A review of upadacitinib in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting the joints and is associated with significant levels of disability and reduced quality of life. Janus kinase (JAK) inhibitors are a relatively new class of small molecule oral treatments and offer an alternative for patients with RA who do not respond to conventional or biologic therapy. Upadacitinib is a JAK inhibitor engineered to be selective for JAK1, and has recently been approved for use in patients with moderate-to-severe RA. The purpose of this article is to provide a comprehensive review of upadacitinib, including preclinical development and characterization, phase I and II studies, and the phase III SELECT program. Ongoing trials of upadacitinib in additional indications, including spondyloarthritis, inflammatory bowel disease, and atopic dermatitis, are also discussed.

Keywords:

• Janus kinase inhibitor
• rheumatoid arthritis
• upadacitinib

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting the joints [1]. RA causes progressive damage to bone and cartilage, and is associated with significant levels of disability, reduced quality of life, and an increased risk of comorbidities [2,3]. The incidence of RA is between 0.5% and 1% worldwide [1], making it one of the most common chronic inflammatory diseases in adults.

The treatment of RA should focus on reducing inflammation in order to prevent joint damage and associated disability [4,5]. Current European League Against Rheumatism (EULAR) and treat-to-target guidelines recommend a treatment target of sustained remission or low disease activity, and treatment should be changed if the target is not achieved [4,5]. In recent years, the development of biologic disease-modifying anti-rheumatic drugs (bDMARDs) has dramatically improved the management of RA. Approved biologics include tumor necrosis factor (TNF) inhibitors, interleukin (IL)-6 inhibitors, abatacept, and rituximab, and these treatments are associated with higher rates of remission and low disease activity compared with conventional synthetic DMARDs (csDMARDs) such as methotrexate (MTX) [3].

However, despite the availability of biologics, real-world data have shown that many patients with RA fail to achieve remission or low disease activity [6,7]. In addition, their subcutaneous route of administration and need for concomitant treatment with MTX, to which many patients have an intolerance or contraindication, means that biologics are not suitable for some patients [8,9]. Furthermore, surveys have shown that patients with RA prefer oral therapies over those requiring injection, and monotherapy over combination therapy with MTX [10,11].

More recently, Janus kinase (JAK) inhibitors have emerged as an alternative advanced treatment option in RA [12,13]. JAK inhibitors are orally administered small molecule drugs, and make up the class of targeted synthetic DMARDs [14]. There are currently multiple JAK inhibitors approved for use in RA by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA): tofacitinib, baricitinib, and upadacitinib. In addition to these, peficitinib is approved in Japan and another (filgotinib) is currently in late-stage development [15]. The purpose of this review is to discuss the mechanism of action and clinical development of upadacitinib, the first JAK1-selective inhibitor to be approved for RA.

The JAK–STAT pathway in rheumatoid arthritis

Many cytokines are implicated in the pathogenesis of RA [2], and inhibition of cytokines such as TNF and IL-6 through the use of biologic therapies has become an important strategy in the treatment of RA [3]. Cytokines that bind to type I/II cytokine receptors mediate their effects through activation of the JAK-signal transducer and activator of transcription (JAK–STAT) pathway [16–19]. Upon cytokine binding to type I/II receptors, JAKs phosphorylate both themselves and their receptors, which in turn allows phosphorylation and activation of STAT molecules. STATs then dimerize and migrate to the nucleus, where they regulate the expression of target genes [16,20].

There are 4 members of the JAK family—JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)—and different combinations of JAKs are associated with different receptor chains, resulting in distinct biologic roles [16,20]. For example, JAK1 and JAK3 are involved in the signaling of common gamma chain cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, which play a key role in adaptive immunity [17,20]. JAK1 also regulates several key proinflammatory cytokines, including IL-6 and interferon gamma (IFNγ), by pairing with either JAK2 or TYK2 [16,21]. In contrast, hormone-like cytokines such as erythropoietin, thrombopoietin, and granulocyte-macrophage colony-stimulating factor signal through JAK2 homodimers, meaning JAK2 plays a key role in the development of red blood cells, platelets, and myeloid cells [13,16,21]. Inhibition of JAKs therefore affects multiple cytokines involved in the pathogenesis of RA, but may also lead to effects on other biologic processes unrelated to RA.

