Abstract
Rheumatoid arthritis (RA) remains a formidable clinical challenge. This is despite remarkable recent advances in our understanding of pathogenesis and the introduction of a variety of novel agents, particularly biologic therapeutics that are potent inhibitors of extracellular immune pathways. Whereas the latter have brought substantial improvements in efficacy and thus outcomes, there remain significant numbers of non- or partial responders to current standard of care. The discovery of key intracellular pathways, particularly kinases that subserve the function of these pivotal cytokine and immune cell receptors implicated in RA pathogenesis, has facilitated the advent of a new phase of RA drug development. Thus, a range of kinase inhibitors has entered clinical trials and one agent has been licenced for use in some regions. Herein we summarise the chequered history of kinase inhibitor development in RA, describing successes and failures alike, and thereafter examine future trends in this exciting field.
Introduction
The last decade has been an exciting time for rheumatologists. Introduction of a range of licenced agents for rheumatoid arthritis (RA) has transformed the therapeutic landscape. There are now five biologic cytokine inhibitors of tumour necrosis factor-α (TNFi), biologic inhibitors of interleukin 1 and 6 receptor (IL-1, -6R), a depleting antibody directed against CD20 (B cell compartment targeting) and a protein construct binding to CD80/CD86 that thereby blocks the co-stimulatory signal required for the activation of T cells . Moreover, biosimilar biologic products are either already or will be shortly approved and thus the range of options grows. Implementation in daily practice has been rapid, pending various health economic environments. Initial concerns for toxicity via immune suppression and immunogenicity (particularly for chimeric protein administration) have been largely quenched via clinical experience and meticulous data collection in registries. Management recommendations have been revised and the prescription of biologics is now routine in rheumatology clinics per protocol and upon observation of sufficient disease progression, or prognostic concern. Although their efficacy is established and a significant proportion of patients respond to these therapies at least partially, there are several issues that rheumatologists face daily. Side effects most commonly related to susceptibility to infection (e.g. tuberculosis, fungi, opportunistic organisms, viral infections) and rare serious adverse events (e.g. progressive multifocal leukoencephalopathy, demyelination) require constant vigilance. Diminution of effect over time perhaps related to development of anti-antibodies is common. Compliance, the route of administration (self-administered sc. injections, iv infusions at hospitals or clinics), co-medication with methotrexate (MTX) because of licence issues, cost burden to the health-care system require consideration. A major question concerns what strategy to follow at the outset of disease – most accept the need to treat early and aggressively, towards a target – but with what? When should one introduce a biologic agent, in whom and after what therapeutic experience? Similarly, we face challenges in choice of agents after several therapeutic failures – the so-called resistant disease. In a disease like RA that is prevalent in approximately 0.8% of the population and causes a significant disease burden with a high associated morbidity and mortality of affected individuals , these various issues comprise significant ongoing unmet clinical need despite recent advances.
This becomes even more important as we start to understand and adopt the idea of RA as a syndrome consisting of different pathogenic subsets with distinct molecular mechanisms as drivers behind the inflammation rather than a definite disease entity . This syndrome in turn drives articular and systemic comorbid disease that demands a life-time approach with a range of ‘modes of action’ of agents ideally chosen in a stratified manner and on a pathogenesis (‘disease stage specific’)-driven basis. Considered thus, we have much work to do to secure the next steps in RA control.
Recent pharmacological research in RA has rediscovered the intracellular possibilities for immune modulation rather than only the extracellular milieu. In essence, the notion is that intracellular signal pathways that are now very well defined to subserve extracellular receptor function may facilitate rather effective leucocyte modulation if appropriately targeted . After several setbacks, which will be discussed later in this review, this approach led finally to the approval of tofacitinib, a pan-Janus kinase inhibitor (JAK) with a higher affinity for JAK1 and 3, by the Food and Drug Administration (FDA) in 2012 for patients with RA and an inadequate response to MTX . Thus, a new phase of RA drug development has been launched.
The varied, complex interactions of intracellular signalling pathways enable cells to respond and adjust to any environmental signal in an agile and dynamic manner. Signal pathways in reality are not a ‘simple’ pathway from cell membrane to nucleus, but rather an integrated network with numerous checkpoints and options for pathway crosstalk, perhaps explaining why several attempts have failed in the past: the p38 mitogen-activated protein kinase (MAPK) inhibitors represent a prominent exemplar in RA . That a functional hierarchy exists however does hold true to some extent and allows conceptual targeting strategies to be devised. Functional signal pathways can be usefully considered as follows. An extracellular ligand binds to its receptor on the cell membrane, driving different intracellular mechanisms often via the activation of kinases. Kinases transfer a phosphate group from adenosine triphosphate (ATP) directly to their substrate, which can be another kinase, a different protein or a lipid ( Fig. 1 ). Downstream of kinase interactions, activation or silencing of transcription factors occurs affecting the expression of their respective target genes. Thereby, change in the cell occurs in a specific way to regulate growth and proliferation, programmed cell death, migration and most importantly for RA activation leading to a cell-specific immune response often exemplified in expression of genes encoding cytokines, chemokines and extracellular matrix enzymes .
