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New Targets, New Therapies: What Does the Future Hold in the Treatment Of RA?

New Targets, New Therapies: What Does the Future Hold in the Treatment Of RA?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial joint inflammation and destruction. Given its systemic nature, RA not only substantially impacts joint health and function, but affects multiple other organ systems as well. The pathophysiology of RA is extraordinarily complicated and has yet to be fully elucidated. Nonetheless, over the last two decades, improved understanding of its pathophysiology has led to substantial breakthroughs in treatment, expanding options beyond conventional disease modifying anti-rheumatic drugs (DMARDs) to include biologics and targeted synthetic DMARDs.1

Understanding of the components that drive the development and progression of RA continue to progress, driving further development of new therapeutic agents. Indeed, one of the most recently approved classes of therapies for RA patients—Janus kinase [JAK] inhibitors—arose thanks to recent research. The arrival of new classes of medication is important for patients with RA, because while there are numerous disease-modifying treatments available in today’s landscape, many individuals affected by RA have a difficult time achieving and/or maintaining adequate disease control and will require a rotating series of lifelong treatments.2,3

Pathophysiology of RA: Back to Basics

While the definitive cause of RA is still unknown, it is believed to arise out of a combination of factors that include genes, environmental triggers, epigenetic modifications, and chance1 Many players are involved, including the innate (e.g., macrophages, dendritic cells, mast cells, neutrophils, and natural killer cells) and adaptive (B and T lymphocytes) immune systems, the complement system (immune complexes), many other cell types (e.g., fibroblast-like synoviocytes, osteoclasts), and signaling molecules (cytokines) and pathways4,5 All of these elements are present in both individuals with and without RA; however, in patients with RA, the process goes awry, with resultant immune dysfunction, chronic inflammation, and tissue injury.4

Given that there are two known major subsets of patients with RA—those with and without anti-citrullinated protein antibodies (ACPA)—the picture is complicated. An estimated 80-90% of patients with RA have detectable ACPAs6 Not only do patients with ACPA-positive RA have a different clinical phenotype than those with ACPA-negative RA, but different genetic association patterns and response of immune cells to citrullinated antigens have been observed between the two groups7 This has given rise to the notion that RA may be best called a “syndrome” representing a variety of distinct pathophysiologic pathways that share a common disease presentation.6,7

Given that ACPA-positive RA is the more common form of the disease, it will be the primary focus of our next section. Referring to Figures 1 and 2 will be helpful as a visual representation of some of the more complex information included in the next sections.

Genetics: Susceptibility Genes

The human leukocyte antigen (HLA).DRB1 gene, one of hundreds of genes found in the HLA complex region on chromosome 6, is one of the best known genes associated with altered susceptibility to RA in patients who test positive for rheumatoid factor (RF) and/ or anti-citrullinated protein antibody (ACPA)1 The HLA complex is a key player in the immune system, helping the immune system differentiate “self” from “non-self” as well as triggering the immune response through the presentation of processed antigens for recognition by the appropriate T cells. The HLA-DRB1 gene encodes directions for a producing cell surface protein called the beta chain. Another gene, the HLA-DRA gene, produces the alpha chain. Binding of the alpha and beta chains forms a functional protein complex called the HLA-DR antigen-binding heterodimer, which is on the surface of antigen presenting cells (APCs). This heterodimer presents foreign protein fragments (peptides) to the immune system, specifically naïve T cells.8

Numerous alleles of the HLA-DRB1 gene have been identified. These HLA-DRB1 alleles code protein beta chains that share a segment of a very similar amino acid sequence, the so-called shared “susceptibility epitope.”6 Some specific alleles for this gene are found to increase susceptibility to RA and are present in up to 60% patients with RA.9,10 Not only have some HLA-DRB1 alleles been associated with susceptibility, they also appear to be tied to disease severity.10

An allele of another gene—the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene—has also been associated with increased susceptibility to ACPA-positive RA11 The PTPN22 gene encodes for lymphoid-specific intracellular phosphatase and may be involved in cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) signaling and T cell activation12 It is believed that approximately 50% of familial aggregation of RA is explained by various alleles at the HLA-DRB1 and PTPN22 gene loci.11