The first JAK inhibitor to be approved for RA, tofacitinib, is a pan-JAK inhibitor that inhibits JAK1 and JAK3, with a smaller effect on JAK2 and TYK2 [12,21]. This was followed by baricitinib, which has a higher affinity for JAK1 and JAK2 over JAK3 and TYK2 [12]. In contrast, upadacitinib was engineered to be selective for JAK1 [22]. The rationale for targeting JAK1 is that the anti-inflammatory effect should be maintained, due to the key role of JAK1 in signaling downstream of proinflammatory cytokines, but effects on JAK2-dependent processes such as production of red blood cells and platelets, and JAK3-dependent processes such as lymphopoiesis, should be minimized [12,22]. As such, a JAK1-selective inhibitor could have an improved benefit–risk profile compared with other less selective JAK inhibitors.

Development and preclinical characterization of upadacitinib

Members of the JAK family are tyrosine kinases that catalyze the transfer of phosphate from adenosine triphosphate (ATP) to various substrates, including their associated cytokine receptors [13,16,21]. JAK inhibitors act as competitive inhibitors of ATP and prevent its binding to the tyrosine kinase domain of JAKs. Upadacitinib was designed to selectively inhibit ATP binding to JAK1 based on structural differences in the ATP binding pocket between JAK1 and JAK2 [22].

Upadacitinib was initially characterized in enzymatic assays using recombinant human JAKs, and demonstrated selectivity for JAK1 over JAK3 and TYK2 [22]. Additional analyses showed no significant activity against a broad panel of 70 other human kinases. These results were confirmed using cellular assays; upadacitinib was shown to be >40-fold more selective for JAK1 versus JAK2, 130-fold more selective for JAK1 versus JAK3, and 190-fold more selective for JAK1 versus TYK2 [22]. Further cellular assays showed that upadacitinib inhibited signaling in response to the JAK1-dependent cytokines, IL-6, IL-2, and IFNγ, with 60-fold more potency than for erythropoietin signaling (which utilizes JAK2) [22].

In rat models of arthritis, upadacitinib improved paw swelling, synovial hypertrophy, inflammation, cartilage damage, and bone erosion compared with control [22]. Importantly, upadacitinib had a lesser effect on reticulocyte production and natural killer cell levels compared with tofacitinib in the rat models, despite comparable efficacy, suggesting that upadacitinib shows selectivity for JAK1 over JAK2 and JAK3 in vivo.

Phase I and phase II studies

Results from phase I studies in healthy volunteers found that upadacitinib had a favorable safety profile with single doses up to 48 mg and multiple doses up to 24 mg twice daily for 14 days [23]. Similar results were seen over 27 days in subjects with RA. The pharmacokinetic profile of upadacitinib showed a short functional half-life, dose-proportional exposure, no accumulation with multiple dosing, and no interaction with MTX [23]. These results led to upadacitinib being advanced into phase IIb dose-ranging studies in patients with RA.

Two phase IIb studies were conducted with upadacitinib in RA: BALANCE-1 in patients with an inadequate response (IR) to TNF inhibitors [24] and BALANCE-2 in patients with an IR to MTX [25]. The 2 studies evaluated upadacitinib at doses of 3 mg, 6 mg, 12 mg, and 18 mg twice daily, with BALANCE-2 also including a 24 mg once daily group. Both studies met their primary endpoint of a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12, with improvements seen across a range of clinical endpoints [24,25]. The onset of action was rapid, with significant improvements observed after 2 weeks of treatment. A dose response was observed, with efficacy appearing to plateau at the 6 mg and 12 mg twice daily doses; no further improvements in efficacy were observed with 18 mg twice daily or 24 mg once daily. Similar to other immunosuppressive therapies, infections were the most common adverse event (AE) of special interest, including 6 cases of herpes zoster reported with upadacitinib across the 2 studies [24,25].

