Kinase Inhibitors

Introduction

For years, there have been efforts to identify and develop small molecule immune modulators, which would have at least the same risk:benefit profile of currently available biologic agents with the advantage of the convenience of oral administration.

Research has identified several potential therapeutic targets, including intracellular enzymes that play a critical role in the mediation of intracellular transduction of cytokine signaling involved in immune regulation. Thus, inhibition of these enzymes presents an attractive strategy for modulating the immune response of T cells, B cells, macrophages and Natural killer (NK) cells.

Janus Kinase (JAK) Inhibition

The Janus kinase (JAK) family of tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) play a critical role in mediating intracellular signal transduction of cytokines involved in immune regulation. After receptor-cytokine interaction, JAKs are activated, resulting in tyrosine phosphorylation of the receptor and subsequent activation of signal transducer and activators of transcription (STATs), which act as transcription factors (Figure 18-1). The phosphorylated STAT proteins dissociate from the JAK complexes, form dimers within the cytoplasm and then are translocated to the nucleus where they associate with gene promoter regions to mediate gene transcription in regulating the host immune response. JAK3, in combination with JAK1, plays a major role in signal transduction from the common gamma receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.1-3 JAK 1 and JAK 2 also modulate IL-6 activity and JAK2 modulates activity of erythropoietin. Thus, inhibition of the JAK kinases is an attractive strategy for modulating the immune response of T cells, B cells, macrophages and NK cells.

Tofacitinib

Tofacitinib (Xeljanz), an orally administered inhibitor of JAK kinases, was the first of a new class of drugs described as small molecule immunopharmaceuticals (SMIPs) and was approved by the Food and Drug Administration (FDA) in 2012. It is currently indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers. Tofacitinib was the first of the Janus kinase inhibitors and the first new oral disease-modifying antirheumatic drugs (DMARD) for RA in many years. Tofacitinib is available for the treatment of RA as either tablets or extended-release tablets.

Mechanism of Action

Tofacitinib is an inhibitor of the JAK family of tyrosine kinases (JAK1, JAK2, JAK3 and TYK2). In enzyme assays using isolated kinase domains of the JAK proteins, tofacitinib inhibited all four members of the JAK kinase family (i.e., JAK1, JAK2, JAK3 and TYK2) with nanomolar potency. However, in cellular assays measuring cytokine-induced intracellular phosphorylation of STAT proteins or STAT-based reporter activity, tofacitinib showed functional specificity for JAK3 and JAK1 over JAK2.

Efficacy

The efficacy of tofacitinib as monotherapy or with background MTX in the treatment of patients with RA was initially demonstrated in four phase 2, placebo-controlled, randomized studies in over 1,000 patients. These studies ranged from 6 to 24 weeks in duration with doses ranging from 1 mg to 30 mg twice daily. Subsequently, the efficacy and safety of tofacitinib were assessed in seven phase 3, randomized, placebo-controlled trials in >4,200 patients with RA.

In Patients With an Inadequate Response to ≥1 DMARDs

ORAL Solo

ORAL Solo, a 6-month phase 3 study assessed the efficacy of tofacitinib monotherapy in 610 RA patients with active disease defined as ≥6 tender and swollen joints with either erythrocyte sedimentation rate (ESR) ≥28 or C-reactive protein (CRP) ≥7 mg/L, who had failed at least one DMARD, including biologic agents. Patients were treated orally with tofacitinib 5 mg or 10 mg bid or placebo. Stable background nonsteroidal anti-inflammatory drug (NSAIDs) and prednisone ≤10 mg/day were allowed. The primary end points at month 3 were ACR20 response, change from baseline in HAQ-DI and proportion of patients achieving disease activity score in 28 joints based on C-reactive protein (DAS28) erythrocyte sedimentation rate (ESR) <2.6.

At month 3, 26.7%, 59.8% and 65.7% of patients in the placebo, tofacitinib 5- and 10-mg‒bid groups, respectively, achieved an ACR20 response (both P <0.0001 vs placebo) (Figure 18-2A). Although not shown in the figure, the proportions of patients who achieved an ACR50 response at month 3 were 31.1% and 36.8% in the 5-mg and 10-mg tofacitinib groups, respectively, compared with 12.5% of placebo-treated patients (P <0.001 for both comparisons). Similarly, the ACR70 responder rates at month 3 were 15.4% and 20.3% in the 5-mg and 10-mg tofacitinib groups, respectively, compared with 5.8% in the combined placebo group (P = 0.003 and P <0.001 for the 5-mg dose and the 10-mg dose of tofacitinib, respectively, vs placebo). Patients who switched from placebo to tofacitinib at month 3 had ACR response rates by month 6 that were similar to the responses seen in patients who received tofacitinib in the first 3 months.

Improvements in health assessment questionnaire (HAQ)-DI from baseline also were significantly greater with tofacitinib 5 mg and 10 mg compared with placebo (-0.50, -0.57 and -0.19, respectively; P <0.001 for both comparisons) (Figure 18-2B). Although the minimal clinically important change for the HAQ-DI is 0.22 points, a more conservative measure of 0.30 points was chosen to indicate a significant change in HAQ-DI. At month 3, 52.9% and 55.7% of patients in the 5-mg and 10-mg tofacitinib groups, respectively, had reductions of at least 0.30 in the HAQ-DI score (indicating improvement) compared with 31.7% in the two placebo groups combined (P <0.001 for both comparisons). Patients who switched from placebo to tofacitinib at month 3 had HAQ-DI scores by month 6 that were similar to the responses seen in patients who received tofacitinib in the first 3 months.

Significant benefits of tofacitinib over placebo in terms of DAS28-4(ESR) <2.6 response rates were not observed. At month 3, the percentage of patients with a DAS28-4(ESR) <2.6 was 5.6% with the 5-mg dose of tofacitinib and 8.7% with the 10-mg dose of tofacitinib, compared with 4.4% with placebo (P = 0.62 and P = 0.10, respectively) (Figure 18-2C). By month 6, the percentages in the 5-mg and 10-mg tofacitinib groups had increased to 9.8% and 14.2%, respectively.

ORAL Sync

Tofacitinib in combination with a background DMARD was evaluated in a phase 3 trial in 792 RA patients with active disease who were incomplete responders to at least one DMARD and/or a biologic agent. Patients were treated with 5 mg or 10 mg of tofacitinib bid or placebo orally in combination with a background DMARD. All patients treated with placebo were switched to tofacitinib 5 mg or 10 mg at 6 months unless they were switched at 3 months because of lack of improvement. The primary end points were the change from baseline in HAQ-DI at month 3 and ACR20 response and the proportion of patients achieving DAS28(ESR) remission at month 6. Stable background NSAIDs and prednisone ≤10 mg/day were allowed.

At month 6, an ACR20 response was achieved by 31%, 53% and 58% of patients in the placebo, tofacitinib 5-mg and 10-mg groups, respectively (both P <0.0001 vs placebo). Similar to patients originally treated with tofacitinib, placebo-treated patients achieved an ACR20 response at month 6 after being switched to tofacitinib at month 3. Significant differences were seen in improvement of the HAQ-DI at month 3 with mean changes in HAQ-DI of -0.46 and -0.56 in the tofacitinib 5-mg and 10-mg groups, respectively, vs less than -0.21 in the placebo group (P <0.0001 vs placebo). Both tofacitinib groups achieved a statistically significant difference compared with placebo in achieving DAS28(ESR) remission at month 6 (3%, 11% and 15%, P <0.05), in the placebo, tofacitinib 5-mg and 10-mg groups, respectively.

