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Emerging treatments for osteoarthritis
Key Points
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Therapeutic innovation in the field of osteoarthritis includes both symptomatic (aimed at relieving pain and improving joint function) and structure-modifying treatments (aimed at slowing down joint deterioration).
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An analysis of the therapies currently under development shows that the intraarticular route is generally favored, even if the systemic route is still being studied with a few compounds.
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Cell therapy, in particular with the use of stem cells, is attracting great interest in view of the number of clinical studies under way and their already wide use in practice. However, they should still be considered today as exploratory avenues as long as there is no evidence of their superiority over placebo.
Osteoarthritis (OA) is the most common disabling disease in adults over 50 years of age. The burden of this disease has increased considerably in recent years and is now in 10th place, up from 13th place 5 years ago. Moreover, patients with knee/hip OA have a 55% excess all-cause mortality compared with the general population mainly due to cardiovascular disease caused by OA-related reduced physical activity. The lack of curative treatment and the low effectiveness of symptomatic treatments largely explain these figures, which will dramatically increase due to the aging population and the global epidemic of obesity if effective therapeutic solutions are not found quickly. Fortunately, a number of academic laboratories and pharmaceutical companies are now taking up the challenge to search for new molecules that target pathways considered to be involved in the pathologic process of this disease. The purpose of this chapter is to take stock of these avenues being explored. Some of them are already sufficiently advanced to be studied in humans, and we will be particularly interested in those that are the most advanced in their development and therefore the most promising. We will distinguish between symptomatic emerging treatments and disease-modifying OA drugs (DMOADs). Nevertheless, it should be noted that this boundary is not always obvious. For example, if we consider that inflammation, a classic pathway involved in pain, is part of the structural pathologic process, then an antiinflammatory treatment could in theory act rapidly on pain and also slow the progression of OA. Thus it could be considered both symptomatic and structure-targeted treatments. This would be the case, for example, for drugs targeting cytokines or their signaling pathways. Similarly, it is not impossible that a disease-modifying treatment could have a symptomatic effect in the medium or long term due to a delay in joint degradation. Although there is no strict correlation between structural progression and symptom severity, it is hoped that an effective DMOAD will delay total joint replacement because of eventually reducing pain and improving function. In this chapter, the term symptomatic emergent treatment will therefore refer to molecules whose main, or even sole, objective is to act on symptoms without signals that might suggest that they would also have a DMOAD effect. This is the case for molecules specifically targeting pain pathways. The term DMOAD will include any treatment in which some (or even all) of their properties suggest that they could delay disease progression. This is of course the case of all molecules that target enzymes that degrade the cartilage matrix or that increase the anabolism of this matrix. But molecules regulating the metabolism of subchondral bone, molecules targeting pathways involved in inflammation and innate immunity within the synovial tissue, as well as cellular therapies with regenerative potential and/or immunomodulatory secretory potential can be included in this category too. For didactic reasons, we will thus separate the subchapters. Nevertheless, the separation is sometimes not so clear in practice, as molecules can in theory have effects on both cartilage and bone, or even effects on both matrices and inflammatory pathways.
Emerging Symptomatic Treatments ( Fig. 191.1 )
Drugs Targeting the Nerve Growth Factor Pathway
Nerve growth factor (NGF) is a neurotrophic mediator discovered in 1950 that can promote the growth and survival of peripheral sensory and sympathetic nerve cells in mammals. This neuropeptide can also amplify nociceptive pain by increasing the synthesis and sensitization of neurons to several neurotransmitters involved in pain such as substance P or calcitonin gene-regulated peptide. Once activated, peripheral tissues produce and release NGF, which will exert its effects either directly on sensitive neurons via receptors (TrkA and p75NTR) present on their surface, activating a number of signaling pathways, or indirectly by activating mast cells. A distinction is made between anti-NGF antibodies and pharmacologic inhibitors of TrkA receptor.