Usually, the efficacy of a protein kinase inhibitor is measured and indicated by the half-maximal inhibitory concentration, also called IC 50 . The IC 50 is a measure of effectiveness in an in vitro setting and should therefore be interpreted with caution as one moves to clinical use in human beings or indeed any in vivo model system. It provides a quantitative measure of the antagonist drug potency and is defined as the concentration of an antagonist that is required for a 50% inhibition of a kinase.
Although the idea of inhibiting specific kinases to obtain a significant change in cell function has been long established, several obstacles have to be overcome to achieve this goal. First, clarity has to be gained as to whether a signalling molecule is functionally crucial in diseased tissue, but, in contrast, less commonly expressed in healthy tissue or generally less important for normal cellular functions. Second, the discovery and synthesis of selective kinase inhibitors is a chemical challenge, as in many cases the ATP-binding site in contrast to the target-binding site of the kinases is the major target for inhibition ( Fig. 1 ). However, creating highly selective inhibitors of this site without also inducing off-target effects is nearly impossible. That is why most of the current generation of kinase inhibitors actually target many kinases, which in turn makes attribution of side effects and toxicity to single kinases difficult. Third, specificity of a kinase function must be clear as many kinases also belong to evolutionarily important pathways for host defence and cell homoeostasis. Unsurprisingly therefore, target selectivity and attendant toxicity dominate consideration of the introduction of these new compounds. Despite these challenges, there has been great success already achieved with kinase inhibitors in other conditions than RA, for example, imatinib for chronic myeloid leukaemia , sunitinib for renal cell carcinoma or ruxolitinib for myelofibrosis . The arrival of tofacinib in RA now brings the possibility of similar success.
Matters are not however straightforward. In theory, the oral bioavailability of small-molecule therapeutics is for many patients a great plus in contrast to self-administering injections or going to clinics or hospitals on a regular basis for infusions or injections. Moreover, small molecules are more cheaply produced pharmaceutical agents than the often expensive and highly controlled production of biologics. In addition to this, new clinical agents may be supported by a biomarker panel, which aims to pick up patients who might respond best to the investigational product (IP) yielding for a level of stratification and a personalized medicines approach. Some have raised concern however about potential market satiation. With many approved drugs for RA now available, the advantages and disadvantages of a new compound will receive ever-closer scrutiny in the future, particularly with respect to toxicity. Thus, this has in turn led to discrepancies of licencing status manifest, for example, with as tofacitinib that is approved by the FDA, but not by the European Medicines Agency (EMA).
This review will consider in chronologic order those kinase inhibitors that have been tested in the past, but failed to progress to phase III trials or halted in phase III trials due to efficacy or safety concerns. Much was learnt through these trials that directly fostered more translational research and influenced later trials. We will also cover the present status of kinase inhibitors in RA followed by a short outline of what may be expected in the near future with a focus on ongoing clinical trials. In each section, we will refer to the current understanding of the mechanism of action of the kinase, the efficacy of its inhibition and the safety profile, if data are available.
Past
p38 MAPK inhibitors
Mechanism of action
The early origins of targeting kinases in rheumatoid diseases, especially RA, was probably in the late 1980s in a programme called CSAID (cytokine suppressive anti-inflammatory drugs) at GlaxoSmithKline (formerly SmithKline & French) . Basically, the programme was initiated to explore the possibility of small-molecule inhibitors to target IL-1β and TNF-α production from lipopolysaccharide (LPS)-treated monocytes based on cellular functional assays, comprising an attractive approach at that time . The preferred target of this programme was p38 MAPK . With retrospect, these programmes and derivatives focussed too much on p38α MAPK rather than investigating alternative intracellular kinases as potential targets that integrated the totality of TNFR or IL-1R dependent function. The result of this multi-year, multi-candidate, multi-company approach has been disappointing as many of the phase II trials in RA either failed their primary endpoint or had to be ceased due to dose-limiting toxicity .
p38 MAPK belongs to the superfamily of typical MAPKs that are downstream of MAP3Ks and MAPKKs and that can be broadly split into three distinct subgroups ( Fig. 2 ): the aforementioned p38 MAPK, the extracellular signal-regulated protein kinases (ERK) ERK1 and ERK2 and, lastly, the c-Jun NH 2 terminal kinases (JNK) . While the ERK kinases are expressed in all cells and crucial for important cell functions such as proliferation and differentiation, the three JNK isoforms (JNK1, JNK2 and JNK3) are all linked to metalloproteinase production and thereby extracellular matrix regulation . Amongst the atypical MAPKs are ERK3, ERK4 and ERK7 as well as Nemo-like kinase (NLK), but their physiological functions are not yet fully determined .