Numerous (>100) genetic loci outside the HLA locus involved in immune regulation have also been identified as modestly contributing to ACPA-positive RA susceptibility and severity; this is a rapidly expanding list6 Many are associated with critical pathways involved in the pathogenesis of RA, including genes involved with lymphocyte stimulation, activation, and differentiation, genes involved with nuclear factor-.B (NF-.B) signaling pathways, and other pathways1,10 It is important to note that the significance of many of these gene variants differs across different populations (e.g., northern European vs Asian descent).10

Environment

Similarly, environmental factors such as smoking, cumulative childhood stress, periodontal, and dysbiosis of the gastrointestinal and respiratory microbiome have been implicated as potential triggers for the development of RA, especially ACPA-positive disease. Examples of infectious agents believed to be autoimmunity triggers include Epstein-Barr, cytomegalovirus, E. coli, Chikungunya virus, hepatitis B virus, A. actinomycetemcomitans, and P. gingivalas1,13,14 This is based upon evidence that autoantibodies can be detected in patients with RA before the development of joint symptoms, suggesting joints may not be the triggering spot for autoimmunity7 This has led many to believe RA may arise from interactions of the external environment with the immune system, primarily at mucosal surfaces6 Lastly, compared with males, females are 2-3 times more likely to develop RA. While reasons for this have not yet been fully identified, it is believed to reflect a combination of hormonal effects (e.g., estrogen and prolactin, which are both considered proinflammatory hormones) and neuroimmunological
interactions.1,15

What Happens When Environment Meets Genetics?

It is generally accepted that the pathophysiology of RA reflects the interplay of environmental factors, epigenetic changes, and altered post-translational modification of proteins. This, combined with susceptibility genes, results in the loss of tolerance and the downstream effects of autoimmunity (see Figure 1).

One key player in this process is the calcium-dependent enzyme peptidyl arginine deiminase (PAD). Expression of the gene that codes for PAD has been shown to increase with environmental infections or stressors, such as periodontal disease or smoking, and is considered a normal physiological response4,6,16 PAD facilitates the post-translational citrullination of proteins that are found throughout the body7,16 Furthermore, the process of neutrophil extracellular trap (NET)osis, which has been shown to be activated by infection, clearance of dead cells, and cigarette smoke, leads to the formation and release of chromatin NETs. This can also contribute to citrullination of proteins as well as the enhanced expression of proinflammatory genes and production of pro-inflammatory cytokines16 More recently, other epigenetic modifications producing post-translationally modified antigens, such as carbamylated, acetylated, and methylated proteins, have been identified as another source of autoantibodies, but their role in the potential development of RA remains unclear.7,17

It is also believed that infectious agents and their products are involved in the pathophysiology of RA through several other mechanisms.

The Immune Response and Loss of Tolerance

As a result of post-translational modifications, the immune system no longer recognizes these modified proteins as “self.” The innate immune response is the first line of response against this “foreign” threat and includes immune cells such as macrophages, dendritic cells, mast cells, and B-cells4 Upon encountering antigens, local immune effector cells become activated and produce inflammatory chemokines and cytokines in order to eliminate the threat18 In addition, some of these immune cells—primarily macrophages and dendritic cells—also act as APCs, processing the antigen and traveling from the site of infection to the closest lymph nodes to present the antigen to naïve T cells, thus initiating the adaptive immune response.5

What differentiates the response in patients with RA from those without the disease is not the post-translational modification of proteins and the immune response to these altered proteins per se, but rather binding of the altered peptides to RA-associated HLA-DR alleles and the subsequent presentation of the antigen to T cells. Data indicate that citrullinated vimentin peptides bind more avidly to the RA-associated HLA-DR antigen-binding heterodimer binding pocket compared with non-citrullinated vimentin.