In Patients With an Inadequate Response to ≥1 TNF Inhibitors—ORAL Step

In the ORAL Step study, 399 RA patients with active disease despite concurrent MTX therapy who had previously failed at least one TNF inhibitor were treated orally with either 5 mg or 10 mg of tofacitinib or placebo twice daily. Patients remained on a stable dose of MTX (7.5-25 mg/week) throughout the study. After 3 months, all placebo-treated patients were switched to either tofacitinib 5 mg or 10 mg. The end points at month 3 were the HAQ-DI change from baseline, ACR20 response and the proportion of patients achieving DAS28(ESR) ≤2.6. At month 3 (as well as at month 6), significantly more patients who received tofacitinib 5 mg or 10 mg achieved ACR20 compared with those who received placebo (Table 18-1).

In addition, at month 3, the proportion of patients achieving ACR50 and ACR70 responses also were significantly greater in those treated with either dose of tofacitinib compared with placebo. Significantly superior results were also seen in improvements in HAQ-DI and in the proportion of patients achieving DAS28(ESR) remission (Table 18-1). After being switched to tofacitinib, patients initially treated with placebo achieved levels of efficacy generally comparable to those who were treated with tofacitinib for 3 months (Table 18-1). Onset of efficacy was observed at week 2 as measured by significant changes in ACR20 vs placebo.

In Patients With an Inadequate Response to MTX—ORAL Standard

The 12-month ORAL Standard study treated 717 patients with active RA and an inadequate response to MTX with either tofacitinib 5 mg or 10 mg bid orally, 40 mg of adalimumab subcutaneously once every 2 weeks, or placebo. Adalimumab was used as an active comparator, which allowed for the estimation of the relative efficacy and safety of tofacitinib compared with an anti-TNF biologic agent. However, no head-to-head comparisons were made in this study and comparisons were not measured at pre-specified endpoints, as is common with formal noninferiority trials. Patients remained on stable doses of MTX throughout the study. Placebo-treated patients were switched to tofacitinib 5 mg or 10 mg twice daily at month 6 or month 3 if they were nonresponders. Primary efficacy end points were ACR20 response rates, DAS28-4(ESR) remissions at month 6 and change in HAQ-DI at month 3.

A significantly greater percentage of patients receiving either of the tofacitinib doses than those receiving placebo met the criteria for an ACR20 response at month 6 (Figure 18-3). The percentage of patients with DAS28-4(ESR) remission was also significantly greater with each tofacitinib dose compared with placebo (Figure 18-4). The mean changes from baseline in HAQ-DI scores at month 3 were also significantly greater with tofacitinib 5 mg (-0.55) and tofacitinib 10 mg (-0.61) than with placebo (-0.24) (P <0.001 each tofacitinib dose vs placebo). Regarding secondary end points, significantly greater ACR50 and ACR70 responses were also seen with tofacitinib doses compared with placebo.

Patients who completed participation in ORAL Standard or discontinued for reasons other than treatment-related serious AEs were invited to continue treatment in ORAL Sequel, a long-term extension study. All eligible patients were switched to tofacitinib 10 mg bid with or without csDMARDs. Efficacy endpoints included ACR20/50/70 response rates, and mean changes in HAQ-DI and DAS28-4(ESR) scores. A greater proportion of patients in the adalimumab to tofacitinib group and the blinded to open-label tofacitinib group experienced improvement in signs and symptoms of RA, as measured by ACR response rates and reductions in mean DAS28-4(ESR), during the first 3 months of ORAL Sequel as compared to the last 3 months of ORAL Standard. Numerically greater improvements in physical function, as measured by reduction in HAQ-DI scores from baseline, were also observed in both treatment groups. Overall, results from ORAL Sequel support the possibility of switching patients directly from adalimumab to tofacitinib 10 mg bid. However, the extension study included only those patients who completed ORAL Standard, a potentially biased selection process which may have led to greater improvements among patients in the study.

Stage 3B/4 Study of Tofacitinib Vs Adalimumab—ORAL Strategy

ORAL Strategy was a 12-month, double-blind, head-to-head, noninferiority study that directly compared the efficacy and safety of tofacitinib monotherapy, tofacitinib in combination with methotrexate (MTX) and adalimumab in combination with MTX. The study enrolled 1146 adult patients with active RA who had an inadequate response to previous MTX treatment. All patients were treated with MTX for a minimum of 4 months and with a stable dose of 15 to 25 mg per week for at least 6 weeks prior to baseline. All other csDMARDs were discontinued before baseline. Eligible patients were randomized to receive tofacitinib 5 mg twice daily, tofacitinib 5 mg twice daily in combination with MTX, or adalimumab 40 mg every other week with MTX.

The primary endpoint of the study was the proportion of patients achieving an ACR50 response at 6 months. Secondary endpoints included the proportion of patients attaining an ACR20 and ACR70 response at 6 months, the proportion of patients achieving low disease activity at 6 months as defined by SDAI ≤11, CDAI ≤10, DAS28-4(ESR) <3.2 and DAS28-4(CRP) <3.2, the proportion of patients attaining remission at 6 months as defined by SDAI ≤3.3, CDAI ≤2.8, DAS28-4(ESR) <2.6, DAS28-4(CRP) <2.6 and ACR–EULAR Boolean remission criteria, and others.

At 6 months, ACR50 response was achieved in 38% of patients who received tofacitinib monotherapy, 46% of patients who received tofacitinib and MTX and 44% of patients who received adalimumab and MTX (Figure 18-5). Treatment with tofacitinib and MTX was non-inferior to adalimumab and MTX; this was not shown for tofacitinib monotherapy vs tofacitinib and MTX or vs adalimumab and MTX. Superiority was not found between any treatment group. ACR20 and ACR70 response rates showed similar trends.

In general, the secondary efficacy endpoint responses were similar between combination treatment arms and higher than in the tofacitinib monotherapy group. At 6 months, 50% of patients in the tofacitinib and MTX group had low disease activity at 6 months, as indicated by SDAI (≤11), compared with 47% in the adalimumab and MTX group and 43% in the tofacitinib monotherapy group. The proportion of patients with low disease activity as indicated by CDAI, DAS28-4(ESR), and DAS28-4(CRP) were consistent with those as indicated by SDAI (≤11). The absolute least squares mean changes from baseline in SDAI at months 6 and 12 were greater in patients who received tofacitinib and MTX or adalimumab and MTX than in those who received tofacitinib monotherapy (Figure 18-6). Thirteen percent of patients in both the tofacitinib and MTX and adalimumab and MTX groups attained remission at 6 months, as assessed by SDAI (≤3·3), which was higher than in the tofacitinib monotherapy group. The proportion of patients who had remission at 6 months and 12 months as indicated by CDAI, DAS28-4(ESR), DAS28-4(CRP), and ACR–EULAR Boolean remission criteria were consistent with those as indicated by SDAI. Safety measures were similar between treatment groups.

ORAL Strategy was designed to help clinicians decide on appropriate treatments for patients with RA and an inadequate response to MTX. ORAL Strategy demonstrated that tofacitinib 5 mg twice daily with MTX achieved clinically meaningful responses and showed similar efficacy and safety measures to adalimumab with MTX. These results indicate that the addition of tofacitinib or adalimumab are equally efficacious strategies in patients with an inadequate response to MTX, and more effective than switching to tofacitinib alone.

Long-Term Efficacy

Wollenhaupt and associates examined the pooled efficacy and safety data from two open-label studies involving 4102 patients who had participated in qualifying phase 1, 2 and 3 studies of tofacitinib. (The long-term safety results are discussed below.) Patients had been treated for a total duration of 5963 patient-years. The mean duration of treatment was 531 days. A total of 20.8% of patients discontinued from these long-term extension studies over 60 months. ACR20, ACR50 and ACR70 response rates were consistent over time between months 1 and 48. At month 1, ACR20, ACR50 and ACR70 response rates for patients initially treated with tofacitinib 5 or 10 mg twice daily were 72.5%, 48.0%, and 27.4%, respectively; corresponding rates at month 48 were 74.4%, 49.6% and 34.1%, respectively. Mean DAS28-4(ESR) was 6.3 at baseline and was reduced to ~3.6 between month 1 and 48. Mean HAQ-DI score was 1.4 at baseline and improved to approximately 0.8 between month 1 and 48.