p38 MAPK is particularly activated by proinflammatory cytokines relative to other MAPKs and is directly involved, in turn, in production of cytokines, mainly IL-1, IL-6 and TNF-α . There are four p38 MAPKs of which the α, β and δ forms are widely expressed . In RA synovial tissue, the phosphorylated α and γ isoforms dominate over the other two and are mainly localised to macrophages (α and γ) and fibroblasts (γ) . The α isoform however has been postulated to be the most important one in mediating inflammation . Monocytes, macrophages, CD4+ T cells, neutrophils and endothelial cells express p38α strongly . Upstream kinases of p38 MAPK comprise MKK3 or MKK6 that in turn are activated in response to inflammatory or stressful stimuli. Both, MKK3 and 6, independently contribute to the p38 activation and therefore cytokine production . The major downstream kinase of p38α and β MAPK is MAPKAPK-2, which has been described to be involved in many cellular processes such as proliferation, differentiation and programmed cell death . It has been proposed that especially the post-transcriptional regulation of expression of inflammatory response genes is probably the most important cellular process that p38 MAPKs are involved in, besides activating transcription factors . Yet, such post-transcriptional regulation has been only partly understood. Tristetraprolin (TTP), an mRNA-binding protein, is possibly implicated in this process as it is immediately stimulated by MAPKAPK2 activation. This leads to hyperphosphorylation of TTP causing TTP to dissociate from mRNA. TTP is capable of binding to AU-rich elements in the 3′ untranslated region (UTR) of mRNAs and thereby promotes destabilization of mainly cytokine mRNA as exemplified by its involvement in a classical negative feedback loop for TNF-α . In summary, blocking p38 MAPK activity leads to an increased capability of TTP to bind and destabilize cytokine mRNA and thus its expression rendering p38 an attractive surrogate for cytokine suppression. This assumption was supported by highly promising studies of selective p38 inhibitors in animal models of arthritis . Inhibition led to amelioration of synovial inflammation, bone and cartilage destruction. Taken together, there was quite substantial preclinical data to support clinical studies with selective p38 inhibitors and many studies thus ensued (more information in Table 1 ).
| Pki | Family | Cellular expression | Cell signalling pathways | Physiological role | Animal models |
|---|---|---|---|---|---|
| p38 mitogen-activated protein kinase (MAPK) (subtype α, β, γ and δ, of which α is believed to be most important for inflammation) | Typical MAPKs (Serine/threonine protein kinases) | Subtypes α,β and δ are widely expressed, γ mainly by muscle tissue; in RA synovial tissue: α and γ colocalizes with macrophages, fibroblasts with β and γ, granulocytes with δ, the subtypes α and γ were the most prominently phosphorylized ones | Downstream of stress signals, cytokine receptors and growth factor receptors; hierarchically activated after MAP3K and MKK3/6 activation | Important role in inflammation, but also other physiological processes | p38 α KO mice die at midgestation; p38 β, γ and δ KO mice and double p38 γ/δ KO mice are viable, but lack an apparent phenotype, furthermore p38 β KO did not moderate RA for instance; mice lacking of both activators of p38 MAPK activation MKK3/6 are not viable; Inhibition of p38 α in animal models of arthritis (mice and rats) leads to improvement of the disease course |
| Spleen-tyrosine kinase (SYK) | Non-receptor tyrosine kinase | Widely expressed in all cells including mostly haematopoietic cells (B cells, granulocytes, mast cells, neutrophils), but also synoviocytes, osteoclasts, vascular endothelial and epithelial cells | B cell receptor (BCR) Fcg receptor (FcγR) Fce receptor (FcεR) T cell receptor (TCR) Integrins C-type lectins collagen receptor glycoprotein VI | B cell development and activation Degranulation of granulocytes and mast cells Release of cytokines Osteoclast differentiation Platelet activation and thrombus formation | SYK-deficient mice show three major phenotypes: perinatal lethality, a petechiated appearance in utero and lack of mature B cells |
| Janus kinase (JAK) | Non-receptor tyrosine kinase | Widely expressed | Downstream of type I and II cytokine-receptors including interferons, many interleukins (e.g. IL-2, -6, -7), CSF; Also erythropoetin, thrombopoetin, growth hormone, prolactin and leptin | JAK1 + JAK2: host defence, haematopoiesis, growth, neural development JAK3 + TYK2: primarily important for immune responses | JAK1 or JAK2 deletion not viable in mice JAK3 loss-of-function mutations leads to SCID TYK2 loss-of-function mutations leads to immunodeficiency |
| Bruton’s tyrosine kinase (BTK) | Non-receptor tyrosine kinase | Haematopoietic cell populations: lymphoid (B cells) myeloid (monocytes, macrophages, mast cells, and neutrophils) | B cell receptor (BCR) Fcg receptor (FcγR) Fce receptor (FcεR) | B cell development and activation cytokine production | X-linked immunodeficiency (Xid) mice: mutation in BTK gene–>decreased susceptibility to develope CIA |
