Small molecule inhibitors for the treatment of RA

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Kay McNamee PhD

Fiona McCann PhD
The Kennedy Institute of Rheumatology

Nuffield Department of Orthopaedics,

Rheumatology and Musculoskeletal Sciences,

University of Oxford, UK

Rheumatoid arthritis (RA) is a debilitating autoimmune condition that affects around 1% of the population. Disease is characterised by joint inflammation, cartilage damage, bone destruction and chronic pain, and if left untreated can result in profound disability. Pathophysiology is attributed to over-production of proinflammatory cytokines, with tumour necrosis factor alpha (TNFα), identified as a pivotal mediator. Control of RA has improved significantly in recent years with the development of drugs that target TNFα, namely infliximab, etanercept and adalimumab. Anti-TNFα biologics, usually taken in combination with methotrexate (MTX), are highly effective at reducing inflammation and restricting joint damage, thereby slowing disease progression, with approximately 70% of RA patients showing an American College of Rheumatology 20% improvement (ACR20). However, despite the unequivocal success of biologics, there remains a substantial subset of patients who do not adequately respond to this treatment strategy. A major disadvantage with biologic therapies is that they must be delivered either subcutaneously or intravenously, and are expensive to produce. Thus, there is a significant need for more cost-effective drugs that can be orally administered and target proinflammatory cytokines. Small molecular weight inhibitors (SMI compounds with a molecular weight of less than 1kDa), have been much explored for their potential to treat RA and other autoimmune disorders. Here, we discuss the SMI currently in development, their proposed mode of action and the impact on drug development in RA.

Protein kinases
SMI currently being investigated in inflammatory diseases are largely targeted to intracellular signalling pathways, the most explored of which target kinases (Table 1). Imperative for cellular processes, kinases are attractive targets as they often act upstream of inflammatory mediators such as TNF and hence selective blockade can regulate inflammatory processes.

The mitogen-activated protein kinases (MAPKs) are one such pathway well described in inflammation. They comprise three groups; p38, c-Jun N-terminal kinase (JNK) and extracellular-regulated protein kinase (ERK). There has been significant interest in p38 as therapeutic target as it is expressed in the RA synovium, and blockade of p38 reduces expression of cytokines implicit in the pathogenesis of RA. p38 Inhibitors have proved effective in suppressing disease in animal models of arthritis, providing a clear rationale for a trial in RA patients.(1) However, numerous p38 inhibitors have now been synthesised including SCIO-469 (Scios), pamapimod (Roche), VX-702 and VX-745 (Vertex) and so far none have progressed to a phase III clinical trial. The first generation p38 inhibitors failed in the clinic owing to toxicity in the liver and central nervous system(1,2) and subsequently substantial efforts have been made to enhance specificity. This increased their tolerability, but they have repeatedly failed to demonstrate efficacy in the treatment of RA. However, targets upstream of p38 might yet prove fruitful. Despite the failure of targeting MAPKs to date, focus on other kinases important in immune responses has continued.