Radiographic Response

Two studies (ORAL Scan and ORAL Start) were conducted to evaluate the effect of tofacitinib on structural joint damage. The progression of structural joint damage was assessed radiographically, measured by change from baseline in mTSS, the erosion score and joint space narrowing score, at months 6 and 12.

In the 24-month ORAL Scan study, 797 patients with active RA receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg or 10 mg twice daily, or placebo to tofacitinib at 5 mg or 10 mg twice daily (crossover at 3 months). Treatment response rates (ACR20) for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (both P <0.0001) (Figure 18-7). At month 6, rates of remission (DAS28-4[ESR]) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% and 16.0% (P <0.0001), respectively, vs 1.6% for placebo. Tofacitinib 10 mg twice daily plus background MTX reduced the progression of structural damage compared with placebo plus MTX at month 6. Tofacitinib 5 mg twice daily exhibited similar effects on mean progression of structural damage (not statistically significant). Analyses of erosion and joint space narrowing scores were consistent with the overall results (Figure 18-8). In the placebo plus MTX group, 74.1% of patients experienced no radiographic progression (mTSS change ≤0) at month 12 compared with 86% (P <0.001) and 86.4% (P <0.01) of patients treated with tofacitinib 5 or 10 mg twice daily plus MTX, respectively.

In the 24-month ORAL Start study, 958 MTX-naïve patients with active RA were randomized 2:2:1 to receive tofacitinib 5 mg or 10 mg twice daily, or MTX 10 mg/week with 5 mg/week increments every 4 weeks to 20 mg/week. Mean changes from baseline in mTSS and ACR70 response at 6 months were statistically superior for both doses of tofacitinib vs MTX (Figure 18-9). Secondary endpoints, including ACR20 and ACR50 responses, were significantly better with tofacitinib vs MTX at all timepoints (Figure 18-7). Tofacitinib monotherapy inhibited the progression of structural damage compared with MTX at months 6 and 12. Analyses of erosion and joint space narrowing scores were consistent with the overall results. In the MTX group, 64.9% of patients experienced no radiographic progression at month 24 compared with 79.9% (P <0.001) and 83.7% (P <0.001) of patients treated with tofacitinib 5 or 10 mg twice daily, respectively.

Safety

A boxed warning for serious infections, mortality, malignancy, major adverse cardiovascular events (MACE), and thrombosis is included in the prescribing information for tofacitinib. Patients taking tofacitinib are at an increased risk of serious infections, including active tuberculosis, invasive fungal infections (including cryptococcosis and pneumocystosis), and opportunistic infections caused by other bacterial and viral pathogens (including herpes zoster). If a serious infection develops, tofacitinib should be interrupted and only resumed once the infection is controlled. In patients with chronic or recurrent infection, the risks and benefits of tofacitinib should be carefully considered. Before, during and after tofacitinib therapy, patients should be closely monitored for signs and symptoms of infection. Testing for latent tuberculosis should be performed before and during therapy; however, tuberculosis testing should be performed during therapy even in patients who tested negative for a latent infection. A large post-marketing safety trial in patients ≥50 years of age with at least one cardiovascular (CV) risk factor, ORAL Surveillance, reported higher overall mortality with tofacitinib compared to a TNF blocker (see the Post-marketing JAK Kinase Inhibitor Safety section below). Lymphoma and other malignancies have been observed in patients taking tofacitinib; current or past smokers are at higher risk of malignancy. A higher incidence of MACE (cardiovascular (CV) death, myocardial infarction [MI], and stroke) was observed with tofacitinib than with a TNF blocker in ORAL Surveillance, with increased risk in current or past smokers. Tofacitinib should be discontinued in patients with a history of MI or stroke. Thrombosis events, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have been documented in patients on JAK inhibitor therapy for inflammatory conditions. Data from ORAL Surveillance show a higher rate of thrombosis in tofacitinib-treated patients than in TNF blocker-treated patients. Tofacitinib should be avoided in patients at risk of thrombosis and discontinued if symptoms of thrombosis occur.

Additional warnings and precautions in the tofacitinib prescribing information include gastrointestinal perforations, laboratory abnormalities (including neutropenia, lymphopenia, anemia, lipid elevations and liver enzyme elevations), use of live vaccines during or immediately before tofacitinib therapy and risk of gastrointestinal obstruction (for the non-deformable extended-release formulation).

In the analysis of long-term safety data from the pooled results of two open-label studies involving patients who had participated in qualifying phase 1, 2 and 3 studies of tofacitinib, 437 (10.7%) of the 4,102 patients treated for a mean duration of 531 days discontinued from these long-term open-label studies due to adverse events. A total of 13,932 treatment-emergent adverse events (TEAEs) were reported in 3,152 patients (76.8%).

The most commonly reported class of TEAEs was infections/infestations (50.8%), followed by gastrointestinal (GI) disorders (23.6%) and musculoskeletal and connective tissue disorders (23.4%). Nasopharyngitis (8.7%), upper respiratory tract infection (7.2%) and urinary tract infection (4.5%) were the most frequent investigator-reported TEAEs. Serious adverse events were reported in 630 (15.4%) patients with an incidence rate of 11.1/100 patient-years. Serious infection events were reported in 4.5% of patients with an incidence rate of 3.1/100 patient-years. Decreased hemoglobin (>2 g/dL to <3 g/dL or hemoglobin >7 g/dL, but <8 g/dL) was observed in 109 patients (2.7%). Increases in aminotransferase levels (≥3 upper limit of normal with normal baseline) were observed in 2.2% (alanine) and 1.2% (aspartate) of evaluable patients. Moderate to severe neutropenia (neutrophil cell count <1.5 × 103/mm³ but ≥0.5 × 103/mm³) was reported in 30 patients (0.7%); no serious neutropenia (neutrophil cell count <0.5 × 103/mm³ )was reported. A confirmed increase in creatinine (>50% from baseline) was noted in 136 (3.3%) patients. Mean overall values for laboratory safety tests were stable over time and consistent with phase 2 and 3 studies.

Cohen and coworkers examined the pooled data across phase 2, phase 3 and long-term extension studies of tofacitinib (n = 4789) to determine the incidence rates of all-cause mortality and infections. In these studies, tofacitinib was administered as monotherapy or in combination with MTX or other nonbiologic disease-modifying antirheumatic drugs. Exposure to tofacitinib was 2098 patient-years in the phase 3 trials, and 3243 patient-years in the long-term studies (Table 18-2).

There were a total of 14 Cardiovascular Safety Endpoint Adjudication Committee (CV-SEAC)-classified all-causality deaths in the phase 3 trials (six due to infections, three other [noncardiac], two cardiac, one cancer, one trauma and one cause unknown.) In the long-term studies, there were a total of 31 CV-SEAC–classified all-causality deaths (six due to infection, six cancer, three cardiac, two other [noncardiac], two suicide and one cause unknown). Eleven other deaths were not adjudicated.

The overall rate of serious infection was 3.09 events per 100 patient-years and rates were stable over time. In phase 3 and long-term studies, bronchitis, herpes zoster, influenza, nasopharyngitis, upper respiratory tract infection, and urinary tract infection were the most common infection adverse events in patients treated with tofacitinib. Infection adverse events were the most common cause of permanent discontinuation of tofacitinib in both phase 3 and long-term studies, but this was due in part to discontinuation criteria requiring study withdrawal in the case of serious infection. The rates of serious infection in patients treated with tofacitinib was similar to that of approved biologic DMARDs; however, rates of herpes zoster infection were higher than reported with biologic agents. Administration of the shingles vaccine should be considered in patients receiving JAK inhibitors.

The mechanisms of action of this JAK inhibitor may lead to potential adverse events, such as infections (including viral infections), lipid elevations and anemia. Lipid elevations may be due to the effects of JAK 1 and 2 on IL-6 and anemia may be due to the effects of JAK 2 on erythropoietin. As with all new mechanisms of action molecules, there are questions about long-term tolerability, including rates of serious infections, including viral and opportunistic infections, rates of malignancy including lymphoma and the frequency of significant anemia.