| Phosphoinositide 3-Kinase (PI3K) | Lipid kinase | PI3Kα + β ubiquitously expressed PI3Kγ more restricted to haematopoietic cells PI3Kδ selective for T cells and neutrophils | Downstream of (cytokine) receptor tyrosine-dependent pathways (PI3Kα, β and δ) or Downstream of (chemokine) G-protein coupled receptors (PI3Kγ) | Cell survival, growth, proliferation, migration, metabolism and differentiation | PI3Kγ-deficient less amenable to destructive arthritis |
Efficacy
The first full report of a clinical trial with a p38 MAPK inhibitor was available in 2009 . Three different doses (50, 150 and 300 mg daily) of the selective p38α inhibitor pamapimod (RO4402257) in RA patients were not significantly better compared to patients receiving MTX (step up from 7.5 mg/week to 20 mg/week). In fact, the American College of Rheumatology response rate of 20% (ACR20 response) was lower in all three groups than with MTX (23%, 18% and 31% vs. 45%, respectively) . A second phase II trial with pamapimod compared the same doses plus 25 mg and 75 mg twice daily to placebo in patients on background MTX therapy. The results showed only slightly higher response rates achieved for most of the dosage regimens (31–43%), but there was no significant advantage over placebo (34%). Talmapimod (SCIO-469) and VX-702, both selective p38α inhibitors, have also been evaluated in 12-week phase II trials in RA with no clear efficacy emerging . Talmapimod did not show any significant efficacy compared to placebo in RA patients on background MTX therapy for all IP dosages . By contrast, VX-702 seemed to perform slightly better in phase II studies (one comparing only to placebo and one to placebo on background MTX) but numerically higher ACR20 response rates were mostly not significant and thus there was no convincing evidence that an adequate disease-modifying agent could be derived in the long term . Of interest, however, was an initial decline of the C-reactive protein (CRP) levels throughout most of the conducted studies, also noted in other evaluated inflammatory conditions such as Crohn’s disease . This reduction was never maintained throughout the study period, but usually described as rapid but not persistent phenomenon. The consistency between studies suggests that this may be a real effect that, in turn, suggests single or multiple biologic adaptions may allow a therapeutic ‘escape’ from p38 regulation .
Safety
To date, there is no meta-analysis available for single IPs as insufficient numbers of patient have been treated with these drugs. One meta-analysis of doramapimod (BIRB-796), pamapimod and talmapimod revealed a significantly increased incidence rate (IR) of dizziness (relative risk, RR 2.36 (1.20–4.63)) . Surprisingly, adverse event (AE) rates for serious AEs, discontinuation due to AE, hypertransaminasaemia, nausea, diarrhoea and headache were not significantly higher than in the respective comparator group . This might arise from several reasons including the chosen statistical analysis as well as the heterogeneity of the compounds and the comparator group (only placebo vs. MTX or placebo plus MTX). Detailed review of the individual studies however provides a different perspective. Many study programmes were terminated because of three major safety issues, namely liver toxicity, cutaneous lesions or rash, and in case of VX-745, central nervous system (CNS) penetration led to a CNS inflammatory syndrome in dogs . Examples include: SCIO-469 (higher frequency of AEs compared to placebo with a predominance of cutaneous lesions and elevated liver enzymes ), SCIO-323 (development was halted because of cutaneous AEs ), AMG-548 (16% of patients in a phase I trial showing increased liver enzymes during a 14-day period ), BIRB-796 (stopped because of increased liver function abnormalities ).
So, what led to this expensive clinical and intellectually disappointing failure? Was it a matter of dosing? There was an initial effect on CRP levels that was not sustained. Higher concentrations, as seen in the 300-mg group of pamapimod, led to higher discontinuation and AE rates (up to 21%), possibly due to off-target blockage of other kinases. Was it a matter of biodistribution? There was a well-documented side effect of dizziness and the unexpected CNS inflammatory syndrome in dogs. It has to be said that the limitations seen with the initial compounds such as VX-745 or BIRB-796 have been overcome in the development of more specific and less lipophilic agents thereafter, but the observed clinical effect remained rather modest. Was p38α the wrong or not the only important isoform – p38γ phosphorylation was also noted in RA synovium? On the background of recent data, which also attribute an anti-inflammatory role to p38α (intrathecal injection of p38 inhibitors led to inflammation suppression even when used in rather low doses), this could be the case . Finally, it has to be considered that p38 is simply not sufficiently functionally relevant for the inflammation underlying RA – perhaps it is more a secondary amplification pathway rather than a true masterswitch capable of inhibiting a critical functional node in the synovial inflammatory response (for an overview of published phase II trials, see Table 2 ). None of the p38 inhibitors have therefore progressed to phase III trials in RA, but still there is ongoing clinical research with p38 inhibitors. Just recently, a phase III trial in acute coronary syndrome has opened that will investigate the effect of losmapimod, a new p38 inhibitor, on plaque stabilization .