Based on the results of an exposure–response analysis of BALANCE-1 and BALANCE-2, extended-release regimens of upadacitinib 15 mg and 30 mg once daily were predicted to provide the optimal balance of benefit–risk in patients with moderately to severely active RA [26], with these doses selected for the upadacitinib phase III program.

Efficacy of upadacitinib in the phase III program

Overview

The phase III SELECT program consisted of 6 global phase III, double-blind, randomized-controlled trials of upadacitinib in RA, of which 5 have results available (the 6th trial, SELECT-CHOICE, is ongoing). A 7th trial, the phase IIb/III SELECT-SUNRISE study, was performed exclusively in Japanese patients. The key characteristics of each study are summarized in Table 1. All studies met their primary endpoints and all ranked secondary endpoints, including clinical, radiographic, functional, and patient-reported outcomes. In general, efficacy was comparable between the upadacitinib 15 mg and 30 mg once daily doses.

Table 1. Summary of the SELECT phase III program.

	SELECT-EARLY [29]	SELECT-NEXT [27]	SELECT-SUNRISE [32]^a	SELECT-MONOTHERAPY [15]	SELECT-COMPARE [30,31]	SELECT-BEYOND [28]	SELECT-CHOICE [NCT03086343]
Population	MTX-naïve	csDMARD-IR	csDMARD-IR	MTX-IR	MTX-IR	bDMARD-IR	bDMARD-IR
Background therapy	—	csDMARDs	csDMARDs	—	MTX	csDMARDs	csDMARDs
Upadacitinib dose(s)	7.5 mg QD^a 15 mg QD 30 mg QD	15 mg QD 30 mg QD	7.5 mg QD 15 mg QD 30 mg QD	15 mg QD 30 mg QD	15 mg QD	15 mg QD 30 mg QD	15 mg QD
Comparator	MTX	Placebo	Placebo	MTX	Placebo Adalimumab	Placebo	Abatacept
Number of patients enrolled	1002	661	197	648	1629	499	657
Primary endpoint	ACR20^b/50^c at week 12; DAS28-CRP <2.6^c, mTSS change from BL^b at week 24	ACR20^c, DAS28-CRP ≤3.2^d at week 12	ACR20 at week 12	ACR20^c, DAS28-CRP ≤3.2^d at week 14	ACR20^c, DAS28-CRP <2.6^d at week 12	ACR20^c, DAS28-CRP ≤3.2^d at week 12	Change in DAS28-CRP (non-inferiority) at week 12

^a Japanese patients only. ^bPrimary endpoint for the Pharmaceuticals and Medical Devices Agency. ^cPrimary endpoint for the Food and Drug Administration. ^dPrimary endpoint for the European Medicines Agency.

ACR20/50: 20%/50% improvement in American College of Rheumatology criteria; bDMARD: biologic disease-modifying anti-rheumatic drug; BL: baseline; csDMARD: conventional synthetic disease-modifying anti-rheumatic drug; DAS28-CRP: 28-joint Disease Activity Score with C-reactive protein; IR: inadequate response; mTSS: modified Total Sharp Score; MTX: methotrexate; QD: once daily.

SELECT-NEXT and SELECT-BEYOND

SELECT-NEXT and SELECT-BEYOND assessed upadacitinib 15 mg and 30 mg once daily in combination with csDMARDs in patients with an IR to csDMARDs and bDMARDs, respectively (Table 1) [27,28]. SELECT-NEXT enrolled 661 patients, whereas SELECT-BEYOND included 498. Both studies had separate primary endpoints according to regulatory requirements: ACR20 at week 12 was the primary endpoint for the FDA, whereas 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) ≤3.2 at week 12 was the primary endpoint for the EMA [27,28].