Dosage and Administration

The recommended dose of tofacitinib is 5 mg twice daily, or 11 mg once daily with the extended-release formulation. Both formulations may be used as monotherapy or in combination with MTX or other nonbiologic DMARDs. Use of tofacitinib in combination with biologic DMARDs or potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended. Tofacitinib is approved after patients have received a trial on anti-TNF therapy. Dosing should be discontinued in patients with an absolute neutrophil or lymphocyte count <500 cells/mm³ and interrupted in patients with a hemoglobin level of <8 g/dL, a decrease in hemoglobin of more than 2 g/dL, or an absolute neutrophil count 500-1000 cells/mm³ and continued only once the values normalize.

The dose of tofacitinib should be reduced to 5 mg once daily in patients:

• With moderate or severe renal insufficiency
• With moderate hepatic impairment
• Receiving potent inhibitors of cytochrome P450 3A4 (CYP3A4) (eg, ketoconazole)
• Receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (eg, fluconazole).

The use of tofacitinib is not recommended in patients with severe hepatic impairment.

Baricitinib

In 2018, baricitinib became the second JAK inhibitor to be approved by the FDA for the treatment of patients with RA. Baricitinib is indicated for the treatment of adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF antagonist therapies. The confirmatory phase 3 trials of baricitinib included two doses, 2 mg and 4 mg, but due to safety concerns, only the 2-mg dose received FDA approval. In the European Union, the 4 mg dose is approved for treatment of RA.

Mechanism of Action

Baricitinib is a once-daily oral, selective and reversible JAK1 and JAK2 inhibitor. Several cytokines implicated in the pathogenesis of RA signal through JAK1 and JAK2, including interferons, interleukin-6 and granulocyte-macrophage colony-stimulating factor. In kinase assays, baricitinib demonstrates approximately 100-times greater inhibition of JAK1 and JAK2 compared to JAK3.

Efficacy

Support for the efficacy and safety of baricitinib in the treatment of patients with RA comes from an extensive clinical trial program, consisting of four phase 3 studies (RA-BEACON, RA-BUILD, RA-BEGIN, RA-BEAM) and an extension study of RA-BUILD, RA-BEYOND. These studies ranged from 24 to 52 weeks in duration with doses ranging from 1 mg to 8 mg once daily. The approval of the 2-mg dose of baricitinib was based on the RA-BEACON and RA-BUILD trials.

In Patients Who Were csDMARD-Experienced and Refractory to or Intolerant to ≥1 bDMARDs— RA-BEACON

In patients with RA who do not respond to csDMARDs, such as MTX, biological therapies that target T or B cells and cytokines have been shown to improve outcomes. However, in some patients, these biologic DMARDs are ineffective or have unacceptable side effects. In a phase 2 study, baricitinib was shown to be effective in patients with RA and an inadequate response to conventional DMARDs. To further assess the safety and efficacy of baricitinib in treatment-experienced patients, RA-BEACON investigated baricitinib in patients with RA who had failed previous treatment with several csDMARDs and one or more biologic DMARD.

RA-BEACON was a 24-week study that enrolled 527 adult patients with moderate-to-severe active RA who had an inadequate response or intolerance to one or more TNF inhibitor therapies with or without other biologic DMARDs. At trial entry, patients must have been receiving at least one csDMARD regularly for at least 12 weeks, with stable doses during the preceding 8 weeks. Eligible patients were then randomized 1:1:1 to receive either 2-mg baricitinib, 4-mg baricitinib, or placebo once daily, in addition to any pre-enrollment therapies. From week 16, nonresponding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint of the trial was ACR20 response at week 12 for 4-mg baricitinib compared to placebo. Secondary endpoints included ACR50 and ACR70 responses, physical function as assessed by the HAQ-DI, disease activity as assessed by DAS28-CRP and DAS28-ESR and CDAI and SDAI scores.

At week 12, 49% of 2-mg baricitinib-treated patients, 55% of 4-mg baricitinib-treated patients and 27% of placebo-treated patients reached the ACR20 endpoint (P ≤0.001 for both comparisons; Figure 18-10). Improved ACR20 response rates with baricitinib were observed as early as week 1. Patients randomized to the baricitinib groups also had significant improvements in two of the major secondary measures compared to placebo at week 12: DAS28-CRP and HAQ-DI (P ≤0.001 for all comparisons).

Of the patients enrolled in RA-BEACON, 42% had received one biologic DMARD, 30% had received two biologic DMARDs and 27% had received three biologic DMARDs. Importantly, subgroup analysis demonstrated no significant differences in efficacy based on the number of prior biologic DMARDs, the number of prior TNF inhibitors among patients who had received only TNF-inhibitor biologic DMARDs, or the number of prior biologic DMARDs that were not TNF inhibitors. Overall, the RA-BEACON trial demonstrated that once-daily baricitinib is an effective treatment option for patients with active RA that is refractory to aggressive standard-of-care treatment with both csDMARDs and biologic DMARDs.

In Patients Who Were Refractory to or Intolerant of ≥1 csDMARDs—RA-BUILD

RA-BUILD was a 24-week phase 3 study that evaluated the safety and efficacy of baricitinib in adult patients with moderately to severely active RA who had an inadequate response or intolerance to conventional DMARDs. Eligible patients were naïve to biologic DMARDs. Patients with insufficient response to treatment must have been taking conventional DMARDs for at least the preceding 12 weeks, with stable doses for the preceding 8 weeks. Six hundred eighty-four (684) patients were randomized 1:1:1 to receive once-daily placebo, 2-mg baricitinib, or 4-mg baricitinib, plus any stable background therapy. From week 16, nonresponding patients could be rescued to receive baricitinib 4 mg once daily.

The primary endpoint was the proportion of patients in the 4-mg baricitinib group achieving ACR20 response at week 12 compared to placebo. Secondary endpoints included physical function as assessed by HAQ-DI score, disease activity assessed by DAS28-CRP, SDAI score, and others. Patient-reported outcomes were recorded using a diary through week 12 and included data on morning joint stiffness duration and severity and worst tiredness and joint pain. Radiographic joint damage was also assessed using patients’ radiographs and van der Heijde modified Total Sharp Score.

At week 12, 66% of 2-mg baricitinib–treated patients and 62% of 4-mg baricitinib–treated patients reached the ACR20 endpoint, compared to 39% of patients in the placebo group (P ≤0.001 for both comparisons; Figure 18-11). In the baricitinib 2-mg and 4-mg groups, significant improvements were also observed for major secondary endpoints, including HAQ-DI, DAS28-CRP and SDAI. Additionally, in only the baricitinib 4-mg group, significant improvements were observed for morning joint stiffness duration and severity and worst tiredness and joint pain.

Progression of structural joint damage was also assessed in RA-BUILD. Compared to placebo, statistically significant reductions were observed at week 24 in both baricitinib groups (2-mg and 4-mg baricitinib) for the total score and joint space narrowing (Figure 18-12). Compared to placebo, a significant improvement in the component of erosion was only observed in the 4-mg baricitinib group. The percentage of patients with no radiographic progression, defined by cumulative percentile change in mTSS ≤0.5 at week 24, was 77.4% for placebo, 81.7% for baricitinib 2 mg (not significant vs placebo) and 88.9% for baricitinib 4 mg (P ≤0.01 vs placebo).

Most patients enrolled in RA-BUILD had received treatment with two or more prior csDMARDs and most were receiving background MTX, alone (49%) or in combination (23%) with another csDMARD. Subgroup analysis revealed no significant differences in efficacy based on the background therapy patients received. The data presented in RA-BUILD suggest that once daily oral baricitinib is an effective agent for treating the signs and symptoms of RA in patients who have failed csDMARDs, although the non-approved 4-mg baricitinib was most effective.

