R788

The status of fostamatinib in the treatment of rheumatoid arthritis

Abstract

Fostamatinib (R788) is a prodrug rapidly converted to its active metabolite on oral administration. This (known as R406) is a potent inhibitor of spleen tyrosine kinase, required for the expression of a number of proinflammatory cytokines. Fostamatinib has shown significantly superior efficacy (when compared with placebo) in the control of patients with rheumatoid arthritis not responding to methotrexate in Phase II clinical trials. Treatment emergent adverse events with a higher frequency than in those on placebo included diarrhea, hypertension, urinary tract infections, neutropenia and elevated transaminases. The studied doses have shown a linear pharmacokinetic pattern and the administration of methotrexate does not affect it. Fostamatinib may have a role in the therapy of patients with rheumatoid arthritis with poor response to conventional therapy. If these results are confirmed once Phase III studies are completed, it may find a place in the evolving treatment algorithm for rheumatoid arthritis.

KEYWORDS: fostamatinib • kinase inhibitors • rheumatoid arthritis • SYK kinase

Introduction

Rheumatoid arthritis (RA) is a common auto- immune disease that is associated with progres- sive disability, systemic complications, early death and socioeconomic costs. Its cause is unknown, and the possible outcomes require a cautious approach to define prognosis in indi- viduals [1]. In spite of this, the current under- standing of the pathogenesis of RA has led to the development of new therapeutic approaches that have resulted in significant improvements in the evolution of patients. According to these advances, the prevailing treatment strategy is to initiate aggressive therapy soon after diagnosis and to escalate the therapy with multiple disease- modifying antirheumatic drugs (DMARDs) aiming to control inflammation and to preserve both structure and function of the musculo- skeletal system, as well as to limit the systemic impact of the disease. This should be guided by a comprehensive assessment of disease activ- ity, in pursuit of clinical remission [2]. However, treatment of RA remains far from perfect. The conventional and biologic disease-modifying agents currently available may sometimes fail or produce only partial responses. There is a lack for predictive biological markers for prognosis as well as for therapeutic response and toxicity. Remission is infrequent and rarely sustained, requiring the continuation of therapies. Patients with RA have a higher mortality rate than healthy persons and also a higher prevalence of cardiovascular and other systemic complications that compromise prognosis.
Notwithstanding, significant advances in the knowledge of the pathogenic steps that initiate and that tend to perpetuate the disease have fostered the development of a growing body of therapeutic agents that allow an optimistic view for the near future. RA causes synovial inflammation and hyperplasia; manifested as swelling of joints, the production of autoantibodies, including rheumatoid factor and anticitrullinated protein antibody, destructive changes of bone and cartilage; manifested as deformity and a number of systemic features, including cardiovascular, pulmonary and skeletal disorders. In the tissue-damage characteristic of R A, there is a complex interplay of cytokines, autoantibodies, immune complexes and a cellular array including macrophages, neutrophils, synoviocytes, B cells, T cells, osteoclasts and mast cells. These cells play a key role in inflammation by releasing lipid mediators of inflammation, cytokines, nitric oxide, reactive oxygen intermediates, matrix metalloproteinases and proinflammatory cytokines [3]. Chronic inflammation depends on communication networks among different cells types. These networks involve extracellular mediators (cytokines, chemokines and matrix-degrading proteases) orchestrating the participation of cells in the process. These mediators are reflected by a number of intracellular transcription factor pathways, communicating information about inflammatory stimuli to the cell nucleus [3].
