Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a systematic literature research

Rheumatoid arthritis

In total, 39 primary reports of clinical trials on JAKi in patients with RA were included (low RoB: n=28; unclear RoB: n=9; conference abstracts: n=3; for details on study characteristics, RoB analyses, baseline characteristics and efficacy outcomes, see online supplemental appendix tables S2.1.1, S2.2.1, S2.3.1 and S3.1).

TOFA was effective in reducing signs and symptoms of RA as well as inhibition of radiographic damage progression. These studies were performed in methotrexate (MTX)-naïve patients,¹⁹ patients with IR to MTX,^{20 21} or conventional synthetic disease-modifying drugs (csDMARDs)^{1 22–27} or to tumour necrosis factor alpha inhibitors (TNFi) and other biological (b)DMARDs^{1 28 29}; structural outcomes were only studied in MTX-naïve and MTX-IR patients. In MTX-IR patients, van Vollenhoven et al showed numerically similar response rates of TOFA and adalimumab (ADA), which was used as an active comparator but not powered for non-inferiority in the ORAL Standard trial.³⁰ ORAL-Strategy, a head-to-head trial comparing TOFA 5 mg two times per day monotherapy and TOFA 5 mg two times per day plus MTX with ADA 40 mg every other week (EOW) plus MTX, proved non-inferiority between the combination therapy arm but not for the TOFA monotherapy arm compared with the two combination arms (table 2).³¹

Studies on BARI also revealed the efficacy of BARI 2 mg and 4 mg once daily (OD) in csDMARD-naïve,³⁶ MTX and csDMARD-IR,^37–40 and patients previously not responding to bDMARDs, compared with placebo.² In RA-BEAM, BARI 4 mg was statistically superior clinically over placebo and ADA 40 mg EOW in MTX-IR patients (table 2).³² In a randomised tapering substudy of RA-BEYOND, Takeuchi et al showed that patients on BARI 4 mg OD who had achieved low disease activity according to the Clinical Disease Activity Index (CDAI, ≤10) and were subsequently randomised to reduce the BARI dose from 4 mg to 2 mg OD mostly maintained their disease state, although less so than continuing full dose (CDAI≤10 at week 48: continued BARI 4 mg vs tapering to BARI 2 mg: 80% vs 67%; patients achieving CDAI≤2.8, that is, remission: BARI 4 mg vs 2 mg: 40% vs 33%); there was a numerically lower rate of non-serious infections in the tapering arm.^{41 42}

UPA was investigated in eight trials, also provided good efficacy results across various patient populations with RA (MTX-naïve, MTX-IR, csDMARD-IR, TNF-IR and bDMARD-IR) compared to placebo and both as monotherapy and when combined with MTX.^{3 37 43–50} A head-to-head comparison of UPA+MTX with ADA 40 mg EOW + MTX demonstrated superiority (clinically and functionally) of UPA+MTX versus ADA+MTX and versuss placebo + MTX (table 2).^{33 34} In SELECT-MONOTHERAPY, MTX-IR patients were either randomised to blinded UPA 15 mg OD, UPA 30 mg OD or continued MTX for 14 weeks. UPA showed statistically superior responses in clinical and functional outcomes, compared to continued MTX (ACR20 at week 14: 68%, 71% and 41% for UPA 15 mg OD, 30 mg OD and continued MTX, respectively).^{44 45}

Treatment with FILGO in MTX-IR patients showed superiority compared to placebo in four phase II RCTs.^{4 51 52} FILGO monotherapy (DARWIN 2) was superior to placebo after MTX washout (ACR20 at week 12: 67% vs 66% vs 73% vs 29% for FILGO 50 mg OD, 100 mg OD, 200 mg OD and placebo, respectively).^{4 51 52} FILGO in combination with MTX also showed superiority over placebo + MTX in DARWIN 1 (ACR20 at week 12: 56% vs 64% vs 69% vs 57% vs 60% vs 79% vs 44% for FILGO 50 mg OD, 100 mg OD, 200 mg OD, 25 mg two times per day, 50 mg two times per day, 100 mg two times per day and placebo, respectively).⁴ DEC (JAK-3 selective) showed superiority over placebo in three trials; however, no clear dose–response relationship exists in ACR responses.^53–55 PEF, another pan-JAKi (JAK 1–3), was investigated in two global trials, where it failed to reveal significant efficacy (Genovese 2017: ACR20 at week 12: 22.0% vs 36.8% vs 56.3% vs 29.3%; Kivitz 2017: 43.9% vs 61.5% vs 46.4% vs 57.7% vs 44.4% for PEF 25 mg OD, 50 mg OD, 100 mg OD, 150 mg OD and placebo, respectively). But in several Japanese RA study populations (MTX-naïve, MTX-IR, csDMARD-IR), it showed significant improvement of signs and symptoms and physical function compared to placebo.^56–62