The Long-Term Extension Study of RA-BUILD—RA-BEYOND

After completing the 24-week RA-BUILD study, patients could enroll in the long-term extension study, RA-BEYOND. The study assessed the effect of baricitinib over an additional 24 weeks, for a total treatment period of 48 weeks, on radiographic progression of structural joint damage. Patients were ineligible for enrollment if they demonstrated significant uncontrolled laboratory abnormalities, had known hypersensitivity to baricitinib, or if they prematurely discontinued baricitinib during RA-BUILD. Of the 684 patients randomized into RA-BUILD, 583 entered RA-BEYOND. Patients entering RA-BEYOND continued to receive 2 mg baricitinib or 4 mg baricitinib or were switched to 4 mg baricitinib if they had received placebo.

At week 48, primary linear extrapolation (LE) analysis found that both doses of baricitinib significantly inhibited progression of structural joint damage compared to placebo, in terms of mTSS and the subcomponents of bone erosion and joint space narrowing (Figure 18.13). However, the observed/last observation carried forward (LOCF) method of analysis found that only the 4-mg dose significantly inhibited radiographic progression.

Safety

The prescribing information for baricitinib contains a boxed warning for serious infections, mortality, malignancy, MACE and thrombosis. Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral and other opportunistic infections, have occurred in patients receiving baricitinib. If a serious infection develops, baricitinib should be interrupted until the infection is controlled. Prior to starting baricitinib, a test for latent tuberculosis should be performed; if it is positive, treatment for tuberculosis should be started prior to starting baricitinib. Monitor all patients for active tuberculosis during treatment, even if the initial latent tuberculosis test was negative. Data from ORAL Surveillance, a large post-marketing safety trial in patients ≥50 years of age with at least one CV risk factor who were taking tofacitinib revealed a higher overall mortality with tofacitinib compared to a TNF blocker (see the Post-marketing JAK Kinase Inhibitor Safety section below), which may also apply to baricitinib. In ORAL Surveillance, patients who received tofacitinib had a higher incidence of MACE (CV death, MI and stroke) than patients who received a TNF blocker. The risk of MACE is higher in current or past smokers. In patients that have had an MI or stroke, baricitinib should be discontinued. Thrombosis events, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, some fatal, have occurred in patients treated with baricitinib. In placebo-controlled trials, venous thromboses were reported in two patients (0.6 per 100 patient-years) treated with 2-mg baricitinib and seven patients (0.8 per 100 patient-years) treated with 4-mg baricitinib during a 0 to 52-week treatment period. Similarly, arterial thromboses were reported in three patients (0.9 per 100 patient-years) treated with 2-mg baricitinib and three patients (0.3 per 100 patient-years) treated with 4-mg baricitinib. Lymphoma and other malignancies have also been observed in patients treated with baricitinib, with current or past smokers being at higher risk.

Other warnings and precautions include gastrointestinal perforations, laboratory abnormalities (including neutropenia, lymphopenia, anemia, liver enzyme elevations and lipid elevations) and use of live vaccines with baricitinib.

The most common adverse events, occurring in ≥1% of baricitinib 2-mg– and 4-mg–treated patients in placebo-controlled trials, included upper respiratory tract infections, nausea, herpes simplex and herpes zoser.

In RA-BUILD, rates of adverse events were similar across treatment groups during the treatment period, with 71%, 67% and 71%, of patients experiencing an adverse event in the placebo, 2-mg baricitinib and 4-mg baricitinib groups, respectively.20 Serious adverse events were infrequent and occurred at similar rates across treatment groups. Discontinuation due to adverse events was also infrequent and occurred in 4% of patients in the placebo and 2-mg baricitinib groups and 5% of patients in the 4-mg baricitinib group. Infections were more common in the 4-mg baricitinib group, but this difference was small and nonsignificant. Changes in laboratory values were mostly of small magnitude and transient, with abnormalities leading to discontinuation occurring in <1% of patients. Similar to what was observed in other trials, baricitinib was associated with increases in serum creatinine, serum creatine kinase, platelets and LDL and HDL cholesterol and mean reductions in neutrophils. As in other trials, grade 3 or 4 creatine phosphokinase abnormalities were mostly reported in patients who reported preceding exercise or physical activity or had elevated baseline levels.

Dosage and Administration

Baricitinib is available as 2-mg–immediate-release tablets. The recommended dose is 2 mg once daily, given orally with or without food. Baricitinib may be used as monotherapy or in combination with MTX or other DMARDs. However, combination use with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. Dosage of baricitinib should be modified in cases of lymphopenia, neutropenia, or anemia.

Treatment with baricitinib is not recommended in patients:

• With an absolute lymphocyte count <500 cells/mm³,
• With an absolute neutrophil count <1000 cells/mm³,
• With hemoglobin <8 g/dL,
• With estimated GFR of <60 mL/min/1.73 m²,
• With severe hepatic impairment, or
• Taking strong Organic Anion Transporter 3 (OAT3) inhibitors, such as probenecid.

Upadacitinib

Upadacitinib received FDA approval for the treatment of RA in 2019, becoming the third JAK inhibitor to be approved for this indication. Upadacitinib is indicated for the treatment of adults with moderately to severely active RA who have had an inadequate response or intolerance to one or more TNF blockers. The approval of upadacitinib was based on positive results from the SELECT clinical trial program, which included the five studies described below.

Mechanism of Action

Upadacitinib is a JAK inhibitor that was rationally designed for JAK1 selectivity using comparative data from JAK protein crystal structures. In biochemical assays, upadacitinib demonstrated activity against JAK1 with >2-fold, >40-fold and >100-fold selectivity over JAK2, JAK3 and TYK2, respectively. These results were confirmed in cell-based assays, in which upadacitinib exhibited an even greater selectivity for JAK1 over JAK2 (>40-fold), JAK3 (>130-fold) and TYK2 (>190-fold).

Efficacy

The efficacy and safety of upadacitinib for the treatment of RA was assessed in the SELECT clinical trial program, which included studies in patients with an inadequate response to bDMARDs (SELECT-BEYOND), csDMARDs (SELECT-NEXT), or MTX (SELECT-MONOTHERAPY and SELECT-COMPARE), as well as patients with early RA, many of whom were treatment-naïve (SELECT-EARLY). The studies in the SELECT program had a placebo- or comparator-controlled period which ranged from 12 to 48 weeks in duration, often with a multi-year extension period. In most trials, upadacitinib was administered at a 15 mg or 30 mg once-daily dose.

In Patients Who Were csDMARD-Experienced and Had an Inadequate Response or Intolerance to ≥1 bDMARDs—SELECT-BEYOND

SELECT-BEYOND was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial which assessed the safety and efficacy of upadacitinib in patients with RA and an inadequate response or intolerance to bDMARDs. Eligibility criteria included age ≥18 years, RA diagnosed ≥3 months before enrollment and active disease despite ≥3 months of treatment with ≥1 bDMARD or intolerance or toxicity to any bDMARD. Unlike in RA-BEACON and ORAL Start, the eligibility criteria did not require prior failure of or intolerance to a TNF inhibitor. Patients must also have been on csDMARD therapy for ≥3 months and on a stable dose for ≥4 weeks before enrolment.

A total of 499 eligible patients were randomized (2:2:1:1) to receive upadacitinib 15 mg (n=165), upadacitinib 30 mg (n=165), placebo until week 12 and upadacitinib 15 mg thereafter (n=85), or placebo until week 12 and upadacitinib 30 mg thereafter (n=84) (all administered once daily). Patients continued receiving their csDMARD therapy (up to 2 agents) for the first 24 weeks of the trial. The primary endpoints were the proportion of patients achieving ACR20 at week 12 and the proportion of patients achieving a DAS28-CRP score of ≤3.2 at week 12. The key secondary endpoints included ACR50, ACR70, changes from baseline in DAS28-CRP, HAQ-DI and SF-36 PCS (all at week 12) and ACR20 at week 1.