The tyrosine kinases Janus (Jaks) and Syk kinases have emerged as front runners from recent RA clinical trials owing to favourable efficacy. Jak family members bind cytokine receptors which are crucial for mediating signal transduction of cytokines in immune regulation. CP-690 550 (tofacitinib, Pfizer) is a JAK family antagonist currently in clinical trials for RA and other autoimmune diseases including IBD, psoriasis and psoriatic arthritis.(3) The initial proof of concept monotherapy study was conducted in RA patients who had failed to respond to either biologics or MTX alone. At the end of the six-week study, patients receiving tofacitinib had shown a significant response (compared to placebo) for ACR20 from the first week for all doses and for ACR50 and ACR70 from week two for the highest dose.(4) This was followed up with two phase IIb 24-week studies designed to evaluate tofacitinib in combination with MTX in patients who had previously exhibited an inadequate response to MTX. The second trial compared the efficacy of tofacitinib as a monotherapy with the anti-TNF biologic adalimumab. In the MTX combination study, patients were treated with tofacitinib at either 1,3,5,10,or 15 mg twice daily or 20mg once daily and MTX or placebo. All doses, with the exception of the 1mg/twice daily, showed significant ACR20 response by week 12, with the 5, 15 and 20mg doses also demonstrating increased ACR50 and ACR70 responses.(4) In addition, the 3,10,15 and 20mg doses conferred significant DAS28 remission. In the second study, patients were given either adalimumab at 40mg every other week or tofacitinib at 1,3,5,10,or 15mg twice daily. Patients treated with adalimumab showed increased ACR20 response by week 12. When treated with tofacitinib, patients exhibited higher ACR20, ACR50 and ACR70 responses and a reduced DAS28 score with the 10 and 15mg doses.(4) These encouraging results have led to further evaluation of tofacitinib efficacy in five independent phase III trials, with all five successfully meeting their endpoints. One trial raised concern when four deaths were reported,(5,6) with one fatality due to respiratory failure attributed to tofacitinib. Most other adverse events incurred were mild, and largely due to infection.(6) Tofacitinib may present a promising alternative to biologics, but more long term safety analysis is warranted for further progress. Other Jak inhibitors currently in development are INCB-28050/LY3009104 (Eli Lilly, Incyte) and VX-509 (Vertex), a JAK 1/2 and JAK 3 inhibitor respectively which are currently in phase II trials for RA.(6)

Another SMI kinase targeted of interest is R788 (fostmatinib, Rigel). Fostmatinib acts by targeting spleen tyrosine kinase (Syk), an intracellular tyrosine kinase that is important in the regulation of signalling in many immune cells. Syk is also involved in osteoclast ‘bone-eating’ cells responsible for erosions seen within the arthritic joint. The first trial to assess fostmatinib in RA was conducted in 2008. The phase II trial compared three doses of fostmatinib (50, 100 or 150mg twice daily) to placebo in patients already taking MTX. The 100 and 150mg doses showed an improvement compared with the placebo at 12 weeks; with over 65% of patients achieving an ACR20 response (versus placebo response of 38%).(7) The next three-month trial considered how fostmatinib would perform in patients in which treatments with biologics had previously failed.(8) Discouraging results reported no significant differences between fostmatinib and placebo. However, fostmatinib did have an effect on MRI scores measuring synovitis, but ultimately this reduced synovitis did not prevent progressive bone erosion.(8) Despite this, fostmatinib has performed sufficiently well in the phase II trials to continue into phase III trials for RA, due to be completed in 2013.

Although research for oral treatments has been largely dominated by kinase targets, there are alternative SMI in development including those targeting cell surface receptors, TLR antagonists and PDE4 inhibitors (Table 2).

Human CC chemokine receptor 5 (CCR5) is a chemokine cell surface receptor expressed by T cells and macrophages associated with the migration of immune cells to the rheumatoid synovium. CCR5 expression is elevated in T cells in active RA synovium and increased levels CCR5 ligands (MIP and RANTES) have been implicated in the pathogenesis of RA. Treatment of an animal model (non-human primate) of RA with a CCR5 antagonist resulted in reduced clinical score, joint swelling and bone erosion (referenced in 9). Maraviroc (Pfizer) is a non-competitive antagonist of CCR5, previously assessed in HIV therapy clinical trials and most recently evaluated in a phase IIa study to assess safety and efficacy in RA patients receiving MTX. Maraviroc was well tolerated in patients at a dose of 300mg twice daily, and by week 12, ACR20 responses were 30% for maraviroc and 19.1% for placebo, though statistical significance was not reached.(9) The lack of efficacy observed concurred with another study where an alternative CCR5 antagonist also failed to show any evidence of therapeutic effect in RA.(10)