PsA, ankylosing spondylitis and SLE

In PsA, three trials (all with low RoB) were published (for details, see online supplemental appendix tables S2.1.2, S2.2.2, S2.3.2 and S3.2). TOFA was investigated in two phase III trials, showing efficacy not only regarding signs and symptoms of arthritis but also physical function, skin disease, dactylitis and enthesitis.^{5 63} Similar results across many outcomes (although not formally tested) in patients with csDMARD-IR PsA were observed with TOFA compared to ADA 40 mg EOW (table 2).⁵ Treatment with FILGO 200 mg OD in EQUATOR resulted in significant improvements compared to placebo regarding signs and symptoms of arthritis, PsO and enthesitis.⁶⁴

In ankylosing spondylitis, two trials in patients with IR to non-steroidal anti-inflammatory drugs were available for analysis, one on TOFA and one on FILGO (for details, see online supplemental appendix tables S2.1.3, S2.2.3, S2.3.3 and S3.3).^{6 65} In a phase II trial (unclear RoB), TOFA significantly improved clinical outcomes of spinal mobility, pain and function as well as inflammatory changes by MRI, with a clear dose–response.⁶ In phase II trial (low RoB), FILGO improved disease activity significantly more than placebo across various outcome measures.⁶⁵

Only limited data on JAKi in SLE were published (two trials, one with high RoB, one with low RoB; for details, see online supplemental appendix tables S2.1.4, S2.2.4, S2.3.4 and S3.4).^{7 18} In a phase II study, Wallace et al investigated BARI in patients with SLE and active skin or joint disease. Significantly more patients achieved a SLEDAI-2 K resolution of arthritis or rash at week 24 with BARI 4 mg OD (but not BARI 2 mg OD) compared to placebo treatment.⁷

Chronic plaque PsO, AD and alopecia

Ten trials on patients suffering from chronic plaque PsO were included in this SLR (for details, see online supplemental appendix tables S2.1.5, S2.2.5, S2.3.5 and S3.5), eight with low, one with unclear and one with high RoB, respectively. TOFA showed significant improvements in skin disease compared to placebo in patients who were candidates for systemic therapy or phototherapy.^{8 35 66 67} Bachelez et al could demonstrate non-inferiority of TOFA 10 mg two times per day compared with etanercept 50 mg twice weekly in achieving a Psoriasis Area and Severity Index (PASI) 75% response as well as clear or almost clear skin (as evaluated by the physician global assessment, PGA) at week 12 (table 2).³⁵ In a withdrawal and retreatment trial, patients with treatment response to TOFA 5 mg or 10 mg two times per day at week 24 were re-randomised to placebo or their previous TOFA dose. Moreover, 23.3% and 26.1% of the patients withdrawn from TOFA 5 mg and 10 mg two times per day, respectively, could maintain their PASI75% response (compared to 56.2% and 62.3% with ongoing TOFA 5 mg or 10 mg two times per day) after 16 weeks. Following 16 weeks of retreatment, 36.8% and 61% of the patients who relapsed after treatment withdrawal, could again achieve a PASI 75% response (compared with 63% and 73.8% of the patients continuously treated with TOFA 5 mg or 10 mg two times per day, respectively).⁶⁸ A dose-finding study investigating BARI showed BARI 8 mg OD as well as 10 mg OD (but neither 2 mg OD nor 4 mg OD) to be significantly better than placebo in achieving the primary end point (PASI75% at week 12).⁶⁹ A JAK-1 selective JAKi, itacinib (INCB039110), showed promising results in a 28-day proof-of-concept PsO trial.⁷⁰ BMS-986165, considered as selective TYK2 inhibitor, showed better clearing of PsO than placebo at week 12.⁷¹

Topical TOFA showed greater improvements in pruritus and eczema area and severity compared to vehicle treatment in AD.⁷² Another topical pan-JAKi (JTE-052) showed rapid and significant AD improvements over vehicle treatment, with numerically similar results to open-label topical tacrolimus, but potential unblinding during the study (high RoB).⁷³

Further, systemic treatment with BARI showed promising results in improving signs, symptoms and patient-reported outcomes of AD.⁷⁴ Dose-dependent responses to UPA with significant differences compared to placebo were demonstrated in a phase II study in patients with moderate to severe AD (% change from baseline in Eczema Area and Severity Index at week 16: 39% vs 62% vs 74% vs 23% for UPA 7.5 mg OD, 15 mg OD, 30 mg OD and placebo, respectively).^{9 10}