| Pki | Phase | Patient cohort | Study design | Dosage | ACR20 response rates or alternative primary endpoint | Time (weeks) | N | Primary outcome measure(s) | Clinical trials no. | Status | Published (only fully published studies, no meeting abstracts) | Company |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P38 MAPK inhibitors (selected phase 2 displayed, no phase 1 included, no phase 3 performed) | ||||||||||||
| Talmapimod (SCIO-469) | 2 | No other background medication than HCQ allowed | RD, DB, PBO-ctrl | 30 mg, 60 mg (both po 3× daily), 100 mg (ER po 1× daily) | No significant difference at week 12 between SCIO-469 and PBO | 12 | 302 | ACR20 response | NCT00089921 | Completed | Genovese MC et al. J Rheumatol. 2011 | Scios |
| Pamapimod (RO4402257) | 2 | MTX-IR | RD, DB, PBO-ctrl on background of MTX | 50, 150 or 300 once daily po 25, 75 twice daily po | Pamapimod groups: 31–43%; PBO: 34% (ns difference) | 12 | 327 | ACR20 response | NCT00316771 | Completed | Alten RE et al. Ann Rheum Dis. 2010 | Hoffmann-La Roche |
| Pamapimod (RO4402257) | 2 | >90% DMARD-IR <10% Biological-IR | RD, DB, MTX-ctrl | 50, 150 or 300 once daily po | Pamapimod groups: 23%, 18%, and 31%, respectively MTX group: 45% | 12 | 204 | ACR20 response | NCT00303563 | Completed | Cohen SB et al. Arthritis Rheum 2009 | Hoffmann-La Roche |
| VX-702 | 2 | MTX-IR no concomitant DMARDs permitted (Study 304) | RD, DB, PBO-ctrl on background of MTX | 10 mg once daily or 10 mg once daily for 7 days followed by 10 mg twice weekly (intermittent group) | VX-702 group: 40% ( p = 0.064) or 44% ( p = 0.047), respectively PBO:22% | 12 | 117 | ACR20 response | NCT00395577 | Completed | Damjanov N et al. Arthritis Rheum 2009 | Vertex Pharmaceuticals |
| VX-702 | 2 | DMARD-IR Stable DMARD (sulphasalazine and antimalarials) background permitted (VeRA study) | RD, DB, PBO-ctrl | 5 mg or 10 mg once daily po | VX-702 group: 36% or 40%, respectively PBO: 28% (ns difference) | 12 | 313 | ACR20 response | NCT00205478 | Completed | Damjanov N et al. Arthritis Rheum 2009 | Vertex Pharmaceuticals |
| SYK inhibitors | ||||||||||||
| Fostamatinib (R788) | 2 | 80% DMARD-IR and 20% Biological-IR | RD, DB, PBO-ctrl on background of MTX | 50 mg, 100 mg or 150 mg twice daily | 100 mg group: 65% 150 mg group: 72% PBO: 38% 50 mg group: 32% | 12 | 189 | ACR20 response | NCT00326339 | Completed | Weinblatt ME et al. Arthritis Rheum 2008 | AstraZeneca/Rigel |
| Fostamatinib (R788) | 2 | 85% DMARD-IR and 15% Biological-IR Stable DMARD background permitted | RD, DB, PBO-ctrl on background of MTX | 100 mg twice daily 150 mg once daily | 100 mg group: 67% 150 mg group: 57% PBO: 35% | 24 | 457 | ACR20 response | NCT00665925 | Completed | Weinblatt ME et al. N Engl J Med 2010 | AstraZeneca/Rigel |
| Fostamatinib (R788) | 2 | ≥1 current or previous Biological-IR Stable DMARD background permitted | RD, DB, PBO-ctrl on background of MTX | 100 mg twice daily | R788: 38% PB0: 37% | 12 | 219 | ACR20 response | NCT00665926 | Completed | Genovese MC et al. Arthritis Rheum 2011 | AstraZeneca/Rigel |
| Fostamatinib (R788) | 2b | ≤2 DMARD-IRs or DMARD-naive | RD, DB, PBO-ctrl and non-inferiority to adalimumab | 100 mg twice daily (A) or 100 mg twice daily for 4 weeks than 150 mg daily (B) or 100 mg twice daily for 4 weeks than 100 mg daily (C) or 40 mg adalimumab every 2 weeks (D) | ΔDAS-28(CRP) vs PBO at 6 weeks: A: Δ0.56 ( p = 0.006) B: Δ0.49 ( p = 0.022) C: Δ0.22 ( p = 0.280) ΔDAS-28(CRP) vs adalimumab at 24 weeks: A: Δ-0.72 ( p = 0.005) B: Δ-0.61 ( p = 0.020) C: Δ-0.72 ( p = 0.004) | 24 | 279 | ΔDAS-28(CRP) vs PBO at 6 weeks ΔDAS-28(CRP) vs adalimumab at 24 weeks | NCT01264770 | Completed | Taylor PC et al. Ann Rheum Dis 2014 | AstraZeneca/Rigel |