Both studies met the primary endpoints at week 12 with the 2 doses of upadacitinib [27,28]. In SELECT-NEXT, rates of ACR20 at week 12 were 64% with upadacitinib 15 mg, 66% with upadacitinib 30 mg, versus 36% with placebo (p<.0001) and rates of DAS28 ≤ 3.2 were 48%, 48%, and 17%, respectively (p<.0001) [27]. In SELECT-BEYOND, ACR20 was achieved by 65%, 56%, and 28% of patients in the upadacitinib 15 mg, upadacitinib 30 mg, and placebo groups, respectively (p<.0001); corresponding rates for DAS28-CRP ≤3.2 were 43%, 42%, and 14% (p<.0001) [28]. In addition, significant results with upadacitinib versus placebo at week 12 were seen for more stringent endpoints such as ACR50 and ACR70, as well as key patient-reported outcomes such as Health Assessment Questionnaire-Disability Index (HAQ-DI), pain, and morning stiffness. Similar to the phase II studies, onset of efficacy was rapid, with both doses of upadacitinib showing significant improvements in ACR20 after 1 week of treatment and ACR50 after 2 weeks [27,28]. Thus, the safety and tolerability of upadacitinib in combination with csDMARDs has been shown in RA patients with an IR to csDMARDs and/or bDMARDs.

SELECT-EARLY and SELECT-MONOTHERAPY

SELECT-EARLY and SELECT-MONOTHERAPY assessed upadacitinib as monotherapy in MTX-naïve patients and patients with an IR to MTX, respectively [15,29]. Both of these studies used MTX monotherapy as an active comparator.

In SELECT-MONOTHERAPY, 648 MTX-IR patients were randomized to monotherapy with upadacitinib 15 mg or 30 mg, or to continue MTX monotherapy [15]. The primary endpoint was ACR20 for the FDA and DAS28-CRP ≤3.2 for the EMA at week 14. Both doses of upadacitinib met the primary endpoints at week 14 (p<.0001 for both upadacitinib groups versus MTX); response rates for ACR20 were 68%, 71%, and 41% with upadacitinib 15 mg, upadacitinib 30 mg, and MTX, with rates of 45%, 53%, and 19%, respectively, for DAS28-CRP ≤3.2. Upadacitinib at both doses also led to improvements in all ranked secondary endpoints, including DAS28<2.6, HAQ-DI, and morning stiffness [15]. Thus, upadacitinib monotherapy has the potential to provide a treatment option for patients who are intolerant to MTX or who prefer a treatment regimen without MTX.

In SELECT-EARLY, 945 MTX-naïve patients with poor prognostic factors (≥1 bone erosion on X-ray, or positivity for both rheumatoid factor and anti-citrullinated protein antibody) were randomized to upadacitinib 15 mg, upadacitinib 30 mg, or MTX as monotherapy [29]. The primary endpoint for SELECT-EARLY was ACR50 at week 12 for the FDA and DAS28-CRP <2.6 at week 24 for the EMA. Radiographic endpoints, as assessed by the modified Total Sharp Score (mTSS), were also included. Both primary endpoints were met: rates of ACR50 at week 12 were 52.1% and 56.4% with upadacitinib 15 mg and 30 mg versus 28.3% with MTX (p<.001), and rates of DAS28-CRP <2.6 at week 24 were 48.3%, 50.0%, and 18.5%, respectively (p<.001) [29]. Both doses of upadacitinib significantly reduced radiographic progression at week 24 versus MTX and significantly increased the proportion of patients with no radiographic progression (change in mTSS ≤0).

SELECT-COMPARE

SELECT-COMPARE was the largest study in the upadacitinib phase III program and was powered to assess the superiority of upadacitinib versus adalimumab [30]. A total of 1629 MTX-IR patients were randomized to receive upadacitinib 15 mg once daily, placebo, or adalimumab 40 mg every other week while continuing treatment with MTX. The primary endpoint was ACR20 for the FDA and DAS28<2.6 for the EMA with upadacitinib versus placebo at week 12. ACR50, DAS28 ≤ 3.2, change in pain severity score, and change in HAQ-DI comparison of upadacitinib versus adalimumab at week 12 were ranked secondary endpoints.