Several hematopoietic cells, including neutrophils, mast cells, macrophages, dendritic cells, natural killer cells and B lympho- cytes express Fc receptors. These, on activation give way to a number of cytoplasmic signaling steps. An important compo- nent of these steps is spleen tyrosine kinase or SYK. Once the activated Fc receptor is engaged, its internal tyrosine activa- tion motifs are phosphorylated, activating SYK. This, in turn, phosphorylates several downstream targets. In the inflam- matory pathway distal to SYK, the targets include a series of MAPKs including ERK, JNK and p38 [4], as illustrated in FIGURE 1. The synovial tissue of patients with RA expresses SYK and the levels of phosphorylated SYK are significantly increased in RA synovium when they are compared with those found in that from patients with osteoarthritis [5]. It has been found that there is a link between the activation of SYK in synoviocytes of patients with RA with the activation of JNK. The inhibition of SYK blocks the TNF-α activation of JNK, and this leads to a reduced expres- sion of genes regulated by JNK such as those related to IL-6 and MMP-3 [4–6]. These observations support the notion of a role for SYK inhibition in the control of clinical manifestations of RA, and they have been further supported by studies in animal models, where the treatment with R788 and R406 in rodent collagen-induced arthritis, have shown a significant reduction in inflammation and bone erosion [7].
The purpose of this communication is to review the development and current status of an inhibitor of SYK.
Chemistry, pharmacodynamics & pharmacokinetics Fostamatinib (R788), whose formula is C23H24FN6O9P·Na2·6H2O and molecular weight is 732.51, is a prodrug that following oral administration, is rapidly converted to a metabolite referred to as R406 by the action of the intestinal microsomes found in the mucosa. R406 is a potent selective inhibitor of SYK [4,6,8].
Phase I studies involving healthy volunteers have established the pharmacokinetic and pharmacodynamic properties, as well as the safety of fostamatinib at orally administered single doses (80–400 mg) and multiple doses of up to 250 mg twice daily (b.i.d.) for periods extending up to 20 days [9]. Following single doses, it was rapidly and extensively converted to R406 (peak exposure of fostamatinib in plasma was less than 7 ng/ml). At multiple doses of 160 mg, the tmax ranged from 1.08 to 1.25 h. A dose-related increase in R406 exposure, by area under the curve estimates, was seen at doses of 80–250 mg of fostamatinib. Average terminal half-life ranged between 13 and 21 h, with a steady state achieved in 3–4 days. A high fat/high calorie meal increased the tmax and lowered the Cmax, but did not affect the area under the curve. R406 is metabolized in the liver. Plasma protein binding is 98.2% [6], and the primary route of elimination of R406 and its metabolites is through biliary excretion [8].
A study in healthy volunteers used a biomarker for SYK activa- tion and inhibition, and showed a 50% maximum response con- centration (EC50; for R406 inhibition of SYK) of approximately 500 ng/ml [101]. Data on the plasmatic concentration obtained from pharmacokinetic and safety studies of a range of orally administered doses up to 250 mg b.i.d. in human volunteers, have suggested that it would be appropriate to include b.i.d. oral doses of 50–150 mg in the dose-ranging studies to test if the SYK inhibi- tory concentrations of R406 would have a positive clinical impact on RA. The pharmacokinetic interactions of R788 and metho- trexate (MTX) were explored in a study of 16 patients with RA. It found no significant alterations in the plasma levels of R788 or R406, while the concentration of MTX and its metabolites were not altered. This suggests that the pharmacokinetic inter- action between MTX and fostamatinib (R788) is not significant [10].

Clinical efficacy

A Phase IIa study (identified as TASKi1) enrolled 189 patients with active RA despite MTX therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-con- trolled trial. The primary end point was the American College of Rheumatology (ACR) 20% improvement criteria response rate at week 12. Patients were maintained with their own stable doses of MTX, nonsteroi- dal anti-inflammatory agents; prednisone up to 10 mg/day and other nonbiological DMARDs.