| Fostamatinib (R788) | 3 | Single TNFi-IR | RD, DB, PBO-ctrl on background of MTX | 100 mg twice daily or 100 mg twice daily for 4 weeks than 150 mg daily | 100 mg group: 36.2% ( p = 0.004) 150 mg group: 27.8% ( p = 0.168) PBO: 21.1% | 24 | 323 | ACR20 response | NCT01197755 | Completed | Genovese MC et al. J Rheumatol 2014 | AstraZeneca/Rigel |
| Fostamatinib (R788) | 3 | MTX-IR | RD, DB, PBO-ctrl on background of MTX | 100 mg twice daily or 100 mg twice daily for 4 weeks than 150 mg daily | 100 mg group: 49% ( p < 0.001) 150 mg group: 44.4% ( p = 0.006) PBO: 34.2% | 52 | 918 | ACR20 response after 24 weeks | NCT01197521 | Completed | Weinblatt ME et al. Arthritis Rheum 2014 | AstraZeneca/Rigel |
| JAK inhibitors (only phase III trials for tofacitinib, too extensive if other JAK inhibitors included) | ||||||||||||
| Tofacitinib (CP-690,550) | 3 | ORAL Solo: distinguishing feature – IP monotherapy DMARD-IR <30% Biological-IR | RD, DB, PBO-ctrl | 5 mg or 10 mg twice daily po | 5 mg group: 59.8% ( p < 0.001) 10 mg group: 65.7% ( p < 0.001) PBO: 26.7% | 24 | 611 | ACR20 response after 12 weeks HAQ-DI after 12 weeks DAS28-ESR <2.6 after 12 weeks | NCT00814307 | Completed | Fleischmann R et al. N Engl J Med 2012 | Pfizer |
| Tofacitinib (CP-690,550) | 3 | ORAL Standard: distinguishing feature – active comparator = adalimumabDMARD-IR <10% Biological-IR | RD, DB, active comparator, PBO-ctrl on background of MTX | 5 mg or 10 mg twice daily po | 5 mg group: 51.5% ( p < 0.001) 10 mg group: 52.6% ( p < 0.001) adalimumab group: 47.2% ( p < 0.001) PBO: 28.3% | 52 | 717 | ACR20 response after 24 weeks HAQ-DI after 12 weeks DAS28-ESR <2.6 after 24 weeks | NCT00853385 | Completed | van Vollenhoven RF et al. N Engl J Med 2012 | Pfizer |
| Tofacitinib (CP-690,550) | 3 | ORAL Scan: distinguishing feature – x-ray DMARD-IR <25% Biological-IR | RD, DB, PBO-ctrl on background of MTX | 5 mg or 10 mg twice daily po | 5 mg group: 51.5% ( p < 0.001) 10 mg group: 61.8% ( p < 0.001) PBO: 25.3% | 104 | 800 | ACR20 response after 24 weeks Δ mTSS after 24 weeks HAQ-DI after 12 weeks DAS28-ESR <2.6 after 24 weeks | NCT00847613 | Completed | van der Heijde D et al. Arthritis Rheum 2013 | Pfizer |
| Tofacitinib (CP-690,550) | 3 | ORAL Sync: distinguishing feature – background DMARDs DMARD-IR <15% Biological-IR | RD, DB, PBO-ctrl on background of DMARDs | 5 mg or 10 mg twice daily po | Treatment difference to PBO (ACR20): 5 mg group: 21.2% ( p < 0.001) 10 mg group: 25.8% ( p < 0.001) | 52 | 795 | ACR20 response after 24 weeks HAQ-DI after 12 weeks DAS28-ESR <2.6 after 24 weeks | NCT00856544 | Completed | Kremer J et al. Ann Intern Med 2013 | Pfizer |
| Tofacitinib (CP-690,550) | 3 | ORAL Step: distinguishing feature – TNFi-IR <15% previous non-TNFi | RD, DB, PBO-ctrl on background of MTX | 5 mg or 10 mg twice daily po | 5 mg group: 41.7% ( p < 0.0024) 10 mg group: 48.1% ( p < 0.001) PBO: 24.4% | 24 | 399 | ACR20 response after 12 weeks HAQ-DI after 12 weeks DAS28-ESR <2.6 after 12 weeks | NCT00960440 | Completed | Burmester GR et al. Lancet 2013 | Pfizer |
| Tofacitinib (CP-690,550) | 3 | ORAL Start: distinguishing feature – MTX-naive | RD, DB with comparison to MTX | 5 mg or 10 mg twice daily po | ACR70 at 104 weeks 5 mg group: 34.4% ( p < 0.001) 10 mg group: 37.6% ( p < 0.001) MTX: 15.2% No radiographic progression at 104 weeks 5 mg group: 79.9% ( p < 0.001) 10 mg group: 83.7% ( p < 0.001) MTX: 64.9% | 104 | 958 | Comparison of baseline and month 6 scores of PA hand and AP foot radiographs ACR70 response at all time points Incidence and severity of adverse events and clinical laboratory abnormalities Summary of changes in physical examination compared to baseline by patient Mean change from baseline in vital signs measurements | NCT01039688 | Completed | Lee EB et al. N Engl J Med 2014 | Pfizer |
| BTK inhibitors | ||||||||||||