Both primary endpoints were met at week 12 with upadacitinib versus placebo (71% versus 36% for ACR20 and 29% versus 6% for DAS28<2.6; both p<.001) [30]. In addition, upadacitinib showed superiority to adalimumab based on ACR50 (45% versus 29%; p<0.001). A higher proportion of patients who received upadacitinib versus adalimumab achieved DAS28-CRP ≤3.2 (45% versus 29%; p<.001), as well as a greater change in pain severity score (–32.1 mm versus –25.6 mm; p<.001) and HAQ-DI (–0.60 versus –0.49; p<.01) at week 12. Upadacitinib also reduced radiographic progression compared with placebo at week 26 (p<.001) and increased the proportion of patients with no radiographic progression (change in mTSS ≤0; p<.01) [30].

Results seen over the first 26 weeks of SELECT-COMPARE were maintained through to week 48, with rates of low disease activity and remission, as well as improvements in pain and function, remaining superior with upadacitinib versus adalimumab [31]. During the first 26 weeks of SELECT-COMPARE, patients with an insufficient response to adalimumab were switched to upadacitinib, and patients with an insufficient response to upadacitinib were switched to adalimumab. Although both switch groups responded to the new treatment, a higher proportion of patients who switched to upadacitinib from adalimumab achieved Clinical Disease Activity Index (CDAI) ≤10 at 6 months after switching versus patients who switched from upadacitinib to adalimumab (53% versus 41%) [31].

SELECT-SUNRISE

In contrast to the global phase III studies, the SELECT-SUNRISE study was performed exclusively in Japanese patients with RA [32]. A total of 197 patients with an IR to csDMARDs were randomized to placebo or upadacitinib 7.5 mg, 15 mg, or 30 mg once daily in combination with csDMARDs for 12 weeks. All upadacitinib doses met the primary endpoint of ACR20 response at week 12 compared with placebo (75.5%, 83.7%, and 80.0% versus 42.9%; p<.001) [32]. However, the 7.5 mg dose of upadacitinib did not improve rates of more stringent endpoints such as remission defined by Simplified Disease Activity Index (SDAI) or CDAI, whereas significant differences in these endpoints were seen in the 15 mg and 30 mg groups.

Safety in the upadacitinib phase III program

The safety profile of upadacitinib in patients with RA was assessed using an integrated analysis of SELECT-NEXT, SELECT-BEYOND, SELECT-EARLY, SELECT-MONO THERAPY, and SELECT-COMPARE [33]. A total of 3834 patients received ≥1 dose of upadacitinib in these trials (n = 2630 received upadacitinib 15 mg and n = 1204 received upadacitinib 30 mg), resulting in 4020.1 patient-years of exposure. For comparison, placebo data were pooled from SELECT-NEXT, SELECT-BEYOND, and SELECT-COMPARE; MTX monotherapy data were pooled from SELECT-EARLY and SELECT-MONOTHERAPY; and adalimumab + MTX data were taken from SELECT-COMPARE [33]. AEs of special interest, based on the safety profile of other JAK inhibitors and immunosuppressants in general, included infections, herpes zoster, malignancies, major adverse cardiovascular events (MACE), and venous thromboembolism.

The most commonly reported AEs were upper respiratory tract infection, nasopharyngitis, and urinary tract infections in the upadacitinib 15 mg group and upper respiratory tract infection and nasopharyngitis in the upadacitinib 30 mg group [33]. Rates of serious AEs and AEs leading to discontinuation were higher with upadacitinib 30 mg compared with upadacitinib 15 mg (Figure 1). Rates of serious AEs with upadacitinib 15 mg were comparable with adalimumab but higher than with MTX; rates of discontinuation were comparable with upadacitinib 15 mg, adalimumab, and MTX. There was a total of 35 deaths across the phase III program, 15 of which were adjudicated as cardiovascular deaths (with myocardial infarction the most common cause) [33]. Rates of death were comparable across treatment groups.

