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A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients With Crohn’s Disease
Clinical Gastroenterology and Hepatology 2014;-:-–-
A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients With Crohn’s Disease William J. Sandborn,* Subrata Ghosh,‡ Julian Panes,§ Ivana Vranic,k Wenjin Wang,¶ and Wojciech Niezychowski,# on behalf of the Study A3921043 Investigators *Division of Gastroenterology, University of California San Diego, La Jolla, California; ‡Department of Medicine, University of Calgary, Calgary, Alberta, Canada; §Gastroenterology Department, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain; k Global Medicine Development, Pfizer Inc, Sandwich, United Kingdom; ¶Global Innovative Pharma Division, and #Global Medicine Development, Pfizer Inc, Collegeville, Pennsylvania BACKGROUND & AIMS:
Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through g-chain– containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn’s disease.
METHODS:
Patients (N [ 139; age, ‡18 y) with moderate-to-severe active Crohn’s disease were assigned randomly to groups given 1 mg (n [ 36), 5 mg (n [ 34), or 15 mg (n [ 35) tofacitinib or placebo (n [ 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn’s Disease Activity Index score of ‡70 points [Response-70]). Secondary end points included clinical remission (Crohn’s Disease Activity Index score of <150 points) at week 4.
RESULTS:
A clinical response was observed in 36% (P [ .467), 58% (P [ .466), and 46% (P ‡ .999) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 47% of patients given placebo. Clinical remission was observed in 31% (P [ .417), 24% (P [ .776), and 14% (P [ .540) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 21% of patients given placebo. The 15-mg dose of tofacitinib reduced levels of C-reactive protein and fecal calprotectin from baseline. Adverse and serious adverse events were similar among groups. Dose-dependent increases in low- and high-density lipoprotein cholesterol were observed in patients given the 5- or 15-mg doses of tofacitinib.
CONCLUSIONS:
There were no significant differences in the percentage of patients with moderate-to-severe active Crohn’s disease who achieved clinical responses (Response-70) or clinical remission after 4 weeks’ administration of tofacitinib (1, 5, or 15 mg) or placebo twice daily. However, a large percentage of patients given placebo achieved Response-70 or remission. Reductions in C-reactive protein and fecal calprotectin levels among patients given the 15-mg dose of tofacitinib indicate its biologic activity. ClinicalTrials.gov number: NCT00615199.
Keywords: Tofacitinib; CP-690,550; Crohn’s Disease; Randomized Control Trial.
rohn’s disease is a chronic inflammatory disease of the small intestine and colon characterized by alternating periods of relapse and remission.1 Proven medications for Crohn’s disease include budesonide, corticosteroids, azathioprine, 6-mercaptopurine, methotrexate, and anti–tumor necrosis factor (TNF)a antibodies; not all patients respond to these medications, and serious toxicities are associated with many of them.2 An unmet need exists for novel therapies with alternative mechanisms of action. Tofacitinib is a novel, oral, small-molecule Janus kinase (JAK) inhibitor that is being investigated as a targeted immunomodulator for inflammatory bowel
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disease. It is a highly selective inhibitor of the JAK family of kinases and competes with adenosine triphosphate for binding to the adenosine triphosphate binding site of the kinase domain within JAK enzymes.3,4 In vitro, tofacitinib Abbreviations used in this paper: AE, adverse event; ANC, absolute neutrophil count; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; IBDQ, Inflammatory Bowel Disease Questionnaire; JAK, Janus kinase; LDL, lowdensity lipoprotein; SAE, serious adverse event; TNF, tumor necrosis factor. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.01.029
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preferentially inhibits signaling by receptors associated with JAK3 and JAK1, while showing reduced inhibition for JAK2- and TYK2-associated signaling.4 Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common g-chain–containing receptors for several cytokines, including interleukins 2, 4, 7, 9, 15, and 21, which are integral to lymphocyte activation, proliferation, and function; inhibition of their signaling thus may result in modulation of multiple aspects of the immune response. In addition, inhibition of JAK1 will result in attenuation of signaling by additional proinflammatory cytokines, such as interleukin 6 and interferon-g.4 At higher exposures, inhibition of erythropoietin signaling could occur via inhibition of JAK2 signaling. Many of these pathways have been implicated in the pathogenesis of Crohn’s disease and ulcerative colitis. Tofacitinib has been shown to be beneficial in the treatment of rheumatoid arthritis,5 psoriasis,6 and ulcerative colitis,7 and for the prevention of organ allograft rejection8; the efficacy of tofacitinib for the treatment of Crohn’s disease is unknown. We conducted a 4-week treatment study of tofacitinib in patients with moderate-to-severe active Crohn’s disease.