Upadacitinib demonstrated superiority to the placebo with respect to both primary endpoints. At week 12, 28% of patients in the placebo group achieved ACR20, compared to 65% in the upadacitinib 15 mg (P ≤0.0001) and 56% in the upadacitinib 30 mg (P ≤0.0001) groups (Figure 18-14A). A DAS28-CRP score of ≤3.2 was achieved by 14% of placebo-randomized patients, compared to 43% of patients who received upadacitinib 15 mg (P ≤0.0001) and 42% of those who received upadacitinib 30 mg (P ≤0.0001) (Figure 18-14B).

Compared to the placebo, upadacitinib treatment also resulted in significantly greater rates of ACR50 (P ≤0.0001 for both upadacitinib doses) and ACR70 (P ≤0.0001 for upadacitinib 30 mg but no difference for upadacitinib 15 mg) at week 12 and ACR20 at week 1 (P = 0.0001 for upadacitinib 15 mg and P = 0.0006 for upadacitinib 30 mg). Placebo group patients switched to upadacitinib at week 12 achieved ACR20 rates similar to upadacitinib-group patients by week 24 (Figure 18-14A). At week 12, both doses of upadacitinib were also superior to the placebo with respect to changes from baseline in DAS28-CRP, HAQ-DI and SF-36 PCS and significantly higher proportions of patients in both upadacitinib groups achieved a CDAI score of ≤10 and an SDAI score of ≤11 (Figure 18-14B). The results of SELECT-BEYOND demonstrated that once-daily upadacitinib is an effective treatment for RA in patients with bDMARD-refractive disease, or those with intolerance to bDMARDs.

In Patients Who Had an Inadequate Response to ≥1 csDMARDs—SELECT-NEXT

SELECT-NEXT, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, assessed the safety and efficacy of upadacitinib in patients with RA and an inadequate response or intolerance to csDMARDs – a patient population similar to that in RA-BUILD and ORAL Sync. Patients were eligible for recruitment if they were ≥18 years of age, had RA diagnosed ≥3 months before trial start and had active disease despite ≥3 months of treatment with at least one of MTX, sulfasalazine, or leflunomide.

Eligible patients (n=661) were randomized (2:2:1:1) to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221) (all administered once daily). After a 12-week period, patients in the placebo group were switched (1:1) to upadacitinib 15 mg or 30 mg according to the prespecified randomization assignment. Patients were required to continue a stable csDMARD dose for the first 12 weeks of the trial. The primary endpoints were the proportion of patients achieving ACR20 at week 12 and the proportion of patients with a DAS28-CRP score of ≤3.2 at week 12. The key secondary endpoints included ACR50, ACR70, DAS28-CRP <2.6, changes from the baseline in DAS28-CRP, HAQ-DI, SF-36 PCS and FACIT-F and duration of morning stiffness (all at week 12), as well as ACR20 at week 1.

At week 12, 36% of patients in the placebo group achieved ACR20, compared to 64% and 66% in the upadacitinib 15 mg and 30 mg groups, respectively (P≤0.0001 against the placebo for either dose) (Figure 18-15A). Upadacitinib was also superior in the proportion of patients achieving a DAS28-CRP score of ≤3.2, with 48% of patients in the upadacitinib 15 mg and 30 mg groups each meeting this endpoint, compared to 17% of patients in the placebo group (P ≤0.0001 against the placebo for either dose) (Figure 18-15B).

Upadacitinib treatment also resulted in significantly higher proportions of patients achieving ACR20 at week 1 (Figure 18-15A), as well as ACR50, ACR70 and DAS28-CRP <2.6 at week 12 (P ≤0.0001 against the placebo for either dose for all endpoints). Compared to patients who received the placebo, patients in both upadacitinib groups also had significantly greater improvements from the baseline in DAS28-CRP, HAQ-DI, SF-36 PCS, FACIT-F and morning stiffness duration.

In Patients Who Had an Inadequate Response to MTX—SELECT-MONOTHERAPY

SELECT-MONOTHERAPY was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial which assessed the safety and efficacy of upadacitinib in patients with RA who had an inadequate response to MTX. Eligible patients were ≥18 years of age and had active RA despite ≥3 months of treatment with MTX (on a stable dose for ≥4 weeks before trial start). Patients were required to discontinue all non-MTX csDMARDs ≥4 weeks (≥8 weeks for leflunomide) before trial start. The key exclusion criteria were previous exposure to a bDMARD or a JAK inhibitor, or a history of non-RA inflammatory disease.

A total of 648 eligible patients were randomized (2:2:1:1) to receive upadacitinib 15 mg once daily (n=217), upadacitinib 30 mg once daily (n=215), or to continue their current MTX regimen (n=216). Patients in the MTX group were switched (1:1) to upadacitinib 15 mg or 30 mg according to the prespecified randomization assignment after week 14. The proportion of patients achieving ACR20 and the proportion of patients with a DAS28-CRP score of ≤3.2 were the primary endpoints (both assessed at week 14). Secondary endpoints included changes from the baseline in DAS28-CRP, HAQ-DI and SF-36 PCS, the proportion of patients achieving ACR50, ACR70 and a DAS28-CRP score of <2.6, and duration of morning stiffness (all at week 14).

Upadacitinib was superior to the placebo plus MTX at week 14 with respect to ACR20, with 68% and 71% of patients in the upadacitinib 15 mg and 30 mg groups, respectively, achieving this endpoint, compared to 41% of patients who received continued MTX (P <0.0001 against either upadacitinib group) (Figure 18-16A). Similarly, 45% and 53% of patients in the upadacitinib 15 mg and 30 mg group, respectively, achieved a DAS28-CRP score of ≤3.2 at week 14, compared to 19% in the continued MTX group (P <0.0001 against either upadacitinib group) (Figure 18-16B).

Significantly higher proportions of patients in the upadacitinib groups achieved ACR 50, ACR70 and DAS28-CRP <2.6 at week 14 compared to patients in the continued MTX group (P <0.0001 against either upadacitinib group for all endpoints). Compared to continued MTX, both upadacitinib doses also resulted in greater improvements from the baseline in DAS28-CRP (P <0.0001), HAQ-DI (P <0.001) and SF-36 PCS (P <0.001) scores. Finally, the duration of morning stiffness was significantly reduced with upadacitinib 15 mg (P = 0.0012) and upadacitinib 30 mg (P = 0.0001) compared to continued MTX.

Compared to Adalimumab In Patients Who Had an Inadequate Response to MTX—SELECT-COMPARE

SELECT-COMPARE was a multicenter, randomized, double-blind, placebo- and active comparator-controlled phase 3 trial which compared the safety and efficacy of upadacitinib and the TNF blocker adalimumab in patients with RA and an inadequate response to MTX. Patients were eligible for inclusion if they were ≥18 years of age and had active RA inadequately responsive to ≥3 months of MTX treatment (taken at a stable dose for ≥4 weeks before trial start). Patients continued their MTX regimen, but non-MTX csDMARDs were discontinued before trial start. Up to 20% of patients were allowed to have <3 months of exposure to ≤1 bDMARD (except adalimumab). Exclusion criteria included prior exposure to a JAK inhibitor or inadequate response to a bDMARD.

Eligible patients (n=1629) were randomized (2:2:1) to upadacitinib 15 mg once daily (n=651), placebo (n=651), or adalimumab 40 mg every other week (n=327). The primary endpoints were the proportion of patients achieving ACR20 and the proportion of patients achieving a DAS28-CRP score of <2.6, both assessed at week 12. Ranked secondary endpoints for the comparison of upadacitinib and adalimumab at week 12 were noninferiority with respect to the proportion of patients achieving ACR50 and DAS28-CRP ≤3.2 and superiority with respect to ACR 50 and mean changes in baseline in HAQ-DI and in the pain severity score measured on a visual analog scale. For the comparison of upadacitinib to placebo, the ranked secondary endpoints were mean change in DAS28-CRP, proportion of patients with DAS28-CRP ≤3.2, mean changes in HAQ-DI, SF-36 PCS, morning stiffness duration, and FACIT-F and the proportion of patients with a CDAI score of ≤10. Additional secondary endpoints included the mean change in the mTSS score of radiographic progression and the proportion of patients with no radiographic progression (change in mTSS of ≤1), both assessed at week 26.