Figure 1. Event rates of serious AEs, AEs of special interest, and deaths in the global upadacitinib SELECT phase III program (reproduced with permission from Cohen et al. [33]). ^aPBO pooled (12–14 weeks): n = 1042. ^bMTX pooled (mean exposure of 36 weeks): n = 530, includes patients on MTX monotherapy censored at time of switch/addition of upadacitinib. ^cADA 40 mg EOW (mean exposure of 42 weeks): n = 579. ^dUpadacitinib 15 mg pooled (mean exposure of 53 weeks): n = 2630. ^eUpadacitinib 30 mg pooled (mean exposure of 59 weeks): n = 1204. ^fDeaths included non-treatment-emergent deaths (3 on upadacitinib 15 mg, 3 on upadacitinib 30 mg, and 1 on ADA). ^gMACE was defined as CV death, non-fatal MI, and non-fatal stroke. ^hVTE was defined as deep vein thrombosis and pulmonary embolism. ADA: adalimumab; AE: adverse event; CI: confidence interval; CV: cardiovascular; E: events; EOW: every other week; MACE: major adverse cardiovascular events; MI: myocardial infarction; MTX: methotrexate; NMSC: non-melanoma skin cancer; PBO: placebo; PYs: patient-years; UPA: upadacitinib; VTE: venous thromboembolic event.

As shown in Figure 1, the frequency of AEs of special interest with upadacitinib was similar with patients receiving MTX or adalimumab, with the exception of herpes zoster (which was higher with both upadacitinib doses versus comparators) and serious infection (which was higher with upadacitinib 30 mg versus the other treatment groups). The majority of herpes zoster cases were non-serious and involved a single dermatome, with no central nervous system involvement observed. Herpes zoster appeared to be more common in Japanese patients compared with patients from other regions [32]. Types of serious infection were consistent with what would be expected in patients with RA and included opportunistic infections, active tuberculosis, invasive fungal infections, and bacterial and virus infections, with pneumonia being the most common [33]. Rates of opportunistic infection were comparable across groups (Figure 1), and the majority were non-serious mucosal candidiasis. There were 6 non-fatal cases of active tuberculosis reported: 3 in patients receiving upadacitinib 15 mg, 2 in patients receiving upadacitinib 30 mg, and 1 in the adalimumab group [33]. This suggests that patients should be screened for latent tuberculosis infection prior to starting therapy, and closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib. Rates of malignancy, MACE, and venous thromboembolism were comparable across the treatment groups, and all patients who experienced a MACE had ≥1 cardiovascular risk factor at baseline. However, thrombotic events (deep vein thrombosis, pulmonary embolism, arterial thrombosis) have occurred in patients treated with upadacitinib (and other JAK inhibitors) for inflammatory conditions, many of which were serious with some resulting in death. Therefore, the risks and benefits must be considered prior to initiating treatment with upadacitinib in patients who may be at increased risk for thrombotic events. Gastrointestinal perforation events have also been reported in upadacitinib clinical studies [33], and, therefore, caution should be exercised in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with history of diverticulitis or taking non-steroidal anti-inflammatory drugs). Further, patients treated with upadacitinib presenting with new-onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Rates of laboratory abnormalities were reported in the individual studies [15,27–30]. Across the upadacitinib studies, mean neutrophil counts showed reductions over the first 4–8 weeks of treatment and subsequently plateaued, whereas mean absolute lymphocyte counts showed an initial increase with upadacitinib treatment and then stabilized [33]. Small decreases from baseline in hemoglobin levels were observed with upadacitinib treatment, although mean levels remained within the normal limits [15,27,28,30]. Grade 3 or 4 decreases in hemoglobin were more common with upadacitinib 30 mg compared with upadacitinib 15 mg [15,27,28]. A dose-dependent increase in cholesterol levels was observed with upadacitinib, but the ratio of low-density cholesterol to high-density cholesterol remained constant [33]. These results suggest that upadacitinib treatment should be avoided in patients with low absolute lymphocyte (<500 cells/mm³) or neutrophil (<1000 cells/mm³) counts, or low hemoglobin levels (<8 g/dL), with evaluation of laboratory parameters at baseline and thereafter according to routine patient management. In Japanese patients, upadacitinib 7.5 mg did not lead to a decrease in the frequency of AEs (59% versus 57% with 15 mg), serious AEs, or laboratory abnormalities compared with the 15 mg dose in the SELECT-SUNRISE study [32].

Future indications

Upadacitinib is being evaluated in a range of inflammatory diseases in addition to RA, with a number of phase II and phase III trials ongoing.