Anti-NGF antibodies
The first human studies of the use of a systemically injected antibody to NGF for the treatment of OA pain date back to 2005 with tanezumab, a human immunoglobulin G2 (IgG2) antibody raised against NGF. A proof-of-concept phase 2, randomized, placebo-controlled nonsteroidal antiinflammatory drug (NSAID) study whose primary endpoint was WOMAC pain at 16 weeks, in 450 patients with knee OA, found a dramatic effect of tanezumab (administered at baseline and week 8 at a dose of 10, 25, 50, 100, or 200 μg per kilogram of body weight intravenously) compared to the NSAID control. Several companies then embarked on the adventure of developing an anti-NGF for knee and hip OA including Regeneron, Amgen, AstraZeneca, Abbott, Johnson & Johnson, and Janssen. But in 2010 the development programs of anti-NGFs were interrupted by the FDA because of the discovery of more frequent serious joint adverse events in the groups treated with an anti-NGF than in the control groups. These events proved to be mostly rapid progressive OA or, more rarely, osteonecrosis. A mitigation plan was then applied, allowing the authorization to resume clinical trials 2 years later. This plan included the prohibition to co-prescribing NSAID on a chronic manner, to reduce dosages, to exclude patients who have already had osteonecrosis. However, in 2012, the development program was again halted by U.S. Food and Drug Administration (FDA) due to adverse changes in the sympathetic nervous system of mature animals, with the FDA requesting additional information. Finally, FDA agreed in 2015 to lift the partial clinical hold on the tanezumab development program after a review of a robust body of nonclinical data characterizing the sympathetic nervous system response to tanezumab. As of today, there are only two anti-NGF antibodies in development, tanezumab (Pfizer and Eli Lilly) and fasinumab (Regeneron and Teva).
Tanezumab
Pfizer and Eli Lilly took advantage of these interruption periods to develop a subcutaneous form of their antibody. Thus whereas prior to 2010 published trials concerned only intravenous treatments, from 2015 onwards, the subcutaneous route will be preferred.
An initial US pivotal study evaluated the efficacy and safety of subcutaneous administration of tanezumab 2.5 mg on day 1 and at week 8 (n = 231), tanezumab 2.5 mg on day 1 and 5 mg at week 8 (n = 233), and placebo. From the start of the study to the end of the 16-week period, mean WOMAC pain scores decreased from 7.1 to 3.6 in the group receiving 2.5 mg tanezumab, from 7.3 to 3.6 in the group receiving 2.5/5 mg tanezumab, and from 7.3 to 4.4 in the placebo group (differences: −0.60 [−1.07 to −0.13; P = 0.01] for tanezumab 2.5 mg, and −0.73 [−1.20 to −0.26; P = 0.002] for tanezumab 2.5/5 mg). Mean scores for WOMAC physical function and PGA-OA were also statistically significantly decreased. Rapidly progressive OA occurred only in patients treated with tanezumab (2.5 mg: n = 5.2%; 2.5/5 mg: n = 1.4%). The incidence of total joint replacements was 8 (3.5%), 16 (6.9%), and 4 (1.7%) in the tanezumab (2.5 mg), tanezumab (2.5/5 mg), and placebo groups, respectively.
A European and Japanese pivotal study compared two doses of tanezumab (2.5 and 5 mg subcutaneously every 8 weeks) to placebo for 24 weeks followed by a 24-week safety monitoring period. The primary endpoint was a composite endpoint containing WOMAC pain, WOMAC function, and PGA at 24 weeks. Eight hundred and forty-nine patients were randomized and evaluated (placebo n = 282, tanezumab 2.5 mg n = 283, tanezumab 5 mg n = 284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (0.62 ± 0.18, p = 0.0006), WOMAC Physical Function (−0.71 ± 0.17, p < 0.0001) and PGA-OA (−0.19 ± 0.07, p = 0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function but not PGA-OA. With regard to tolerability, rapidly progressive OA was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively, and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%–7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoesthesia (both doses) than placebo.