Upon presentation of the antigen to the T-cell receptor, naïve T cells undergo activation into CD4+T cells, which further differentiate into several subsets of helper cells and regulatory T cells1,19 The type of activated helper T cell is largely dependent on the type of cytokines present20 Regulatory T cells have been shown to inhibit the activation and proliferation of lymphocyte effector cells, thus playing an important role in the suppression of inflammatory response19,21 The relationship between Th17 and regulatory T cells is an area of ongoing interest as they share a common signaling pathway mediated by transforming growth factor-beta (TGF-ß). In the presence of proinflammatory cytokines (e.g., IL-6 or IL-21) and TGF-ß, naïve CD4+ T cells differentiate into Th17. In contrast, in the absence of proinflammatory cytokines, TGF-ß drives differentiation into regulatory T cells20 As such, alterations in the number of and function of regulatory T cells has been observed in autoimmune diseases, including RA, with the proinflammatory milieu supporting Th17 differentiation and Treg suppression, shifting T cell balance toward inflammation1,21 Treatment approaches, such as monoclonal antibodies directed against Th17-related cytokines and receptors (e.g. IL-6, IL-6R, TNF-.), have been shown to be successful in affecting the Th17/Treg balance20 Similarly, low-dose IL-2 has been suggested as a potential therapeutic agent, as it has been shown to selectively promote the expansion of Treg cells in patients with RA, resulting in improved clinical symtpoms.22

Activated helper T cells secrete a number of inflammatory cytokines with a variety of effects on the active immune response, such as B-cell activation, proliferation, and differentiation into plasma cells1 In the case of RA, plasma cells produce specific antibodies against the altered proteins, such as anti-citrullinated and anti.carbamylated protein antibodies; these autoantibodies have been shown to demonstrate cross-reactivity with one another as well as other endogenous epitopes on native proteins7,17 Other autoantibodies in RA have been detected as well, including RF, nuclear antigens (e.g., anti-perinuclear), anti-keratin, and anti-collagen antibodies.23

Transition to Arthritis

Much of the process that causes the development of RA occurs prior to the development of clinically evident arthritis—often preceding it by many years—and reflects a general state of autoimmunity6,24 Interestingly, in the presence of arthralgias, it has been found that only a subset of these “at-risk” individuals will go on to develop active synovial disease in the short-term24 Recent data indicates B-cell receptor (BCR) clones can be detected in the peripheral blood of “at-risk” patients. Results from a validation study of this approach were presented at the 2018 American College of Rheumatology (ACR) annual meeting. They confirmed that an increasing number of dominant BCR clones was associated with an increased risk of developing RA within 3 years, suggesting a potential future role for testing of BCR positivity in patients “at-risk” and preventive therapy in patients with a highly positive test.25

It is still not clear what causes the jump from generalized autoimmunity to a specific disease pathology, or in the case of RA, the localized onset of inflammation in the joint and the subsequent development of clinical disease1 Once synovial joints are involved, activated T and plasma cells interact with a variety of local cells, setting off a cascade of disordered adaptive and innate immune processes (see Figure 2). The end result is chronic joint synovitis, cartilage damage, bone erosion, and ultimately joint destruction as well as systemic manifestations.1

To date, the pro-inflammatory cytokines IL-1, IL-6, IL-17, and TNF-., as well as downstream mediators, have been implicated as the major driving forces for joint destruction18 However, RA is a balancing act of pro- vs anti-inflammatory cytokines, and a large number of other pro-inflammatory cytokines, anti-inflammatory cytokines, and natural cytokine antagonists have been found to play a role in amplifying or modifying the inflammatory response. However, it is challenging to classify cytokines given that many have pleotropic effects and their list is ever expanding26 Furthermore, a variety of other molecules and intracellular signaling pathways have garnered interest for the role they may play in the pathogenesis of RA.

Given the wide array of molecules and pathways involved in the pathophysiology of RA, this has created a number of possibilities for therapeutic targets. Currently approved biologic and small molecule DMARD therapies target several of these cytokines, signaling molecules, or pathways. To date, four classes of biologic and one class of targeted synthetic therapies have received approval by the U.S. Food and Drug Administration (FDA) for the treatment of RA (see Table 1).