In the phase II/III SELECT-AXIS-1 study, 187 patients with ankylosing spondylitis and an IR to ≥2 non-steroidal anti-rheumatic drugs were randomized to upadacitinib 15 mg once daily or placebo [34]. More patients receiving upadacitinib versus placebo achieved an Assessment of SpondyloArthritis International Society 40 response after 14 weeks (52% versus 26%; p = .0003). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported [34]. Based on these results, phase III trials in both ankylosing spondylitis and non-radiographic axial spondyloarthritis are ongoing (NCT04169373).

Two phase III trials of upadacitinib in psoriatic arthritis are currently ongoing, 1 in patients with an IR to ≥1 non-biologic DMARD (SELECT-PsA-1; NCT03104400) and 1 in patients with an IR to ≥1 bDMARD (SELECT-PsA-2; NCT03104374). Top-line results from SELECT-PsA-2 were reported recently [35]. Both the 15 mg and 30 mg doses of upadacitinib met the primary endpoint of ACR20 versus placebo (57% and 64% versus 24%; p<.0001). Both upadacitinib doses also met the ranked secondary endpoints, including patients achieving 75% reduction in the Psoriasis Area and Severity Index at week 16 and rates of minimal disease activity at week 24. The safety profile of upadacitinib was similar to that seen in patients with RA [35].

In a phase II study in Crohn’s disease (CELEST), 220 patients were randomized to a range of upadacitinib doses (3, 6, 12, or 24 mg twice daily or 24 mg once daily) or placebo for 16 weeks of induction therapy [36]. Compared with placebo, more patients achieved a clinical response with upadacitinib 6 and 24 mg twice daily, and an endoscopic response with upadacitinib doses ≥6 mg twice daily at week 16. The safety profile was consistent with the JAK class [36]. Based on these results, 2 phase III trials of upadacitinib are ongoing in Crohn’s disease in patients with an IR to conventional or biologic therapies (NCT03345849 and NCT03345836).

Upadacitinib has also been assessed in patients with ulcerative colitis. In the phase IIb, dose-ranging U-ACHIEVE study, upadacitinib at doses of 15 mg, 30 mg, and 45 mg once daily significantly improved the proportion of patients achieving clinical remission after 8 weeks versus placebo [37]. All ranked secondary endpoints, including endoscopic improvement, were also achieved at week 8 with these doses. The safety profile of upadacitinib in ulcerative colitis was similar to that observed in Crohn’s disease [37]. Phase III trials of upadacitinib in ulcerative colitis are currently ongoing (NCT02819635 and NCT03653026).

More recently, results have been published from a phase IIb trial of upadacitinib in atopic dermatitis [38]. A total of 167 patients with moderate-to-severe atopic dermatitis were randomized to placebo or upadacitinib 7.5 mg, 15 mg, or 30 mg. All doses of upadacitinib met the primary endpoint of percentage improvement in Eczema Area and Severity Index at Week 16, with no dose-limiting toxicity observed [38]. Phase III trials of upadacitinib in atopic dermatitis are ongoing (NCT03607422, NCT03738397, NCT03568318, and NCT03569293).

Upadacitinib is also being investigated in several other indications, with trials ongoing in systemic lupus erythematosus (NCT03978520; phase II), giant cell arteritis (NCT03725202; phase III), and juvenile idiopathic arthritis (NCT03725007; phase I).

Discussion: JAK selectivity in clinical practice

Upadacitinib was engineered to be selective for JAK1 over JAK2, JAK3, and TYK2 [22], in contrast to other JAK inhibitors such as tofacitinib (a pan-JAK inhibitor) and baricitinib (a JAK1 and JAK2 inhibitor). The rationale for this approach was that specifically targeting JAK1 should ensure a strong anti-inflammatory effect whist minimizing side effects associated with the inhibition of JAK2-dependent processes (such as development of red blood cells, platelets, and myeloid cells).