Methods The study (A3921043, ClinicalTrials.gov NCT00615199) was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines established by the International Conference on Harmonisation. The protocol was approved by the Institutional Review Board at each center. All patients provided written informed consent. The study investigators were responsible for adhering to the study procedures described in the protocol. The study was patient-, investigator-, and sponsorblinded. Electronically generated blinded codes could be broken only in emergency situations for reasons of patient safety. All authors had access to the study data and reviewed and approved the final manuscript.
Patients This 4-week, phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted at 48 centers in 12 countries (Belgium, Czech Republic, France, Hungary, Italy, The Netherlands, Poland, Slovakia, South Africa, Spain, United Kingdom, and United States) between January 9, 2008, and October 29, 2009. Eligible patients, aged 18 years and older, had Crohn’s disease for 3 months or longer, with moderateto-severe disease at baseline defined by a Crohn’s Disease Activity Index (CDAI)9 score of 220 to 450. Confirmation of the diagnosis and extent of disease must have been obtained by endoscopy and/or cross-sectional imaging within 24 months before screening. Exclusion criteria included the following: hemoglobin level less than 9.0 g/dL, hematocrit less than 30%, white
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blood cell count less than 3.0 109/L, absolute neutrophil count (ANC) less than 1.2 109/L, or platelet count less than 100 109/L; estimated glomerular filtration rate less than 50 mL/min; total bilirubin, aspartate aminotransferase, or alanine aminotransferase level greater than 2 the upper limit of normal; a history of symptomatic obstructive strictures or short-bowel syndrome; an ostomy, extensive bowel resection (>100 cm), or bowel surgery within 6 months before baseline; chronic or recurrent infections, including latent or inadequately treated Mycobacterium tuberculosis infection; malignancy or history of malignancy, with the exception of adequately treated or excised nonmetastatic basal cell or squamous cell cancer of the skin, or cervical carcinoma in situ. Patients with a positive stool culture for bacterial pathogens and/or a stool test for Clostridium difficile toxin were excluded. Cytomegalovirus disease was not specifically evaluated and excluded because it would require gastrointestinal tissue sample analysis; endoscopy was not part of the baseline procedure.
Study Design and Treatment The study comprised a screening visit within 3 weeks of baseline, a 4-week double-blind treatment period, and a 4-week follow-up period. Patients completed a daily diary of their symptoms from screening onward, and data from the last week before randomization were used to assess baseline symptoms and calculate the baseline CDAI score. Outpatients were randomized 1:1:1:1 to receive the following: oral tofacitinib 1 mg twice daily, 5 mg twice daily, 15 mg twice daily, or placebo twice daily. These doses for this phase 2 study were selected based on the efficacy and safety results from studies in patients with renal allograft, psoriasis, or rheumatoid arthritis to identify the lowest effective dose while including the maximum proposed therapeutic dose.5,6,8 Patients were stratified according to disease activity at baseline (CDAI score, <330 vs 330 points) and randomized (concealed allocation) into the study. The cut-off value of 330 was chosen as a midpoint of the CDAI score inclusion criteria. The planned total number of 136 patients was based on the assumptions of a 30% clinical response rate (Response-70) for placebo and a difference from placebo of 25% in clinical response rate in 1 or more active doses over placebo. Under these assumptions, there was a greater than 84% probability to have an observed difference in Response-70 greater than 15% and have the lower bound of the 80% two-sided confidence interval (CI) for the difference greater than 0.
Concomitant Medications Patients who previously had not received any treatment for Crohn’s disease were excluded from this study. The following concomitant therapies were prohibited: azathioprine, 6-mercaptopurine, methotrexate
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(within 7 days of baseline); cyclosporine, mycophenolate, tacrolimus (within 4 weeks); interferon, and anti-TNFa therapy (within 8 weeks). The following therapies at stable doses were permitted (but not required): 5-acetylsalicylic acid or sulfasalazine (3 weeks before baseline and during treatment); prednisolone 30 mg or less per day or budesonide 9 mg or less per day (2 weeks before baseline); and chronic treatment with antibiotics and rectally administered corticosteroids or 5-acetylsalicylic acid (2 weeks before baseline and during treatment).