| CC-292 | 2a | Female MTX-IR Stable concomitant DMARD permitted | RD, DB, PBO-ctrl on background of MTX | 375 mg po daily (250 mg in the AM and 125 mg in the PM) | NA | 4 | Estimated 80 | ACR20 response | NCT01975610 | Ongoing | No | Celgene Corporation |
| HM71224 | 1 | Healthy adult male volunteers | Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of Single and Multiple Doses | 10–200 mg po daily | NA | Max. 2 | Estimated 62 | Safety and tolerability | NCT01765478 | Not yet recruiting | No | Hanmi Pharmaceutical Company Limited |
In summary, since presumably information was not readily available in the public domain, many parallel trials reached the same disappointing results for participating patients, clinicians, scientists and companies. Several lessons should be taken from the p38 experience: (i) inhibiting kinases higher in the hierarchy of the signal cascade may avoid escape mechanisms, (ii) high specificity of the IP to bind to the respective kinase should be sought, (iii) negative studies should be reported and published and (iv) understanding the biology behind the failure of the compound may lead to the development of new or different approaches to the involved signalling pathway.
SYK inhibitors
Mechanism of action
Spleen tyrosine kinase (SYK) is a member of the non-receptor protein tyrosine kinase family and is expressed in a variety of different cell types, but mainly in haematopoietic cells such as B cells, macrophages, mast cells, neutrophils and basophils, but importantly also by synoviocytes, osteoclasts and vascular endothelial cells . SYK is a 72-kDA protein which contains two SRC homology 2 (SH2) domains and a kinase domain ( Fig. 3 ), and is therefore closely related to the ζ-chain-associated protein kinase of 70 kDA (ZAP70). SYK is able to bind to receptors that contain cytoplasmic regions called immune-receptor tyrosine-based activation motifs (ITAMs) . These are short peptide sequences with two tyrosine residues only 6–12 amino acids apart, which are rapidly phosphorylated after receptor activation. This is a conceptually similar mechanism for all immunoreceptors (B cell receptor (BCRs), T cell receptors (TCRs) and Fc receptors (FcRs)), but not exclusive as many other receptors (C-type lectin, Integrins, glycoprotein VI) use ITAM- or hemi-ITAM-based signalling pathways . SYK can bind to phosphorylated ITAMs via SH2 domains and thus immune complexes, antigens or other receptor ligands, when they associate with their respective receptors lead to phosphorylation of ITAMs, which in turn activate SYK . Downstream of SYK lies a diversity of pathways summarized in Fig. 3 . At the end of this cascade, importantly for RA, lies induction of cellular responses that include cytokine release, differentiation and proliferation and enhanced cell survival .
Antibody–Fc receptor interactions are crucial to RA pathogenesis, and thus SYK inhibition was considered to be a potential new drug target . Moreover, synoviocytes, for example, produce higher amounts of IL-6 and MMP-3 in response to SYK activation, triggered by TNF and IL-1 . SYK expression was also found to be up-regulated in RA compared to osteoarthritis synovium . Further promising data with regard to the potential application of SYK inhibition in RA were gained from animal models of arthritis. R788, a prodrug of the active metabolite R406 and later renamed fostamatinib, inhibited both proinflammatory cytokine production and joint damage . A second selective SYK inhibitor, PRT062607 or P505-15, revealed the same promising results in the collagen antibody-induced arthritis in mouse and collagen-induced arthritis (CIA) in rats with decreased levels of inflammation and ameliorated joint destruction . Rigel, the pioneer in the development of SYK inhibitors , then took fostamatinib and other SYK inhibitors forward to clinical trials in a range of conditions, including RA (more information in Table 1 ).
