitated the initial partial clinical hold in the development program, have now been more clearly defined as the appearance of RPOA and not osteonecrosis, and importantly, risk factors for the development of RPOA have been identified. Currently, studies are being undertaken to determine if an appropriate risk mitigation strategy (outlined above) will be effective at reducing the incidence of RPOA and if so, to what extent. What will be important to define from these prospective studies, over and above an assessment of relative risk, is whether joint damage can occur in non-OA joints and whether additional risk factors for RPOA, which could have clinical utility, can be identified, specifically underlying OA imaging biomarkers, serologic biomarkers, or levels of physical activity.

If the overall safety of tanezumab is considered acceptable, and tanezumab is approved by the FDA for clinical use, defining the population of patients for whom this treatment would be most appropriate will be important. As a first step, those individuals who should not receive tanezumab will need to be identified, and these will likely be individuals with preexisting joint abnormalities that may put them at increased risk of RPOA, such as subchondral insufficiency fractures. On the other hand, tanezumab would be a particularly useful agent for specific populations of individuals for whom NSAIDs are contra-indicated and/or not advised, including people with chronic renal insufficiency, congestive heart failure, and those on anti-coagulation should be prime candidates for an agent such as this. The elderly with chronic musculoskeletal pain are another group in whom both NSAIDs and opioids should be used with extreme care, if at all, and for whom a medication such as tanezumab could provide needed benefit while being better tolerated.

Although tanezumab development has focused primarily on individuals with painful OA, individuals with chronic LBP represent another large group of patients for whom there is clear recognition of the need for more effective and safer therapies. Given the widespread use of opioids for chronic LBP, coupled with the failure of evidence for long-term efficacy of NSAID and opioid treatment, the recognition of opioid misuse and abuse, the potential for addiction, and the lack of a surgical intervention such as exists in OA, tanezumab would be an attractive option for this population if approved. Furthermore, faced with the fact that NSAIDs have two boxed warnings in their prescribing information, both of which warn of the possibility of death with use, the availability of an effective agent with a well-defined safety profile in which infrequent OA progression may be the most serious adverse effect may seem attractive in other chronic pain settings for which current medical treatments are ineffective.

Given the need to complete the large and lengthy safety trials with tanezumab, it is likely to be several years until a filing with the FDA for marketing approval. Important to recognize is how significantly tanezumab has already changed the pain therapeutic landscape. After years of failures, tanezumab has shown that modulating elements of the peripheral pain pathway can result in a clinically valuable agent and that the magnitude of pain relief can be markedly greater than seen with existing analgesic agents. This had already led to a renaissance of interest in new approaches to pain, focusing not only the NGF pathway but also seeking to block other mediators and receptors in the peripheral pain pathway [6]. Such agents are already in clinical trials from which we will learn more about pain physiology and hopefully generate additional families of therapeutic agents to benefit our patients with pain [6].

Table 1.

Published phase III trials for tanezumab use in hip or knee OA.

Study	Number of participants	Demographics	Treatment dose and duration	Study groups	Findings
Balanescu et al. [44]	N = 604, knee or hip OA	Age: 57.2–57.8 years, female 59.6–65.2% across study arms	8-week intervals for 16 weeks	Tanezumab 2.5 mg, 5 mg, 10 mg + diclofenac SR, and placebo	Tanezumab caused significant reduction in WOMAC pain, physical function, and PGA for all doses compared to placebo
Brown et al. [38]	N = 621, hip OA	Age: 61.8–63.3 years, 56.1–66.5% female across study arms	8-week intervals for 16 weeks with follow-up at 32 weeks	Tanezumab 2.5 mg, 5 mg, 10 mg, and placebo	Tanezumab caused significant reduction in WOMAC pain, physical function, and PGA for all doses compared to placebo
Brown et al. [39]	N = 690, knee OA	Age: 60.8–62.2 years, female 54.7–69.2% across study arms	8-week intervals for 16 weeks with follow-up at 32 weeks	Tanezumab 2.5 mg, 5 mg, 10 mg, or placebo	Tanezumab caused significant reduction in WOMAC pain and PGA for all doses compared to placebo
Ekman et al. [41]	N = 828 N = 840, knee or hip OA (report incorporates two studies)	Age: 59.2–61.4 years, female 57.7–65.1% across study arms	Received 2 doses, at baseline and 8 weeks, with follow-up at 16 weeks	Tanezumab 5 mg, 10 mg, naproxen 500 mg, or placebo	5 mg tanezumab improved WOMAC pain, function, and PGA. Effect noted more than with 10 mg dose
Schnitzer et al. [43]	N = 2700, knee or hip OA	Age: 61.3–62.0 years, female 67.7–72.5% across study arms	Received 2 doses, with or without NSAID at baseline and 8 weeks, with follow-up at 16 weeks	Tanezumab 5 mg, 10 mg, and tanezumab + naproxen or tanezumab + celecoxib	All tanezumab groups improved pain and function. Combination therapy did not substantially improve outcome over monotherapy
Spierings et al. [42]	N = 610, hip or knee OA	Age: 57.0–57.8 years, female 59.6–65.2% across study arms	Received 2 doses, with or without NSAID at baseline and 8 weeks, with follow-up at 16 weeks	Tanezumab 5 or 10 mg, controlled release oxycodone 10 or 40 mg every 12 h placebo	WOMAC pain, stiffness, physical function, and PGA improvement with tanezumab

NASID: nonsteroidal anti-inflammatory medications; WOMAC: Western Ontario and McMaster Universities Osteoarthritis; OA: osteoarthritis.

Table 2.

Published phase III trials for tanezumab use in chronic low back pain.

Article	Number of participants	Demographics	Treatment dose and duration	Study groups	Findings
Katz et al.[45]	N = 217, chronic LBP	Age: 49.5–52.2 years, female across study arms 47.7–60.2% across study arms	Single dose of tanezumab and followed for 12 weeks	Tanezumab 200 μg/kg, naproxen 500 mg twice daily or placebo and followed for 12 weeks	Improvement in aLBPI and RMDQ with tanezumab
Kivitz et al. [46]	N = 1347	Age: 49.6–55.9 years, female across study arms 47.7–60.2% across study arms	Two doses of tanezumab every 8 weeks and followed for 16 weeks	Tanezumab 5, 10, or 20 mg every 8 weeks or naproxen 500 mg twice daily and placebo group	Improvement in aLBPI and RMDQ with tanezumab

aLBPI: average low back pain intensity; LBP: low back pain; RMDQ: Roland Morris disability questionnaire.