At week 12, 71% of patients in the upadacitinib plus MTX group achieved ACR20, compared to 36% in the placebo group plus MTX (P ≤0.001) and 63% in the adalimumab plus MTX group (nominal P ≤0.05) (Figure 18-17A). A DAS28-CRP score of <2.6 was achieved by 29% of upadacitinib-treated patients at week 12, compared to 6% of patients who received the placebo (P ≤0.001) and 18% of adalimumab-treated patients (nominal P ≤0.001) (Figure 18-17B).

Upadacitinib plus MTX was superior to adalimumab plus MTX and the placebo plus MTX with respect to both ACR50 and DAS28-CRP ≤3.2 at week 12. In the upadacitinib group, 45% of patients achieved ACR50, compared to 29% of patients in the adalimumab group (P ≤0.001) and 15% of patients in the placebo group (P ≤0.001). A DAS28-CRP score of ≤3.2 was achieved by 45% of upadacitinib-treated patients, compared to 29% of adalimumab-treated patients (P ≤0.001) and 14% of patients who received the placebo (P ≤0.001). Compared to adalimumab, upadacitinib also resulted in significantly greater improvements from baseline in HAQ-DI (P ≤0.01) and the pain severity score (P ≤0.001). Upadacitinib was also superior to both adalimumab and placebo in terms of improvements from baseline in DAS28-CRP, SF-36 PCS, FACIT-F and morning stiffness duration, as well as the proportion of patients achieving a CDAI score of ≤10.

Upadacitinib was superior to the placebo and comparable to adalimumab with respect to inhibition of radiographic progression. At week 26, the mean change from baseline in mTSS was significantly lower in the upadacitinib group compared to the placebo group (P = 0.001) and not significantly different than in the adalimumab group (nominal P = 0.448). Similarly, a significantly higher proportion of patients in the upadacitinib group (83%) and the adalimumab group (87%) showed no radiographic progression, compared to patients in the placebo group (76%) (P = 0.01 for both comparisons).

A unique aspect of the trial design in SELECT-COMPARE was that it allowed switching from one trial medication to the other in patients who did not respond (<20% improvement in tender or swollen joint counts) at week 14, 18, or 22 and in patients who were incomplete responders (CDAI >10) at week 26. A post-hoc analysis of week 48 data, at which point 39% of initially upadacitinib-randomized patients had switched to adalimumab and 49% of initially adalimumab-randomized patients had switched to upadacitinib, revealed that patients randomized to either therapy demonstrated comparable achievement rates for most efficacy endpoints. In contrast, time-averaged response rates (a measure of the proportion of time spent in each response state throughout the 48 weeks of the trial) for CDAI ≤10, CDAI ≤2.8, DAS28-CRP ≤3.2 and DAS28-CRP <2.6 were all significantly higher for patients initially randomized to upadacitinib.

In Patients With No or Limited Exposure to MTX—SELECT-EARLY

SELECT-EARLY, a multicenter, randomized, double-blind, placebo- and active comparator-controlled phase 3 trial, assessed the safety and efficacy of upadacitinib in patients with predominantly early RA who were previously untreated with or had limited exposure to MTX.²⁹ Patients eligible for recruitment must have been ≥18 years of age, had active RA and had symptoms consistent with RA for ≥6 weeks. A maximum of 3 weekly doses of MTX was allowed. MTX and any non-MTX csDMARDs were discontinued in a washout period before trial start. Intolerance to MTX and exposure to any JAK inhibitor or bDMARD were the key exclusion criteria.

A total of 947 eligible patients were randomized (1:1:1) to 7.5-20 mg MTX once weekly (n=315), upadacitinib 15 mg once daily (n=317), or upadacitinib 30 mg once daily (n=315). The primary endpoints were the proportion of patients achieving ACR50 at week 12 and the proportion of patients achieving a DAS28-CRP score of <2.6 at week 24. The key secondary endpoints assessed at weeks 12 and 24 included the proportion of patients achieving ACR20, ACR50 (considered a primary endpoint at week 12), ACR70, or DAS28-CRP ≤3.2, as well as changes from baseline in DAS28-CRP, HAQ-DI and SF-36 PCS. The radiographic outcomes of mean change from baseline in mTSS and the proportion of patients with no radiographic progression (change from baseline in mTSS ≤0) were the key secondary endpoints assessed at week 24 only.

The ACR50 response rate at week 12 was significantly higher in the upadacitinib 15 mg (52%) and 30 mg (56%) groups, compared to the MTX group (28%) (P <0.001 for both comparisons) (Figure 18-18A). The proportion of patients achieving a DAS28-CRP score of <2.6 at week 24 was 48% and 50% in the upadacitinib 15 mg and 30 mg groups, respectively, both significantly higher (P <0.001) than in the placebo group (19%) (Figure 18-18B).

At week 12 and 24, both doses of upadacitinib were superior to MTX with respect to ACR20 (P <0.001), ACR70 (P <0.001), DAS28-CRP ≤3.2 (P <0.001), and changes from baseline in DAS28-CRP (P <0.001), HAQ-DI (P <0.001) and SF-36 PCS (P <0.001). A greater proportion of patients in both upadacitinib groups also achieved ACR50 at week 24 compared to MTX (P <0.001).

Upadacitinib was superior to MTX with respect to inhibition of radiographic progression, with a significantly lower mean change from baseline in mTSS in both the 15 mg (P <0.01) and the 30 mg (P <0.001) group, as well as a significantly higher proportion of patients without radiographic progression in both the 15 mg (P <0.01) and the 30 mg group (P <0.001).

Safety

The prescribing information for upadacitinib includes a boxed warning for serious infections, mortality, malignancy, MACE and thrombosis. Serious infections have occurred in patients taking upadacitinib, including active tuberculosis, invasive fungal infections (including cryptococcosis and pneumocystosis) and other opportunistic bacterial and viral infections (including herpes zoster). Upadacitinib should be interrupted if a serious infection develops and continued only once the infection is controlled. The risks and benefits of upadacitinib should be carefully weighed in patients with chronic or recurrent infection. Patients should be closely monitored for signs and symptoms of infection before, during and after upadacitinib treatment, including testing for latent tuberculosis before and during therapy and testing for tuberculosis even in patients who tested negative for a latent infection. ORAL Surveillance, a large post-marketing safety trial (see the Post-marketing JAK Kinase Inhibitor Safety section below) observed higher overall mortality in patients ≥50 years of age with at least one CV risk factor who were taking tofacitinib compared to a TNF blocker and this risk may also apply to upadacitinib. Data from ORAL Surveillance showed a higher incidence of MACE (CV death, MI and stroke) with tofacitinib than with a TNF blocker. Current or past smokers are at a higher risk of MACE. Upadacitinib should be discontinued in patients with a history of MI or a stroke. Thrombosis events, including deep vein thrombosis, pulmonary embolism and arterial thrombosis, have occurred in patients taking JAK inhibitors for inflammatory conditions. A higher rate of thrombosis in tofacitinib-treated patients was observed in ORAL Surveillance compared to patients who received TNF blockers, which may also apply to upadacitinib. Upadacitinib should thus be avoided in patients at risk of thrombosis and discontinued if symptoms of thrombosis occur. Like with other JAK inhibitors, lymphoma and other malignancies have been reported in patients taking upadacitinib, with current or past smokers being at higher risk.

Other warnings and precautions in the upadacitinib prescribing information include gastrointestinal perforations, laboratory abnormalities (including neutropenia, lymphopenia, anemia, lipid elevations, and liver enzyme elevations) and use of live vaccines during or immediately prior to upadacitinib therapy.