Selective inhibition of JAK-3 via PF‐06651600 and TYK2/JAK1 via PF‐06700841 showed statistically superior results compared to placebo in patients with AA regarding ≥50% improvement from baseline in severity of alopecia tool at 24 weeks (conference abstract, no RoB analysis conducted).⁷⁵

Inflammatory bowel disease

In total, eleven reports on eight trials in inflammatory bowel disease were included, describing four trials on UC (all with low RoB) and four on CD (3 low RoB, 1 unclear RoB; for details, see online supplemental appendix tables S2.1.7, S2.1.8, S2.2.7, S2.2.8, S2.3.7, S2.3.8, S3.7 and S3.8).^{11–14 76–82}

TOFA 10 mg two times per day was effective in UC as induction therapy compared to placebo in UC, with 16.6% vs 8.2% achieving remission (defined as total Mayo score ≤2, with no subscore >1 and a rectal bleeding subscore of 0) at week 8. Patients with clinical response were subsequently randomised to receive TOFA 10 mg two times per day, TOFA 5 mg two times per day or placebo with TOFA being significantly more effective than placebo therapy after 52 weeks (34.3% vs 40.6% vs 11.1% for TOFA 5 mg two times per day, TOFA 10 mg two times per day and placebo, respectively).⁷⁶ Induction therapy in patients with moderate to severe UC with UPA was investigated in a phase II trial, being more effective than placebo in inducing remission (0% vs 8.5% vs 14.3% vs 13.5% vs 19.6% for placebo, UPA 7.5 mg, 15 mg 30 mg or 45 mg OD) at week 8.^{77 78} In a phase IIb study on PEF as induction therapy in UC, the primary end point, establishment of a dose–response relationship was not met. Only PEF 150 mg showed a significant difference (nominal p<0.05) in inducing remission at week 8 compared to placebo (7% vs 15.9% vs 15.9% vs 27.3% vs 15.9% for placebo, 25 mg OD, 75 mg OD, 150 mg OD or 75 mg two times per day).⁷⁹

TOFA was not effective in treating patients with active CD and insufficient response to glucocorticoids and immunomodulatory agents (including TNFi), neither for induction nor maintenance therapy in three phase II trials.^{80 81} A phase II dose-finding study on UPA showed clinical as well as endoscopic improvement in moderate-to-severe CD (clinical/endoscopic remission at week 16: 11%/0% vs 13%/10% vs 27%/8% vs 11%/8% vs vs 14%/14% vs 22%/22% for placebo, 3 mg , 6 mg , 12 mg two times per day, 24 mg OD and 24 mg two times per day, respectively).^{12 14} After 16 weeks of induction therapy, patients were re-randomised to either UPA 3 mg, 12 mg or 24 mg two times per day for maintenance therapy up until week 52. A dose–response in clinical as well as endoscopic outcomes was shown over 36 weeks of treatment in initial responders of the induction phase (clinical/endoscopic remission at week 52: 41.2%/25% vs 62.5%/25% vs 73.3%/37.5% vs 40%/10% for UPA 3 mg , 6 mg , 12 mg two times per day and 24 OD).^{13 14} JAK-1 selective treatment with FILGO 200 mg OD resulted in significantly more patients achieving clinical remission (Crohn’s Disease Activity Index <150 at week 10: 47% vs 23% for FILGO 200 mg OD vs placebo). Results on endoscopic outcomes were numerically higher, although not statistically different at week 10 (50% response: 25% vs 14%, remission: 14% vs 7% at week 10, for FILGO 200 mg OD and placebo, respectively).⁸² Detailed results of trials investigating JAKi and TNFi are shown in table 2.

Safety

All RCTs with a valid comparator (placebo or active treatment arm in the respective time period) were assessed for AEs of special interest (see online supplemental appendix tables S4.1.1–S4.1.8 for details of included reports). Numerically higher rates of serious AEs, infections, serious infections and especially herpes zoster (HZ) were identified when comparing JAKi treatment arms with placebo arms (see online supplemental appendix tables S4.2.1–S4.2.8 for detailed results). AEss of special interest are shown in online supplemental appendix tables S4.3.1–S4.3.8. Liver enzymes and creatine kinase elevations as well as grade 3 or 4 lymphopenia/leucopenia appeared more frequently during JAKi treatment.