Oral b.i.d. oral doses of 100 and 150 mg of fostamatinib were significantly superior to placebo or b.i.d. oral doses of 50 mg at week 12 (ACR20 achieved in 65 and 72% vs 38 and 32% of patients, respectively [p < 0.01]). ACR50 (achieved in 49 and 57% vs 19 and 17% of patients, respectively) and ACR70 (achieved in 33 and 40% vs 4 and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum IL-6 and MMP-3 levels also occurred as early as week 1 in the groups receiving 100 and 150 mg b.i.d. of fostamatinib [11]. Another study (identified as TASKi2) enrolled 457 patients who had active RA despite long-term MTX therapy in a 6-month, double-blind, placebo-controlled trial. Demographics and base- line clinical characteristics were similar among groups. Patients were enrolled with a background therapy of stable doses of MTX, other nonbiological DMARDs, nonsteroidal anti-inflammatory agents and prednisone (up to 10 mg/day). The primary end point was also the ACR20 response. Fostamatinib was administered at a dose of 100 mg b.i.d. or at a dose of 150 mg once daily (q.d.), and both schemes were significantly superior to placebo at month 6. Both dosing regimens were also significantly superior with respect to ACR50, ACR70 and DAS 28-defined remission rate, as shown in TABLE 1 [12]. In this trial, 84% of patients in the fostamatinib and 79% in the placebo group completed the study. In the combined fostamatinib 100 mg b.i.d. and 150 mg q.d. group, the most com- mon reasons for withdrawal were adverse events (5%) and lack of efficacy (6%), with lack of efficacy being the most common reason in the placebo group (12%). Clinically significant effects were noted as early as week one and maximum effect, which was sustained throughout the remainder of the study, by week 6. Another trial (TASKi3), was designed with the objective to assess the efficacy, radiologic response and safety of fostamatinib in RA patients who had failed biologic agents. It included 219 patients with active RA who had a poor response to one or more biologic agents. They were enrolled in a 3-month randomized double-blind study where they were allocated to receive either 100 mg b.i.d. of fostamatinib or placebo. Patients continued with their own stable doses of MTX, nonsteroidal anti-inflammatory agents, prednisone up to 10 mg/day and other nonbiological DMARDs. The primary end point was the ACR20 response rate at month 3. Fostamatinib was also compared with placebo using MRI. Patients were studied using a modified RA MRI scoring system of hand and wrist at baseline and month 3. Demographic and baseline clinical characteristics were similar between groups with the exception of 21% of the fostamatinib patients having failed three or more biologics versus 12% of the patients on pla- cebo. At month 3, no significant difference in ACR responses was achieved between the fostamatinib and the placebo group. Although differences in ACR20 responses were noted at week 6 (p = 0.003), this response difference was not seen at months 2 or 3, primarily because of an increasing placebo response. Significant changes from baseline in C-reactive protein (CRP) and erythro- cyte-sedimentation rate at all time points were achieved in the fostamatinib group versus the placebo group. Interestingly, at the end of the study significant differences in change from baseline between the fostamatinib and placebo groups were observed in RA MRI scoring system osteitis scores (-0.2 in R788 vs +1.2 in placebo [p = 0.058]) and synovitis scores (-0.52 in fostamatinib vs +0.35 in placebo [p = 0.038]), but there was no difference in both groups in the mean change of bone erosion score. In addition, a secondary analysis allowed identifying significant improvements of both ACR and DAS28 response rates in sub- jects who entered the study on the basis of an elevated CRP. The conclusions of this study indicate that there were no differences in the primary end point between both groups. Some differences favored fostamatinib in discrete secondary end points, particularly in those patients who had higher CRP when entering the study. The authors discussed on the possible influence of differences in baseline disease activity and the difficulties in stratifying patients according to the number of previous treatment failures with dis- crete biologic agents, as well as the high placebo response found in some patients with elevated erythrocyte sedimentation rate and normal levels of CRP. They point to the need to consider these findings when planning future studies [13], and currently, active Phase III studies may answer these questions. An analysis of patients involved in Phase II clinical trials and receiving 100 mg b.i.d. of fostamatinib, demonstrated significant improvement in health-related quality of life outcomes, including physical function, pain, fatigue and overall physical health status when compared with those receiving placebo [14]. Safety As seen in the initial 12-week TASKi1 study [11], in the 6-month TASKi2 study, the most common adverse event was diarrhea, which was dose related (please refer to TABLE 2 for details). Transient neutropenia (<1500/mm3) occurred more often in those treated with either dose of fostamatinib than placebo. Elevation of ALT >3 ULN also occurred more com- monly in the fostamatinib groups. An increase in blood pressure was observed at month 1 in patients receiving fostam- atinib as compared with those on placebo. This was most frequently seen in patients with a history of hypertension, and blood pressure was reported as being managed An analysis of long-term safety and tol- erability has included patients from rand- omized, placebo-controlled Phase II trials with fostamatinib, including those identi- fied as TASKi1 [11], TASKi2 [12] (who were on background MTX therapy) and TASKi3 [13] (who were on background therapy of combined DMARDs). This analysis also included patients from the TASKi1 exten- sion and from an ongoing open-label study, and it included a total of 803 patients with 1038 patient-years of exposure, reasonably well balanced across dose groups for age, gender and ethnicity. Key findings are summarized in TABLE 3. Incidence rates for with conventional antihypertensive medications. Mean change from baseline in systolic blood pressure at month 6 was +0.2 mm and +0.6 mm for the 150 mg q.d. and 100 mg b.i.d. groups, respectively, and -1.8 mm for the placebo. By the end of the trial, at month 6, with patients (who required it) receiving antihypertensive therapy, there were no significant increases in blood pressure from the measurements done before exposure to fostamatinib [12].