Investigational agents targeting some of the same or novel mechanisms of action have undergone clinical development, although many have not progressed to or beyond late stage (Phase 3) trials. For example, results from clinical trials targeting other molecules or pathways, such as BLyS (belimumab), BAFF (tabalumab), GM-CSF (mavrilimumab), Syk signaling (fostamatinib), BTK (evobrutinib), IL-6 (sirukumab), IL-17 (secukinumab), IL-20 (fletikumab), IL-12/23 (ustekinumab), IL-21, and IL-23 (guselkumab) have failed to meet expectations and/or development has been halted. Other agents, while approved for use in patients with other various autoimmune diseases, are not currently under active development for RA, such as ixekizumab (anti-IL-17a) and canakinumab (anti-IL-1ß).27-29

The bulk of current late-stage clinical development is centered around interleukins and protein kinase inhibitors, specifically IL-6/IL-6 receptor (IL-6R) and JAK inhibitors.

Interleukin Targets Under Phase 3 Development: IL-6

Numerous cell types produce IL-6, such as T cells, B cells, macrophages, dendritic cells, fibroblasts, osteoblasts, and endothelial cells. IL-6 is a pleiotropic cytokine that is important for its role in B-cell maturation and antibody production, TH17 differentiation and proliferation, and the induction of acute phase reactants, including CRP. IL-6 promotes synovitis and joint destruction through the stimulation of neutrophil migration, osteoclast maturation, pannus proliferation, and fatigue via the hypothalamic-pituitary-adrenal axis (see Figure 3). IL-6 has been found to be elevated in both the serum and synovial fluid of patients with RA30 When IL-6 binds to its receptor (IL-6R), it activates Janus kinase (JAK), a type of tyrosine kinase. JAK activation triggers several intracellular pathways, resulting in increased transcription of target genes with resultant biological activities.31

Given its widespread effects, IL-6 and the IL-6 receptor are important targets for RA disease management. To date, two IL-6 receptor antagonists—tocilizumab and sarilumab—have received FDA approval for use in patients with RA32,33 Two IL-6 pathway antagonists, sirukumab and olokizumab, have progressed to/through phase 3 development. Both bind to IL-6 rather than the receptor and selectively block the final assembly of the signaling complex.34

Olokizumab

Two phase 2 trials as well as open-label extensions of these trials assessed the safety and efficacy of subcutaneous olokizumab compared with placebo in patients with moderately to severely active RA who had failed previous TNF inhibitor therapy. The majority of patients were using MTX at baseline; concomitant MTX use was permitted during the studies. These studies found that the use of olokizumab resulted in significantly greater reductions in Disease Activity Score in 28 Joints-C reactive protein (DAS28-CRP) at Week 12 compared with placebo and demonstrated tolerable safety. One of these studies also included a treatment arm comparing olokizumab with tocilizumab and reported similar safety and efficacy between the two agents34,35 Based upon these findings, three phase 3 studies (CREDO1, CREDO2, and CREDO3) have launched and are actively recruiting patients. These trials are designed to assess the safety and efficacy of olokizumab (64 mg every 2 or 4 weeks) in combination with MTX compared with placebo + MTX or adalimumab (40 mg every 2 weeks) + MTX in patients with moderately to severe RA who have had inadequate response to MTX or TNFi therapy, depending on study design. A fourth phase 3 study—CREDO4—is a long-term extension study for individuals who participated in either the CREDO 1, 2, or 3 trials. The primary outcome for the CREDO 1, 2, and 3 studies is the proportion of patients achieving ACR20 response at Week 12, whereas the long-term extension study is assessing safety and efficacy between weeks 82 and 106.29

Sirukumab

Sirukumab is another subcutaneously administered anti.IL-6 monoclonal antibody. Two dosing regimens (100 mg every 2 weeks and 50 mg every 4 weeks) were evaluated in five phase 3 trials: SIRROUND-M, SIRROUND-D, SIRROUND-T, SIRROUND-H, and SIRROUND-Long-term extension.29