A randomized controlled study evaluated the long-term efficacy and safety (80 weeks total observation) of using tanezumab 2.5 and 5 mg subcutaneously every 8 weeks versus an NSAID in moderate to severe OA of the hip or knee. The tanezumab 5 mg treatment group achieved two of the three primary efficacy endpoints of pain and physical function at 16 weeks. With respect to safety, the rate of joint safety events in the tanezumab arms was higher than that of the NSAIDs at 80 weeks. The incidence of rapidly progressing OA, osteonecrosis and bone failure was 7.1% in the tanezumab 5 mg arm, 3.8% in the tanezumab 2.5 mg arm, and 1.5% in the NSAID group. The incidence of total prosthesis was 8.0% in the 5 mg tanezumab arm, 5.3% in the 2.5 mg tanezumab arm, and 2.6% in the NSAID arm.
Fasinumab
Fasinumab is a human IgG4 antibody raised against NGF developed by Regeneron and co-developed with Teva. A randomized, double-blind, placebo-controlled phase 2 study was conducted in 421 patients with symptomatic knee OA not relieved by standard treatments. Fasinumab was tested at four doses (1, 3, 6, 9 mg) subcutaneously every 4 weeks for 16 weeks with follow-up for an additional 20 weeks. A statistically significant effect on both WOMAC pain and WOMAC function was observed in a non–dose-dependent manner. In contrast, 7% of fasinumab-treated patients and 1% of placebo-treated patients experienced dose-dependent development of arthropathies, with 2 occurring in patients receiving the lowest dose of fasinumab and 10 in patients receiving the highest dose; the majority (16 out of 25) occurred without any symptoms. Fasinumab is currently being studied in another phase 3 placebo- and naproxen-controlled trial in patients with hip or knee osteoarthritis (NCT03161093).
Recently, the FDA and the EMA decided not to grant marketing authorization for tanezumab, considering the unfavorable benefit-risk balance. The difficulty in identifying patients at risk of RPOA, partly due to a lack of understanding of the pathophysiology of RPOA, was a major factor in the decision. Although we have no information regarding the continuation of the fasinumab development program, it seems unlikely that it will continue.
TrkA inhibitors
GZ389988A (Sanofi) is a TrkA inhibitor for intraarticular administration. In a randomized, double-blind, placebo-controlled trial, 104 subjects with knee OA were injected with GZ389988A or placebo. At 4 weeks, a difference in pain between groups of 7.49 (VAS 0–100) (P <0.05) was observed, which persisted for 12 weeks. Transient and limited inflammatory reactions were noted at the injection site.
ASP7962 (Astellas Pharma) is a selective oral TrkA inhibitor. A phase 2a proof-of-concept study investigated the efficacy of administering 100 mg ASP7962 BID for 4 weeks in 215 knee OA patients compared to placebo with naproxen as an active control. No improvement in WOMAC pain and function was noted.
LEVI-O4
LEVI-04 is a p75 neurotrophin receptor fusion protein (p75NTR-Fc) being developed by Levicept as a once-a-month injectable for the treatment of OA and chronic pain. It would restore neurotrophin homeostasis by providing stable binding proteins for the excess neurotrophins present in chronic pain states. A first-in-human study is ongoing (NCT03227796).
MEDI-7352
MEDI7352 is being developed by AstraZeneca for the treatment of chronic pain in OA. It is a bispecific fusion protein that binds nerve growth factor (NGF) to tumor necrosis factor receptor 2 (TNFR2). A randomized, double-blind, placebo-controlled study in knee OA is recruiting (NCT02508155).