serious adverse events, serious infectious events, treatment discontinuations and dose reductions were higher in the group of patients who failed to respond to biologics as compared with all the other groups. The most common adverse events were diar- rhea (27.6%), hypertension (22.8%) and urinary tract infections (12.7%). Among the most common serious adverse events, incidence rate per 100 patient-years were infectious events (3.8) and gastrointestinal events (1.9). Most common serious infectious events were lower respiratory tract and lung infections, primarily pneumonia (1.1), urinary tract infections (0.8) and cellulitis (0.7). The discon- tinuation rate on fostamatinib treatment was highest in the first 6 months of therapy, and the primary reason for discontinua- tions were lack of efficacy (in the biologics refractory group) and adverse events (most commonly diarrhea, neutropenia or increased transaminases). Incidence rates per 100 patient-years for blood pressure 160/100 mmHg and 180/110 mmHg for patients on fostamatinib versus placebo were 18.7 versus 21, and 3.9 versus 0.9, respectively. Moreover, incidence rates per 100 patient-years for neutrophil counts <1500 and <1000/mm3 for patients on fos- tamatinib versus placebo were 12.2 versus 3.7 and 3.0 versus 0, respectively. Authors of this analysis conclude that no new sig- nificant safety concerns were identified with longer-term dosing of fostamatinib. Patients who were refractory to biologics had higher incidence rates of all types of adverse events when compared with inadequate respond- ers to MTX, although confounding factors may still be identified to explain this dif- ference [15]. As these adverse events occur at a higher incidence in patients receiving fostamatinib than in those on placebo (all of them on similar background MTX and/or DMARD therapy), it is easy to speculate that they are attributable to the study drug. Currently available information does not allow further elaboration on possible mecha- nisms for those adverse events and also does not allow conclusions on the safety of dosing fostamatinib in patients with hepatic or renal diseases. Clinical applicability The main therapeutic goal for every patient with RA should be the complete remission of the inflammatory activity of the disease. In order to obtain the greatest impact in preventing joint damage and deleterious outcomes as disability, it is required to control early and aggressively the inflammatory process in the synovium [2,3]. Currently available therapeutic options provide considerable benefits in most patients, especially in those who are treated in early stages. Moreover, a significant proportion of patients with inadequate response to MTX alone or in combination with other DMARDs, will obtain benefits from the addition of biologic agents, including those directed at TNF-α, T-cell costimulation, B cells and IL-6 [2,16,17]. However, the complex processes required producing these therapies, the difficulties involved in current dos- ing (mostly injectable) regimens and their high cost, as well as the risk of infection (and other complications), may limit their availability to a large number of patients. Clearly, there is a need for more options for the management of the difficult cases of RA, as therapeutic failures with currently available agents and their long-term side effects are common in daily practice [2,3,16,17]. The small-molecule inhibitors of enzymes involved in the inflam- matory pathways seem to be an attractive therapeutic approach for RA. As clinical research advances in the knowledge of these agents, including fostamatinib, it will establish where these agents fit in the evolving treatment algorithms for RA. Fostamatinib has not been licensed in any country yet and the conclusions of ongoing Phase III studies are required to confirm its longer-term efficacy and safety in a broader range of RA patients [11–13,18–20]. The interest in small-molecule inhibitors has increased after evi- dence linking some of these approaches with modification in joint inflammation and tissue damage in RA [3,21]. Further clarification of the complex intracellular signaling components, particularly kinases that regulate the functions mediated by the interplay of cytokines and receptors, may facilitate the development of specific therapeutic agents based on small-molecule inhibitors. There are many intracellular signaling pathways active in