Toll-like receptors (TLRs) are classified as pattern recognition receptors (PRRs) and are important in host defence by recognising pathogen-associated molecular patterns (PAMPs) from viruses, bacteria, protozoa and fungi. TLRs have been implicated in RA due to the elevation of several family members (TLR2, 3 and 7) in synovial fibroblasts compared with healthy controls. Stimulation of TLR3 and TLR8 increases TNFα production from RA synovial membrane cultures and inhibition of myeloid differentiation protein 88 (MyD88) and TIR domain-containing adapter protein (TIRAP), crucial for TLR2 and TLR function, reduces cytokine expression in RA synovial cultures (reviewed in 11). VTX-763 (VentiRx Pharmaceuticals) is a SMI that has been shown to inhibit responses to TLR8 stimulation. VTX-763 suppresses TNFα in vitro, and is currently in pre-clinical evaluation for autoimmune disorders.(11) Other SMIs of TLRs currently in phase I trials are DV1179 (Dyanvax) and CPG52364 (Pfizer) for systemic lupus erythematosus. SMIs targeting TLRs are at a very early stage and their impact will not be evident for some time.

Another therapeutic approach is via the inhibition of type 4 phosphodiesterases (PDE4), due to the capacity to suppress TNFα in vitro. PDE4 hydrolyses cAMP to AMP and is expressed in immune cells. By inhibiting PDE4, cAMP is elevated leading to suppression of TNFα production via the protein kinase A pathway (PKA). Due to their anti-inflammatory potential, PDE4 has been considered as a worthy target in the treatment of autoimmune conditions; however, issues with toxicity have prevented previous molecules from reaching the clinic. The development of many PDE4 inhibitors including filaminast, lirimilast, and piclamilast have been discontinued, with their lack of efficacy possibly due to lower dosing to enhance tolerability.

Significance of apremilast
Apremilast (CC-10004 Celgene) is a novel, orally available small molecule that specifically targets PDE4 that has shown efficacy in the treatment of psoriasis, psoriatic arthritis and animal models of arthritis. In a trial conducted into psoriatic arthritis, 43.5% of patients on apremilast (at 20mg twice daily) and 35.8% of patients (40mg apremilast once daily) achieved the ACR20 end point compared to 11.8% of patients taking placebo after a three-month period.(12) Furthermore, in a plaque-type psoriasis trial, apremilast administered at 30mg twice daily met the primary end point of a 75% reduction in the psoriasis area and severity index (PASI) score in 41% of patients compared to 6% in the placebo group over a four-month treatment period.(13) In the murine models of arthritis (collagen induced arthritis (CIA) and collagen antibody induced arthritis (CAIA)), apremilast significantly reduced severity of disease.(14) Importantly, effects of apremilast on behaviour were compared to another PDE4 inhibitor, rolipram that had previously shown efficacy in CIA. Unlike rolipram, apremilast did not reduce locomotion or increase immobility in DBA/1 mice, indicating that this PDE4 inhibitor may be a suitable candidate due to its tolerability, noteworthy for this class of drugs. Indeed, phase II clinical trials are currently underway to assess efficacy of apremilast in Behcet’s disease and RA, with phase III trials for psoriasis and psoriatic arthritis ongoing,15 and phase III trials for ankylosing spondylitis expected in 2012, suggesting that PDE4 inhibition may indeed be an intriguing strategy for treating chronic inflammation.

Conclusions
In summary, SMI have been hailed as having the potential to revolutionise the treatment of chronic autoimmune conditions by providing better delivery routes through oral administration, highly desired by patients as well as reduced costs to healthcare providers via more cost-effective products. In effect, however, the majority of candidate treatments have failed to reach the clinic. This does not mean the end for SMIs in RA, since the targeting of Jak and Syk kinases and PDE4 may yet prove to be efficacious in the long-term, attaining favourable comparisons to established biologics in the clinic. Indeed, SMI may provide a clear alternative for the subset of patients who fail to respond to anti-cytokine agents, but they are considered unlikely to usurp the dominance of biologics in the near future.

References

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