In the SELECT clinical trials program, a total of 3833 patients were treated with upadacitinib, with 2806 patients exposed for ≥1 year. In placebo-controlled trials, the most common adverse events that occurred in ≥1% of patients in the upadacitinib 15 mg group included upper respiratory tract infections (URTI) including acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis and viral URTI (upadacitinib 15 mg: 13.5%; placebo: 9.5%), nausea (upadacitinib 15 mg: 3.5%; placebo: 2.2%), cough (upadacitinib 15 mg: 2.2%; placebo: 1.0%) and pyrexia (upadacitinib 15 mg: 1.2%; placebo: 0%). Adverse reactions that occurred in <1% of patients through week 12 and were more common with upadacitinib than with placebo included pneumonia, herpes zoster, herpes simplex (includes oral herpes) and oral candidiasis.

An integrative analysis of upadacitinib safety data from the SELECT program comprising 4020.1 patient-years of exposure found that upadacitinib 15 mg (the approved dose) has a safety profile similar to other JAK inhibitors, with no new or unexpected safety signals. Compared to the placebo, MTX and adalimumab, upadacitinib was associated with a higher risk of herpes zoster infections and CPK elevations, while observed serious infection rates were comparable to adalimumab and higher than with MTX. Gastrointestinal perforation rates were higher than with adalimumab and MTX only with upadacitinib 30 mg and not with the FDA-approved 15 mg dose. Mortality, malignancy, MACE and venous thromboembolic event rates were comparable across all treatment groups.

Dosage and Administration

Upadacitinib is available as extended-release tablets with three dosage forms: 15 mg, 30 mg and 45 mg. For rheumatoid arthritis, the recommended dose is 15 mg once daily, taken orally with or without food. Upadacitinib may be used as monotherapy or in combination with MTX or other csDMARDs. The use of upadacitinib in combination with other JAK inhibitors, bDMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. No dosage adjustment is required for patients with renal impairment or patients with mild to moderate hepatic impairment.

The use of upadacitinib is not recommended in patients:

• With an absolute lymphocyte count <500 cells/mm³,
• With an absolute neutrophil count <1000 cells/mm³,
• With hemoglobin <8 g/dL,
• With severe hepatic impairment.

Post-Marketing JAK Kinase Inhibitor Safety Data

Because of the dose-dependent increase in the risk for malignancy, MACE and serious infection observed in the clinical trials of tofacitinib, especially for the 10 mg twice daily dose, the FDA approved tofacitinib only at the 5 mg twice daily dose and mandated an additional, post-marketing safety study of tofacitinib.

This study, ORAL Surveillance, was a randomized, open-label, noninferiority trial in patients ≥50 years of age with active RA and ≥1 CV risk factor (current smoker, hypertension, HDL cholesterol <40 mg/dL, diabetes mellitus, family history of premature coronary heart disease, extraarticular RA, or history of coronary artery disease). The key exclusion criterion was history of malignancy, excluding adequately treated non-melanoma skin cancer (NMSC). A total of 4362 patients were randomized (1:1:1) to receive tofacitinib 5 mg twice daily (n=1455), tofacitinib 10 mg twice daily (n=1456), or a TNF blocker (adalimumab 40 mg every two weeks or etanercept 50 mg once weekly) (n=1451). The co-primary endpoints were adjudicated MACE (CV death, non-fatal MI, or non-fatal stroke) and cancer (excluding NMSC). Noninferiority was defined as an upper limit value of the two-sided 95% confidence interval for hazard ratio (HR) of <1.8 for the combined tofacitinib doses against a TNF blocker or <2.0 for tofacitinib 10 mg against tofacitinib 5 mg.

Tofacitinib (combined 5 mg and 10 mg dose) did not demonstrate noninferiority to a TNF blocker with respect to either MACE (HR 1.33, 95% CI 0.91–1.94) or malignancy (HR 1.48, 95% CI 1.04–2.09) and tofacitinib 10 mg was noninferior to tofacitinib 5 mg with respect to both MACE (HR 1.15, 95% CI 0.77–1.71) and malignancy (HR 1.00, 95% CI 0.70–1.43). A higher incidence of adjudicated opportunistic infections, herpes zoster infections and adjudicated NMSC was reported for tofacitinib than for a TNF blocker. Additionally, a higher incidence of all-cause mortality and pulmonary embolism was noted in the tofacitinib 10 mg group compared to either the tofacitinib 5 mg or the TNF blocker group, which led to a tofacitinib dose reduction (to 5 mg twice daily) during the trial, potentially complicating interpretation of dose-effect data.

The response of the regulatory agencies to the findings of ORAL Surveillance differed substantially. The EMA responded by recommending that for patients ≥65 years of age, a history of smoking, or risk factors for CV disease or malignancy, tofacitinib be used only if no alternative is available. The FDA extrapolated from the results to limit the RA indication for the JAK inhibitors baricitinib and upadacitinib in addition to that of tofacitinib, to patients with an inadequate response or intolerance to at least one TNF blocker and to update the boxed warning for all three JAK inhibitors to include a warning for increased mortality and MACE risk.

The post-marketing safety data for tofacitinib was also assessed in population-based observational studies. One analysis used data from the Corrona clinical registry of RA patients to evaluate the incidence rates for MACE, serious infection, herpes zoster infection, malignancy and death among 1999 tofacitinib initiators (3152.1 patient years) and 8358 bDMARD (including TNF blockers, abatacept, anakinra, rituximab, and tocilizumab) initiators (12,869.4 patient years). The incidence rates were not significantly different between the tofacitinib and bDMARD cohort for MACE, serious infection, malignancy, or death, and rates of venous thrombotic events were numerically similar. However, herpes zoster infections were more common in the tofacitinib cohort (adjusted HR 2.32; 95% CI 1.43-3.75).

The STAR-RA trial compared the post-marketing safety of tofacitinib to TNF blockers (infliximab, adalimumab, certolizumab pegol, etanercept and golimumab) using data from Optum Clinformatics, IBM MarketScan and Medicare databases. Database data was split into two cohorts: a “real world experience” (RWE) cohort which included routine care patients, and a “randomized clinical trial (RCT) duplicate” cohort restricted to a patient population similar to that of ORAL Surveillance, ie, patients ≥50 years of age with active RA and ≤1 CV risk factor (history of smoking, hypertension, dyslipidemia, diabetes mellitus, ischemic heart disease, or family history of ischemic heart disease). The primary endpoint was a composite of hospitalization for MI or stroke, but individual CV outcomes, including MI, stroke, hospitalization for heart failure and coronary revascularization, were also assessed.

The RWE cohort comprised 102,263 patients, 12,852 (12.6%) of whom initiated tofacitinib, while the RCT-duplicate cohort included 35,070 patients, with 3497 (10.0%) tofacitinib initiators. The pooled weighted HR for the primary composite outcome in the RWE cohort was 1.01 (95% CI 0.83-1.23), while the pooled weighted HRs for secondary outcomes ranged from 0.93 (95% CI 0.66 to 1.31) for stroke to 1.20 (95% CI 0.98 to 1.46) for all-cause mortality, none of which was statistically significant. However, subgroup analyses suggest that a possible association between tofacitinib and CV outcomes may be affected by baseline CV risk, as the HR for the primary outcome was numerically higher in patients with prior CV disease (1.27; 95% CI 0.95–1.70) than in those without (0.81; 95% CI 0.61–1.07). In the RCT-duplicate cohort, the pooled weighted HR for the primary composite outcome was 1.24 (95% CI 0.90 to 1.69), which also didn’t reach statistical significance but was similar to the HR for MACE reported for tofacitinib 5 mg vs TNF blocker in ORAL Surveillance (1.24; 95% CI 0.81–1.91). The findings of STAR-RA are thus broadly concordant with those of ORAL Surveillance, although further research is needed to fully understand the risk-benefit profile of tofacitinib and other JAK inhibitors in diverse populations of patients with RA.