SIRROUND-M evaluated sirukumab monotherapy in patients with moderate to severe RA who had an inadequate response to MTX or sulfasalazine therapy; results found comparable safety and efficacy between the two sirukumab dosing arms36 Two of the phase 3 studies evaluated sirukumab compared with placebo over 52 weeks of treatment in patients with moderately to severe RA who had an inadequate response to DMARD (SIRROUND-D) or TNF inhibitor therapy (SIRROUND-T]; patients were allowed to continue using any concomitant conventional DMARD therapy that they were on at baseline. Overall, both studies found that sirukumab was well tolerated and significantly improved signs and symptoms of RA compared with placebo.37,38

Lastly, the 52-week, SIRROUND-H study compared the two doses of sirukumab monotherapy to adalimumab monotherapy (40 mg every 2 weeks) in biologic-naïve patients with moderately to severely active RA despite MTX therapy. Both sirukumab dosing regimens demonstrated significantly greater improvements in DAS28-ESR at Week 24 compared with adalimumab; however, ACR50 response rates at Week 24 were similar between the treatment arms. The observed safety profile of sirukumab was consistent with other anti-IL-6 receptor antibodies. 39

Sirukumab’s manufacturer filed a biologic license application with the FDA based upon the results from the pivotal phase 3 studies. However, in 2017, the FDA denied the approval of sirukumab based on emerging safety concerns from the phase 3 studies. Specifically, there was concern regarding the number of patients treated with sirukumab who demonstrated a trend of increased overall mortality compared with those who received placebo, primarily due to major adverse cardiovascular events, infection, and malignancy.40

JAK inhibitors

In contrast to the currently approved biologic DMARDs, which exert their effects through blocking extracellular targets such as cell surface receptors or circulating cytokines, JAK inhibitors target intracellular signaling pathways.

There are four non-receptor protein tyrosine kinase (TYK) members in the JAK family: JAK1, JAK2, JAK3, and TYK241 Each is constitutively bound to the cytoplasmic domain of various cell surface receptors, where they work in pairs. Upon extracellular cytokine or growth factor binding to the cellular cytokine receptor, JAK molecules are activated and phosphorylate the cytokine receptor, creating a docking site for the phosphorylation and activation of two key proteins involved in intracellular signaling, one of which is the signal transducer and activator of transcription (STAT) protein31,42 Upon phosphorylation, the STAT proteins form hetero-or homodimers, which subsequently translocate to the cell nucleus. The activation of these intracellular pathways, including the JAK/STAT pathway, leads to increased gene expression of proinflammatory cytokines, such as IL-6, which further contribute to the pathophysiology of RA.31,43

Downstream effects of activated JAK/STAT pathways depend on the type of cytokine and receptors involved, with different cytokines signaling through different, specific JAK protein combinations. The various combinations and downstream effects are summarized in Figure 4.42

Inhibition of JAK has been shown to block the downstream effects associated with cytokines involved in the pathogenesis and progression of RA41 As such, the development and approval of oral, small molecule, synthetic JAK inhibitors has provided additional treatment options. To date, two JAK inhibitors—tofacitinib and baricitinib—have been approved in the United States for use in patients with RA.44,45

Currently Approved JAK Inhibitors

Tofacitinib was the first JAK inhibitor to receive FDA approval in 2012. Tofacitinib was designed to be predominately JAK3 selective; however, it has been shown to inhibit JAK1 as well as having a smaller effect on JAK2 and TYK2. In contrast, baricitinib, approved by the FDA in June 2018 for the treatment of moderately to severely active RA, was developed to have increased specificity for JAK1 over JAK243-45 This reflects the effort to increase JAK inhibitor selectivity in an attempt to minimize JAK2 inhibition and associated effects, such as negative impacts on hemoglobin, lymphocyte, and neutrophil counts43 Unlike other biologic therapies administered via infusion or injection, JAK inhibitors are oral medications, further differentiating their mechanism of action.

