Emerging therapies

Emerging therapies for osteoarthritis pain

Traditional pharmacological strategies for managing pain in osteoarthritis (OA) include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular treatments and, for severe pain, opioid analgesics. Updates to guidelines, while strongly recommending NSAIDS, have downgraded (or withdrawn) recommendations for paracetamol use, and recommend opioids only as a last resort as there is insufficient evidence of efficacy and the likelihood of adverse reactions^1–3. These treatments are often inadequate, particularly in older patients that are less able to deal with adverse reactions or who possess comorbidities that mean some treatments are contraindicated. Adverse reactions include paracetamol-induced hepatotoxicity, gastrointestinal toxicities from NSAIDs, and the risk of falls, delirium and dependency from opioids⁴.

Long-lasting, effective and tolerable medical treatments for OA pain are required if core first-line therapies such as exercise and lifestyle changes prove insufficient. Current data suggest that joint damage, inflammation, and peripheral and central sensitisation to pain all contribute to OA pain, which may partly explain the relative incongruence between structural damage and perceived pain in patients with OA⁵.

Therapies targeting inflammation

There has been a shift in interest towards therapies that target nociceptive and inflammation pathways, both of which are implicated in OA pain; increasing evidence points to cross-talk between these pathways^6–9. Therapies that target inflammation, such as intra-articular glucocorticoids, are already used in the clinic to treat OA pain. However, there has been limited success in targeting individual proinflammatory mediators, such as tissue necrosis factor (TNF) or members of the interleukin family⁹, with biologics^5,9,10. Some evidence suggests that long-term treatment (>12 months) with anti-TNF can protect against joint damage but that TNF is less involved in pain mechanisms⁵.

Other inflammatory cytokines are being investigated as potential treatment targets in OA. Therapies that facilitate intra-articular delivery of genes encoding anti-inflammatory cytokines may overcome the problem of delivering large biologic molecules into the joint. Currently, multiple experimental therapies that target the cross-talk between the inflammation and nociceptive pathways are under investigation, including the granulocyte–macrophage colony-stimulating factor (GM-CSF)–CC-chemokine ligand 17 (CCL17) chemokine axis^5,9.

Methotrexate is an accepted treatment for rheumatoid arthritis. A pragmatic phase III trial showed methotrexate significantly reduced knee OA pain and improved the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for stiffness and function, but the analgesic effect was clinically borderline¹¹. An ongoing randomised controlled trial (RCT) is examining the effect of methotrexate on pain and synovitis in patients with moderate-to-severe knee OA¹², but more evidence is required for a possible role of methotrexate in relieving OA pain.

Therapies targeting the nociceptive pathway

Investigative therapies associated with the nociceptive (pain) pathway aim to dampen nociceptive signalling in various ways¹³

Nerve growth factor as a target

Nerve growth factor (NGF) is released during injury or inflammation and regulates neuronal survival and pain signalling by binding to and activating tropomyosin kinase A (TrkA) (Figure 1). NGF also binds to the p75^NTR receptor that triggers a cellular signalling cascade known to be associated with mechanical hyperalgesia¹³. Both NGF and p75^NTR appear to be overexpressed in the serum and synovial fluid of patients experiencing pain from conditions such as OA¹⁴. Investigative therapeutic strategies aimed at disrupting NGF-induced pain, therefore, include antibodies and small molecule inhibitors against NGF, TrkA and p75^{NTR 13}(Figure 1).

Figure 1. Pathways of investigative drugs targeting pain in osteoarthritis (Adapted). NGF, nerve growth factor; TrkA, tropomyosin kinase A; TRPV1, transient receptor potential vanilloid 1 (ion channel).

Anti-NGF antibodies

Currently, only one anti-NGF monoclonal antibody, fasinumab, is still being explored in Phase III clinical trials. Trials with two other candidates, fulranumab and tanezumab¹⁵, have been discontinued because of safety concerns, including osteonecrosis and rapidly progressive OA⁵.

Fasinumab is a fully human IgG₄ monoclonal antibody. In randomised, double-blind Phase III clinical trials, OA patients treated with fasinumab at different doses from 1 to 9 mg experienced less knee and hip pain and displayed better physical function than the placebo group^5,16. In a Phase II-III trial, 9 mg of subcutaneous fasinumab every 4 or 8 weeks improved pain and function in patients with chronic low back pain at 16 weeks¹⁷. However, the incidence of arthropathies also increased in both these trials, suggesting that joint-related adverse reactions are a class effect of NGF inhibitors. Data from a long-term safety study of fasinumab (NCT02683239) are expected in 2022¹⁸.

Anti-TrkA and p75^NTR treatments

With the aim of altering NGF-mediated pain, multiple specific TrkA and pan-Trk inhibitors have been assessed in Phase I and II clinical trials for OA pain. Most studies have been small and results have been mixed^19–21. Indeed, many clinical trials have been abandoned or halted in patients with OA, and more studies are needed to confirm the utility of TrkA inhibition in clinical practice.