In the absence of head-to-head trials of JAK inhibitors it is difficult to draw conclusions about the relative efficacy and safety of upadacitinib compared with less selective JAK inhibitors. However, a recent meta-analysis found that upadacitinib and baricitinib showed more favorable efficacy outcomes than tofacitinib and filgotinib, which could reflect differences in selectivity profiles [39]. This meta-analysis showed no significant differences in safety profile across the JAK inhibitors, with a similar likelihood of serious AEs or infections. In addition, although preclinical results suggested that upadacitinib is selective for JAK1, the decreases in hemoglobin levels seen in upadacitinib phase III trials suggest that at clinically relevant doses (particularly the 30 mg dose) upadacitinib may also have some effects on JAK2. This is supported by a recent study showing that upadacitinib inhibited JAK2-dependent signaling in peripheral blood mononuclear cells from healthy donors [40].

One strength of upadacitinib is that, unlike other JAK inhibitors, upadacitinib monotherapy was shown to significantly improve clinical and functional outcomes compared with MTX in patients with an IR to MTX [15]. Superiority of tofacitinib and baricitinib monotherapy over MTX has only been demonstrated in MTX-naïve patients with short durations of RA [41,42]. This provides an indication that upadacitinib monotherapy may provide sufficient efficacy to control disease activity, which may be a consequence of balanced or finely tuned selectivity for JAKs. However, longer term safety analyses, additional meta-analyses, and potentially head-to-head trials will likely be needed to fully elucidate the clinical impact of JAK selectivity in patients with RA.

Summary and conclusions

Upadacitinib, a selective JAK1 inhibitor, has undergone an extensive clinical trial program in RA and has shown efficacy in a range of patient subtypes, including treatment-naïve patients and patients with an IR to csDMARDs or bDMARDs. Upadacitinib has also shown favorable results compared with active comparators such as MTX and adalimumab, and when administered as monotherapy or in combination with csDMARDs. Efficacy was generally comparable between the 15 mg and 30 mg doses of upadacitinib. The safety profile of upadacitinib was in keeping with other JAK inhibitors and immunosuppressants. Serious infections, particularly herpes zoster, tended to be higher with upadacitinib versus comparators as seen with other JAK inhibitors [13,43–45] and serious AEs and discontinuations tended to be higher with upadacitinib 30 mg.

Based on the results of the SELECT phase III program, the 15 mg once daily dose of upadacitinib was approved by the FDA and EMA for the treatment of patients with moderate-to-severe RA and an IR to MTX/other csDMARDs [46,47]. Of note, upadacitinib was approved for use both as monotherapy and in combination with csDMARDs, which may make it a useful option in patients with an intolerance or contraindication to MTX. In Japan, both the 7.5 mg and 15 mg once daily doses of upadacitinib were approved, but it should be noted that 7.5 mg did not lead to decreases in AEs and laboratory abnormalities compared with 15 mg, and did not improve rates of SDAI remission versus placebo.

In conclusion, upadacitinib is a favorable treatment option for patients with an IR to conventional or biologic treatment. Ongoing trials will determine whether upadacitinib can be used in additional inflammatory diseases in the future.

Conflict of interest

Yoshiya Tanaka reports speaking fees and/or honoraria from: Daiichi Sankyo Company Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Chugai Pharmaceutical Co. Ltd, AbbVie GK, Pfizer Japan Inc., YL Biologics, Bristol-Myers Squibb Company, Mitsubishi-Tanabe Pharma Corporation, Novartis, Eisai, Takeda, Teijin, and Janssen Pharmaceutical KK. Research grants from: Asahi-Kasei Pharma Corporation, Mitsubishi-Tanabe Pharma Corporation, Bristol-Myers Squibb Company, Eisai Co. Ltd, Chugai Pharmaceutical Co. Ltd, Takeda Pharmaceutical Company Ltd, Sanofi KK, UCB Japan Co. Ltd, Daiichi Sankyo Company Ltd, Ono Pharmaceutical Co. Ltd.

Additional information

Funding

Medical writing support was provided by John Ewbank, PhD, of 2 the Nth (Cheshire, UK) funded by AbbVie. AbbVie had the opportunity to review a final draft of the article for scientific accuracy, but all content decisions remained with the author.