Real-world, long-term data on the use of JAK inhibitors is obviously limited; however, recent data show that the real-world, long-term safety of both tofacitinib and baricitinib is consistent with that observed in clinical trials. A long-term integrated safety analysis pooled data from 22 clinical studies, including 7,061 patients who had received ≥1 tofacitinib doses either as monotherapy or in combination with a DMARD, translating to 22,875 patient years of tofacitinib exposure. The median drug exposure was 3.1 years, with 30% of patients having more than 5 years of exposure, providing up to 9.5 years of follow-up. The authors reported that the safety profile of tofacitinib was consistent with that found during the drug’s clinical development program in RA and did not increase with long-term exposure.46

Similar results were reported in an integrated analysis of patients with moderate to severely active RA treated with baricitinib, including patients exposed for up to 6 years. Data was pooled from eight randomized trials, representing 3,492 patients receiving baricitinib for 7,860 total patient years of exposure. The authors reported that baricitinib maintained a safety profile similar to that previously reported in the literature, and prolonged exposure was not associated with an increased incidence of adverse events.47

While longer-term data are still needed, at this time, findings in the literature suggest safety profiles (e.g. malignancy, infection) of JAK inhibitors are generally similar to that of biologic agents commonly used to treat RA, with the exception of an increased incidence of certain types of infection, notably viral disease42 Furthermore, even though an overall characteristic safety profile is emerging for JAK inhibitors as a class, speculation exists that differences in safety may emerge for individual agents based on their selectivity.43

JAK Inhibitors Under Phase 3 Development

The newer JAK inhibitors under development have strived to increase JAK selectivity even more. Recent earlier-phase data demonstrate that these efforts are paying off, as reflected in the late-stage clinical development pipeline showing that three new JAK inhibitors are in phase 3 development for the treatment of RA (upadacitinib, filgotinib, and peficitinib) (see Table 2). A fourth JAK inhibitor—decernotinib—was evaluated in earlier phase studies but does not appear to be active in later-stage development.29

Numerous phase 2 studies have investigated upadacitinib, filgotinib, and peficitinib both as monotherapy and in combination with MTX or conventional DMARDs for the treatment of adult patients with moderately to severely active RA who have had a previous inadequate response to therapy. Treatment arms of the studies varied with individual study design. Across these studies, the novel JAK inhibitors were associated with improvements in RA signs and symptoms and were generally well tolerated48-52 Based on these positive results, phase 3 studies are currently underway for each JAK inhibitor.

Upadacitinib: JAK1 Inhibition

Interim results from several of the larger Phase 3 trials evaluating JAK inhibitors have recently been released. In the SELECT-Next study, patients (N=661) with moderately to severely active RA on a stable dose of conventional DMARD therapy but with an inadequate response to it were randomized to receive upadacitinib or placebo in addition to their background therapy. At Week 12, significantly more patients receiving upadacitinib (15 mg or 30 mg once daily) compared to placebo achieved an ACR20 (22.2%, 28.3%, and 8.6%, respectively) and DAS28-CRP low disease activity (48.4%, 47.9%, and 17.2%, respectively) response. Adverse events were more common in the upadacitinib 15 mg and 30 mg arms compared with placebo (56.6% and 53.9% vs. 48.9%, respectively), but very few were serious (4.1% and 2.7% vs. 2.3%, respectively). Similar rate patterns were observed for any infection and serious infection: upadacitinib 15 mg (29.0%, 0.5%), upadacitinib 30 mg (31.5%, 1.4%), and placebo (21.3%, 0.5%). Herpes zoster infections were reported in 1 patient in the placebo and upadacitinib 15 mg arms, and 2 in patients in the upadacitinib 30 mg arm. Safety and tolerability were consistent with observations in phase 2 studies with no new safety signals emerging.53

Interim results from additional trials were reported at the 2018 ACR annual meeting, including results from the SELECT-Monotherapy and SELECT-Compare studies.