Efficacy
Fostamatinib (also R788 or formerly R935788) is the only SYK inhibitor to date that has been evaluated in RA. Fostamatinib targets the ATP-binding site of SYK to block its function and thus, as discussed before, it cannot be considered a pure SYK inhibitor . Fostamatinib has been described to inhibit a combination of SYK-dependent and SYK-independent immune signalling pathways due to the high rate of off-target effects observed (tyrosine kinases FMS-related tyrosine kinase 3 (FLT3), c-Kit, lymphocyte-specific protein tyrosine kinase (LCK), Janus kinase 1 (JAK1) and JAK3, adenosine A 3 receptor ) Rigel went into partnership with AstraZeneca for the phase 2 trial programme called (TASKi) and a subsequent large phase 3 trial programme, OSKIRA. Many studies were undertaken and currently data are available from four phase II trials and two phase III trials . with some data from the remaining terminated studies awaited.
The initial results from phase II studies clearly supported progression to phase III trials, although early awareness of elevated blood pressure that required active management was notable . First, 50, 100 or 150 mg doses taken twice daily were evaluated, but subsequently groups consisted of either 100 mg twice daily or 100 mg bid for 4 weeks, then 150 mg once daily as the 50 mg regimen failed to show any difference compared to placebo. ACR20 response rates in the higher dosage regimes however reached 57–72% in cohorts with mainly single or multiple disease-modifying anti-rheumatic drug (DMARD) inadequate responses and on background MTX therapy . However, in a phase II study with patients who were either single or multiple biologic resistant, fostamatinib was equivalent to placebo on background MTX with or without stable DMARD co-medication . Interestingly, the high response rates from the early studies were not confirmed in a large phase III trial (100 mg group 67% vs. 49% after 24 weeks), although the study protocols and the patient characteristics were somewhat different . But two other study results bear close observation: (i) fostamatinib as mono-therapy was inferior to adalimumab mono-therapy in patients who were either DMARD-naïve or had inadequately responded to ≤2 DMARDs , (ii) only modest effects were observed in the 100 mg twice daily group and insignificant effects were observed in the 150 mg daily group in single TNFi failures . Taken together, the inconsistent efficacy, rather modest effects in the probably more severe group of biologic-resistance and the inferiority towards adalimumab made fostamatinib appear unattractive as a product. This, together with the less favourable side-effect profile than other emerging kinase inhibitors (discussed in the next paragraph), led to cessation of the programme in summer 2013 (overview of fully published phase 2 and 3 trials in Table 2 ).
Portola and their partner BiogenIdec have one specific SYK inhibitor (PRT062607, formerly P505-15) in their pipeline , but apart from a phase I ascending dose trial in healthy volunteers, the current plans and status are unclear to the authors .
Safety
Safety issues were debated during the phase II studies of fostamatinib and a meta-analysis of four studies further informed this discussion . Four AEs were highlighted: the RR was (i) 2.93 (confidence interval (CI) 1.02–8.43) for hypertransaminasaemia, (ii) 2.80 (CI 1.58–5.99) for hypertension, (iii) 5.20 (CI 3.19–8.49) for diarrhoea and (iv) 9.24 (CI 2.22–38.42) for neutropenia . Neutropenia was already disclosed in a letter in 2011 and is the most common laboratory side effect associated with kinase inhibitors . The reported neutropenia was dose-related, but rapid recovery within 3–7 days without the presence of metamyelocytes or myelocytes from this was noted after discontinuation of IP or reduction of dose. Therefore, the authors concluded that SYK inhibition does not affect haematopoiesis and might be more due to blocked release of neutrophils from bone marrow . MTX combination may have exacerbated neutropenia, as in one trial of fostamatinib monotherapy and immune thrombocytopenic purpura (ITP) the fostamatinib dose was even higher, but no neutropenia was observed . Hypertension was documented throughout the different studies reaching frequencies of around 50% at more than one visit for the intervention groups . The effect was even more pronounced in patients with previous hypertension. The mean rise of systolic blood pressure throughout the studies was around 3–5 mm Hg and amenable to treatment . It has been suggested that this effect is due to off-target inhibition on vascular endothelial growth factor receptor 2 (VEGFR2) . Hypertension is unfavourable in a disease syndrome that is already associated with an increased risk of cardiovascular events. Diarrhoea was commonly reported to be higher in the intervention than comparator groups. Elevations of liver transaminases were also transient, sometimes reversible without intervention, but usually returned to normal after dose reduction or discontinuation as seen with neutropenia. Hypertension and neutropenia are critical side effects for a drug in RA patients that are more prone to infections and at higher cardiovascular risk. It is, yet, unclear how these studies and decision to discontinue development in RA will affect the general evaluation of maybe more selective SYK inhibitors in RA.
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