Botulinum Toxin
The idea of using botulinum toxin to relieve chronic pain, particularly OA pain, came about when an analgesic effect of the botulinum toxin prescribed for muscle contractures was observed. It turns out that botulinum toxin, by altering the cell membranes of neurons, causes a defect in the activity of various neurotransmitters involved in nociceptive pain. A first pilot trial was carried out in 60 patients with knee OA divided into three groups: 100 IU, 200 IU of botulinum toxin type A, and 40 mg of methylprednisolone acetate, injected intraarticularly. The results on pain at 8 weeks were sufficiently encouraging (particularly for the 200 IU group) for the first randomized trial comparing 200 IU of the toxin with an injection of physiologic serum to be carried out. At 12 weeks, no statistical difference was noted between the two groups, but a post-hoc analysis showed interesting differences in favor of the efficacy of the toxin in the group of patients with nociceptive pain according to the PainDetect questionnaire. Unfortunately, a second randomized study against saline injection that included 176 patients with nociceptive pain according to the PainDetect questionnaire could not show any differences in pain at 8 weeks. With respect to tolerance, there was a theoretical risk that OA would worsen since this toxin can paralyze muscles and thus cause weakness that can lead to joint instability. This risk has not been observed in clinical studies, at least not in these short-term studies. A trial in in thumb base OA is underway.
Capsaicin
This molecule present in the red chili pepper is responsible for the pungent sensation when ingested. Capsaicin has been shown to bind to TRPV1, a calcium channel receptor present in the nociceptor nerve endings. After a brief period of activation (responsible for a transient increased pain sensation), capsaicin causes desensitization of these nociceptor neurons for a long period of time. CNTX-4975, a synthetic trans-capsaicin, has been tested in knee OA in a randomized multicenter phase 2 trial. Two single doses (0.5 mg and 1 mg) injected intraarticularly were compared to placebo (vehicle) by analyzing the AUC of pain over 12 weeks. It should be noted that precautions were taken at the time of the procedure to avoid the painful flare-up present in the minutes following the injection. To avoid this, a topical application of cold by ice pack around the knee was performed 15 minutes before and 30 minutes after the intraarticular injection of 15 mL of lidocaine. Only then was CNTX-4975 (or the placebo) injected. The difference was statistically significant for the 1 mg dose with an effect size of 0.68. The enrollment of the patients included in the “VICTORY-2” pivotal phase 3 randomized controlled trial was completed in 2019 (NCT03660943).
LMWF5
Intraarticular injection of the low-molecular-weight fraction of 5% human serum albumin is being developed for symptomatic use in knee OA. This albumin fraction has antiinflammatory properties in vitro. Three clinical trials have already been conducted (only one published) testing a single intraarticular injection versus physiologic serum. The published study was a multicenter randomized, vehicle-controlled, double-blind, parallel study designed to evaluate the safety and efficacy of two doses (4 mL and 10 mL) of an intraarticular injection of either LMWF-5 or vehicle control (saline). The primary efficacy endpoint was the difference between treatment groups in the WOMAC pain change from baseline over 12 weeks. This study shows a statistical superiority of LMWF-5 over placebo with a difference of −0.25 on the WOMAC 5-point Likert pain scale at 12 weeks.
Resiniferatoxin
Resiniferatoxin is a potent TRPV1 agonist that produces a selective long-term chemoinactivation of nociceptive primary afferent nerve endings for pain control. A recent promising intraarticular study in canine OA (NCT03542838) opened the door to developing it now in humans. MTX-071 (Mestex-Grunenthal), an open label, single-dose, dose-escalating phase I/IIa study to determine the safety and clinical effects of intraarticular injections of MTX-071 (Lopain) in patients with chronic OA knee-joint pain, has been completed (results not yet presented [NCT02566564]). Grunenthal should soon sponsor 2 pivotal clinical trials. A first-in-human randomized controlled escalating dose study in 40 knee OA patients up to one single intraarticular injection of 30 μg of another resiniferatoxin (Sorrento Therapeutics) has been recently presented showing safety and positive signals for efficacy. Enrollment in a phase 2 clinical trial for patients with knee OA pain has begun (NCT04885972).
Emerging Dmoads ( Fig. 191.1 and Table 191.1 )
Cartilage as the Target
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