The SELECT-Monotherapy study evaluated the safety and efficacy of switching to upadacitinib monotherapy from MTX compared with continuing MTX in patients with an inadequate response to MTX (N=648). At Week 14, a significantly higher proportion of patients receiving upadacitinib monotherapy (15 mg or 30 mg once daily) compared with those continuing MTX achieved ACR20 (67.7% and 71.2% vs. 41.2%, respectively) and DAS.CRP≤3.2% (44.7% and 53.0% vs. 19.4%, respectively) responses. Adverse events were similar across treatment arms, and upadacitinib safety events were consistent with prior studies.54

The SELECT-Compare study compared the safety and efficacy of upadacitinib (15 mg once daily), placebo, and adalimumab (40 mg every other week) in patients with active RA continuing background MTX (N=1,630). At Week 12, patients treated with upadacitinib achieved significantly higher ACR20, ACR50, and ACR70 response rates (70.5%, 45.2%, and 24.9%, respectively) compared with both placebo (36.4%, 14.9%, 4.9%) and adalimumab (63.0%, 29.1%, 13.5%). In addition, low disease activity (DAS28-CRP≤3.2%) or remission (DAS28-CRP<2.6%) was achieved by significantly higher proportions of patients in the upadacitinib arm (45.0% and 28.7%, respectively) compared with placebo (13.8%, 6.1%) and adalimumab (28.7%, 18.0%). At Week 26, the incidence of adverse events and serious infections was similar for upadacitinib and adalimumab, with both higher than placebo. Safety events were consistent with other phase 2 and 3 studies of biologics used to treat RA55 The FDA accepted a new drug application from upadacitinib’s manufacturer in February 2019. A decision on its potential approval for the treatment of patients with moderate to severe RA is expected in the second half of the year.

Filgotinib: JAK1 inhibition

Results from the phase 3 FINCH 2 study were presented at the 2018 ACR annual meeting as well. In this study, 448 patients with moderately to severely active RA on a stable dose of conventional DMARDs and inadequate response/intolerance to one or more biologic DMARD therapies were assigned to receive filgotinib (200 mg or 100 mg once daily) or placebo in addition to their background conventional DMARD therapy.

At Week 12, significantly more patients receiving filgotinib 200 mg or filgotinib 100 mg achieved an ACR20 response compared with placebo: 66.0% and 57.5% vs 31.1%, respectively. Significant differences were also noted for filgotinib 200 mg, filgotinib 100 mg, and placebo for ACR50 (42.9%, 32.0%, 14.9%) and ACR70 (21.8%, 14,4%, 6.8%) response. Differences in response rates were maintained at 24 weeks. Adverse event rates were similar across all 3 treatment arms, including serious adverse events. Four patients (2 in each filgotinib arm) developed uncomplicated herpes zoster infections. Overall, safety findings were consistent with phase 2 data56 Two larger phase 3 studies involving filgotinib are scheduled to be completed in spring 2019 that will provide important information for the future of the drug in patients with RA.

Peficitinib: JAK3/JAK1 inhibition

Interim results for two international phase 3 studies evaluating peficitinib (100 mg/day or 150 mg/day) compared with placebo for the treatment of patients with moderately to severely active RA and an inadequate response to conventional DMARDs, including MTX, were released in early 2018; each study included approximately 500 patients. The RAJ3 study compared the efficacy of peficitinib and placebo, alone or in combination with other DMARDs (if stable dose at baseline) in patients with an inadequate response to at least one DMARD. In this study, open-label etanercept was used as the reference drug. The RAJ4 study, meanwhile, compared the efficacy of peficitinib + MTX vs. placebo in patients with inadequate response to MTX. Both studies met the primary endpoint of ACR20 response rate at Week 12. A co-primary endpoint for the RAJ4 study—the suppression of joint destruction at Week 28 (change in modified total sharp score from baseline)—was also met. The safety analysis of peficitinib in these studies was consistent with previous study data, and no new safety signals emerged. Based on these results, peficitinib’s manufacturer announced that they plan to discuss the data with regulatory bodies in Japan and other Asian countries to support filing a new drug application (NDA)57 It is unclear what next steps entail in the United States at this time.