Assessment of rare events, especially VTE (that is, deep vein thrombosis and pulmonary embolism) remained difficult to assess due to scarcity of data and a largely diverse database on the amplitude of VTE risk related to the underlying disease. One cohort study using claims databases investigated the risk of venous thromboembolism in biological and JAKi-naïve patients with RA (n=50 865) receiving TOFA versus patients receiving TNFi and found a numerically higher, however, statistically nonsignificant VTE risk (pooled propensity score-adjusted HR: 1.33; 95% CI 0.78 to 2.24).⁸³

In some RCTs, compared to placebo, numerically higher rates of DVT/PE were seen in JAKi-treated patients, suggesting an increased risk for venous thromboembolism. However, reports of head-to-head studies did not reveal a clear signal regarding VTE risk when comparing TNFi and JAKi treatment arms during the controlled period (table 3). While the individual reports did not allow to discern major differences between JAKi and placebo or active treatment arms regarding VTEs and PEs, the regulators have published important information after the time point of this SLR. For completeness, we refer to the Food and Drug Adminstration report revealing more VTE/PE for BARI at 4 mg,⁸⁴ and to the EMA report on a still ongoing trial of TOFA versus anti-TNFs in patients with RA with cardiovascular risk factors where significantly more VTE/PE and deaths were seen with TOFA 10 mg two times per day but numerically also for TOFA 5 mg.^{85 86} These important information also led to black box warnings in the package inserts of marketed JAKi and more long-term data will be needed, as also meanwhile partly published for some of the drugs.^87–90

No safety signal could be identified regarding major cardiac adverse events (MACE), malignancies excluding non-melanoma skin cancer. Table 3 shows AEs of special interest in trials comparing JAKi next to TNFi and placebo treatment.

Additionally, 12 reports on integrated safety analyses of RCTs+long-term extension trials (LTEs) were included in the analysis. TOFA RCTs (until March 2015) comprising 19 406 patient-years (PY) of treatment exposure within RA showed stable AEs over time (median exposure 3.4 years). Nasopharyngitis, upper respiratory tract infections and urinary tract infections were the most common AEs. Most common serious infections were pneumonia, HZ, urinary tract infections and cellulitis, with baseline glucocorticoid usage, age and geographic region (Asia) being significant risk factors. No increased incidence rate for malignancies excluding non-melanoma skin cancer (standardised incidence ratio: 1.0; 95% CI 0.8 to 1.1) was observed. Twenty-two gastrointestinal perforations (incidence ratio: 0.11, 95% CI 0.07 to 0.17) were reported, all in patients with concomitant non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoid therapy (NSAIDs + glucocorticoids: n=10; NSAIDs only: n=9; glucocorticoids only: n=3); 13 patients had a history of diverticulitis or diverticulosis and two a history of gastric ulcers.⁹¹ Consistent results were also observed in patients with UC and PsO who were treated with TOFA in RCTs and LTEs.^{92 93} Safety analyses on HZ events in patients with PsO and UC found patients treated with TOFA at increased risk for HZ infection, with age, Asian origin and previous biological use as risk factor as well as dose-dependent higher risks in patients treated with TOFA 10 mg two times per day versus TOFA 5 mg two times per day.^94–96 Although higher levels of low-density lipoprotein, high-density lipoprotein and total cholesterol were observed during TOFA treatment, no signal regarding a higher risk of MACE was found in RA, PsO and UC trials.^97–99

Integrated safety on BARI in RA with 6637 total PY of exposure (median 2.1 years) showed a higher risk for infections including HZ; VTE (including deep vein thrombosis/pulmonary embolism) were reported with BARI 4 mg OD but not for placebo (IR 0.5/100PY, 95% CI 0.3 to 0.7) without differences between BARI 2 mg (IR 0.5/100PY) and BARI 4 mg (IR 0.6/100 PY). These were associated with age, higher BMI, history of DVT/PE and use of selective cyclooxygenase-2 inhibitors. Higher rates of non-melanoma skin cancer were identified in BARI 4 mg OD compared to BARI 2 mg OD-treated patients. Three cases of gastrointestinal perforations were reported in patients taking MTX+NSAIDs, with two patients taking glucocorticoids. Ten cases of tuberculosis (in endemic areas) were observed in BARI-treated patients. No increased risk of MACE or malignancies was identified.¹⁰⁰

Pregnancy is a contraindication for JAKi therapy, and patients were required to use contraception during the RCTs. Therefore, only very limited data (two retrospective analyses) on pregnancy outcomes were available.^{101 102} Clowse et al investigated pregnancy outcomes of patients treated with TOFA in RA (31 maternal cases: TOFA monotherapy n=18, TOFA+MTX n=13; 3 paternal cases) and PsO (16 maternal cases, 41 paternal cases). Similar frequencies of healthy newborns (n=25), no fetal death, seven spontaneous abortions, eight medical terminations and one congenital malformation (pulmonary valve stenosis) were reported until April 2014. These frequencies were consistent with background risks in the general population as well as in patients with RA or PsO, although confounded through concomitant MTX therapy in some patients with RA.¹⁰¹ Further analysis on pregnancies in UC, RA, PsO and PsA RCTs (up to March 2017) reported results in line with the previous report with pregnancy AEs during TOFA treatment appearing similar to those in the general population.¹⁰²