the synovial mem- brane, but clinical trials have provided some indication to identify those hierarchically more important. Phase II studies of tofacitinib, a JAK1 and -3 inhibitor, showing positive clinical outcomes, allow a view of JAK pathways, known mediators of several cytokines, interferon and growth factors; as an important component in the pathogenesis of RA [22,23]. The possibility of finding other intracel- lular targets (including PI3K, Bruton’s tyrosine kinase and other components of the NF-κB pathway) raises hope for newer thera- peutic strategies [3,16]. This rationale has suffered some setbacks. Despite strong theoretical implications of its importance, the tar- geting of P38 MAPK has been disappointing. Clinical trials with two discrete p38 MAPK inhibitors in RA had discouraging results. Neither pamapimod as single therapy [24] nor VX-702 combined with MTX [25] resulted in significant improvement of the disease process. This probably indicates that the molecular signaling net- work in RA has functional redundancy [3]. There are concerns with regard to the safety of kinase inhibitors, in particular in the aspects related to their selectivity and their interaction with some elements (including cytochrome P450) [4,26]. The recognition of the immunomodulatory activity of the inhibi- tion of SYK has led to explore its activity in a number of conditions clinically related to the signaling of Fc or immune complex-based activation. There are reports of significant improvements in the platelet counts in patients with refractory cases of chronic idiopathic thrombocytopenic purpura, which is a condition with well-known linkage to the activity of Fc receptors [27,28]. In addition, inhibi- tion of SYK prevented the onset of lupus nephritis, improved renal function and prolonged survival in a murine model of systemic lupus erythematosus, opening interesting possibilities to explore in the treatment of human lupus [29]. A study in a model of murine- established glomerulonephritis also found significant improvements with fostamatinib [30] There is considerable expectation for the possible role of fostamatinib in the treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukemia [31,32]. Expert commentary & five-year view Currently available results of Phase II clinical trials with fostam- atinib in patients with persistently active RA in spite of MTX therapy have shown significant improvements in comparison with placebo at 3 and 6 months, with a reasonably acceptable toxicity pattern. Available Phase II results in patients whose RA failed to respond to one or more biologic agents do not allow any positive conclusion on the efficacy of fostamatinib in that subgroup of patients. Phase III studies are ongoing and may answer some of the remaining questions. The current treatment of RA is far from perfect. Every patient presents specific challenges, and every rheumatologist is willing to access a wider range of therapeutic options. The efficacy and the safety of fostamatinib still require confirmation from both Phase III and long-term extension studies. If these yield positive results, it may be considered an option for patients with RA and a limited response to MTX and conventional DMARDs. Oral administration represents an advantage and its cost – although this is merely a speculation – may end at lower strata than the cost of current biologics. The eventual role of fostamatinib (after failure to traditional DMARDs or as a single, first-line therapy or even in some subsets of patients who failed to respond to biologics) should be defined from responses obtained from ongoing Phase III trials, which include at least two dosing schemes (150 mg q.d. and 100 mg b.i.d.) either as single therapy (compared with adalimumab) in patients with failure to respond to MTX or to DMARD, and still another trial in patients who failed to respond to MTX and a single biologic agent [101]. In the Phase II trials of fostamatinib, diarrhea, infections, neutropenia and ‘transaminitis’ have been mild to mod- erate and manageable in most cases. In addition, there are appar- ently manageable elevations of blood pressure seen in the Phase II studies. These adverse events will require close monitoring when a larger number of patients are exposed. References 1 MacGregor AJ, Silman AJ. Classification and epidemiology. In: Rheumatology (4th Edition). 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