Biosimilars in RA

No conversation about the evolving treatment options for patients with RA would be complete without addressing the current status of biosimilars. Since 2016, seven biosimilars have been approved by the FDA for use in patients with RA (see Table 3), with the most recent biosimilar, adalimumab-adaz, joining the list on October 30, 2018.58,59
Many additional biosimilars of biologic reference products used to treat RA are under clinical development and/or in FDA review, with a recent review identifying at least 24 biosimilars having either completed or involved in phase 3 evaluation28,29 For instance, manufacturers of two rituximab biosimilars and an adalimumab biosimilar have submitted Biologics Licensing Application paperwork for FDA approval. Approval for one of the two rituximab biologics was declined for reasons not made publicly available while the second is still pending approval.60-62
The FDA filing for the adalimumab biosimilar was accepted in September 2018.63

Findings in the literature indicate that patients can be transitioned from a reference drug to its biosimilar without loss of efficacy or increased risk of adverse events. Given the increasing data supporting the use of biosimilars, the ACR is in the process of reconsidering its position on their use, shifting from one of caution to one that recommends that biosimilars, when appropriate, be incorporated into treatment regimens of patients with RA.64

Beyond comparable safety and efficacy, another question clinicians may have about the use of biosimilars is their relative immunogenicity compared with their reference products, as antidrug antibodies have been associated with reduced efficacy and an increased frequency of infusion reactions for infused biologics. To answer this, both the FDA and European Medicines Agency require at least one clinical trial to establish that there are no clinically meaningful differences between the immunogenicity of the proposed biosimilar compared with the reference product64 For instance, the safety, efficacy, and immunogenicity of adalimumab-adaz was compared with the reference drug (adalimumab) in patients with moderately to severely active RA despite DMARD therapy, including MTX, in a phase 3 study. Data from this study indicated equivalent efficacy and similar safety profiles. From baseline to Week 24, antidrug antibodies were detected in 21.8% of patients in the adalimumab-adaz arm and 24.4% of patients in the adalimumab arm, of which 75.0% and 73.2% were neutralizing, respectively.65

Similar results were found in the phase 3 VOLTAIRE-RA study, which assessed the safety, efficacy, and immunogenicity of adalimumab-adbm compared with adalimumab. The VOLTAIRE-RA study also found that switching from adalimumab to the biosimilar had no impact on efficacy, safety, or immunogenicity66 That said, patients who experience loss of clinical response to a reference biologic due to antibody development should not be switched to its biosimilar as antidrug antibodies to reference biologics have been found to cross-react with their biosimilars.64

It is important to remember that an FDA-approved biosimilar does not directly translate into automatic interchangeability with its reference product. A biosimilar needs to first meet additional criteria and be designate by the FDA as interchangeable in order to be automatically substituted for its reference product by pharmacists. Currently, no biosimilars have received FDA designation as interchangeable with the reference product59,67 However, Boehringer Ingelheim, the manufacturer of adalimumab-adbm, has indicated that they are conducting clinical trials to assess the interchangeability of their product with adalimumab in the treatment of plaque psoriasis68 Biosimilars may be approved for use in the same indications for which the reference product is used (“extrapolation of indications”);64 thus, if adalimumabadbm receives interchangeability designation for plaque psoriasis, it may also extend to RA.

In anticipation of biosimilars being deemed interchangeable in the future, a ACR position statement states that the ACR believes that only prescribing providers should be allowed to substitute a biosimilar for the reference biologic or to switch among biosimilars…and in jurisdiction where substitution by someone other than the prescribing provider is lawful, the prescribing provider and the patient should be notified immediately when a substitution is made.69

Summary

It is clear that the understanding of the pathophysiology of RA has greatly improved in recent years and continues to help drive innovation in approaches to treatment, but it is still an unfolding story. As more is learned, it will continue to be the foundation on which future therapies used to treat RA are built.
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