Another possible strategy to dampen NGF-mediated pain is to target its binding partner, p75^NTR. A Phase I clinical trial (NCT03227796) of the p75^NTR-Fc fusion protein (LEVI-04) in patients with OA knee pain was completed in March 2021²². To date, study results have not been published.

Ion channel modulators

Ion channels have been implicated in OA pain, one of which is the transient receptor potential vanilloid 1 (TRPV1) channel that is localised in sensory neurons¹³. TRPV1 modulators desensitise the end terminal of these primary afferent pain fibres (Figure 1). The best studied TRPV1 agonist is CNTX-4975, a synthetic capsaicin administered by intra-articular injection. There are currently two ongoing Phase III clinical trials for CNTX-4975 in patients with chronic moderate-to-severe OA knee pain (NCT03429049²³ and NCT03661996²⁴), after the efficacy of a single intra-articular dose of 0.5 mg was previously demonstrated^5,25. VICTORY-2, another Phase III trial of intra-articular CNTX-4975-05 for moderate-to-severe OA knee pain (NCT03660943), was completed in June 2021, with results pending^5,26. An oral TRPV1 antagonist, NEO6860, is also being investigated for OA knee pain²⁷.

Disease-modifying osteoarthritis drugs (DMOADs)

A DMOAD is a drug that modifies the underlying OA pathophysiology, thereby inhibiting structural damage to prevent or reduce long-term disability and offer potential symptomatic⁵. The symptom–structure discordance in OA complicates the application of these potential therapeutics for pain relief, at least in the short term; long-term trials are needed to determine if structural effects translate into clinical benefits for patients or if they reduce the need for joint replacement. Many candidates are currently being investigated. Those showing promise include drugs promoting cartilage repair, TissueGene-C, Cathepsin K and sprifermin⁵.

Drugs promoting cartilage repair

One promising drug under investigation is sprifermin, a recombinant human fibroblast growth factor 18 (FGF18). FGF18 is an important anabolic factor in chondrogenesis, chondrocyte proliferation and cartilage repair in healthy and damaged cartilage. In a phase II trial, intra-articular injections of sprifermin every 6 or 12 months had positive effects on cartilage thickness. In post hoc analyses, the structural effect did improve WOMAC pain scores²⁸. Whether the structural benefits persist over time and translate into clinical benefits, along with long-term safety, remains unclear. Lorecivivint, which inhibits the Wnt signalling pathway in bones and joints, also shows promise⁵.

TissueGene-C

Intra-articular injection of this drug delivers transforming growth factor-β (TGF-β) to the joint. Dysregulation of TGF-β signalling in chondrocytes occurs in both ageing and OA cartilage. A 52-week, placebo-controlled phase III trial (n = 163) reported that TissueGene-C improved OA symptoms and showed trends towards structural improvements on MRI⁵. After suspension for technical issues, one phase III trial (NCT03203330) has resumed with intra-articular injection of TissueGene-C.

Cathepsin K

Cathepsin K is involved in bone resorption and is expressed in OA synovium and chondrocytes. A cathepsin K inhibitor, MIV-711, reduced cartilage damage, prevented bone resorption, and decreased biomarkers of bone and cartilage remodelling in animal models of OA and in a phase II trial. It has a good safety profile, but there was no change in pain score, the endpoint of the trial, so clinical efficacy remains unclear²⁹.

Challenges in interpreting findings of clinical trials on therapies for osteoarthritis pain

Several characteristics of pain in general, and osteoarthritis (OA) pain in particular, increase the challenges of interpreting the results of clinical trials exploring potential new therapies^5,10:

• Pain is a subjective experience and so is challenging to measure. The numerous methods of measuring pain that are used in clinical trials (visual analogue scales, numeric rating scales, functional assessments, patient-reported outcome measures) make comparing the results of trials difficult. A further complication is the varying degrees of psychometric robustness of the measures³⁰.
• The biopsychosocial model of pain recognises that physical, psychological, behavioural and social factors can modulate an individual’s experience/perception of pain³¹. The interrelationships of these factors may confound the outcomes of clinical trials if the measurement of pain used fails to account for key domains.
• OA is heterogenous in both clinical and pathophysiological terms – it affects multiple joints through different processes and varies substantially in its clinical and radiographic presentation. Thus, OA in different joints, and in different patients, may respond differently to the same treatment, confounding trial results. 'Pain phenotyping' of patients would help overcome this, but is very challenging⁵.
• OA can progress at different rates. For example, knee OA often progresses slowly. Therefore, if clinical trials of disease-modifying drugs have follow-ups of <12 months, they may miss meaningful changes in structure and possible translation into clinical benefits⁵.

References

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