Efficacy and Safety Evaluations The primary efficacy end point was the proportion of clinical responders at week 4, defined as a decrease in CDAI score of 70 or more points from baseline (Response70). At the time of finalizing the design, both Response-70 and Response-100 were used in Crohn’s disease trials. Taking into account the short duration of this trial, a lower hurdle of Response-70 was considered appropriate as a primary end point for this proof-of-concept study. Secondary efficacy end points at week 4 included Response-100, and the clinical remission rate (a reduction in CDAI score to <150 points). Patients who withdrew from the study or who required rescue medications were analyzed as nonresponders. Other parameters measured included improvement in quality of life, as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ)10 (range, 0–224 points; score 170 points indicates clinically inactive disease) at baseline and weeks 4 and 8; improvement (a decrease from baseline in the number of open draining fistulas of 50% for 2 consecutive visits) or remission (closure of all fistulas that were draining at baseline for 2 consecutive visits) of enterocutaneous fistulas measured by the Fistula Drainage Assessment; and a change from baseline in C-reactive protein (CRP) and fecal calprotectin levels at every visit. A colonoscopy for assessment of mucosal healing was not permitted during the trial. The frequency and severity of all adverse events (AEs) were recorded throughout. Blood and urine samples for standard hematology and chemistry assessments, urine samples for urinalysis, and fecal samples for calprotectin were collected at baseline and weeks 1, 2, 4, and 8.
Statistical Analysis The planned primary analysis was to explore the dose-response relationship for Response-70 by fitting a 3-parameter Emax model to the log-odds of the observed rates. A term was included for baseline CDAI score. Estimates of the treatment differences from the fitted response function and associated 80% CIs for each active dose vs placebo were calculated. Results were backtransformed to give point estimates of the difference in proportions and associated 80% CIs. In addition, the observed response rates and the pairwise 2-sided P values
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from the Fisher exact test for comparisons vs placebo also were obtained. Similar methods were planned for Response-100 and clinical remission. No adjustments for multiple comparisons were made because of the exploratory nature of the study. The population for the analyses of efficacy parameters included all randomized patients who had either withdrawn as a treatment failure or had completed 1 or more weeks of dosing and had 1 or more valid CDAI scores during the active double-blind phase. Safety data were summarized descriptively. A post hoc summary was performed to look at the response in patients with different baseline CRP levels, baseline fecal calprotectin levels, prior immunosuppressant use, and prior anti-TNFa use.
Results Patient Disposition and Demographics In total, 236 patients were screened; 139 (58.9%) patients were randomized to receive tofacitinib 1 (n ¼ 36), 5 (n ¼ 34), or 15 mg twice daily (n ¼ 35), or placebo twice daily (n ¼ 34); 126 (90.6%) patients completed the study (Supplementary Figure 1). One patient with a baseline CDAI score of less than 150 from the 5-mg twice-daily group was excluded from all efficacy analyses. Baseline demographic characteristics were similar between groups (Table 1). Steroids (meprednisone, prednisone, prednisolone, or methylprednisolone) were used at baseline by 41.2%, 38.9%, 35.3%, and 34.3% of patients in the placebo and tofacitinib 1-, 5-, and 15-mg twice-daily groups, respectively; the median prednisone equivalent dose was 15.0 mg in the placebo group and 20.0 mg in each of the tofacitinib groups.
Efficacy At week 4, the observed rates for the primary end point of Response-70 were 36.1% (n ¼ 13; P ¼ .467), 57.6% (n ¼ 19; P ¼ .466), and 45.7% (n ¼ 16; P .999) of patients receiving tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 47.1% (n ¼ 16) of placebo patients. The model-predicted Response-70 rates at week 4 were 44.8% (80% CI, 38.2–51.5; P ¼ .667), 48.0% (80% CI, 41.3–54.7; P ¼ .558), and 49.9% (80% CI, 40.7–59.0; P ¼ .527) for patients in the tofacitinib 1-, 5-, and 15-mg twice-daily groups, respectively, vs 42.9% (80% CI, 33.8–52.0) for placebo patients (Figure 1A).
Secondary End Points At week 4, the observed rates for Response-100 were 30.6% (n ¼ 11; P .999), 45.5% (n ¼ 15; P ¼ .212), and 37.1% (n ¼ 13; P ¼ .611) of patients in the tofacitinib 1-, 5-, and 15-mg twice-daily groups, respectively, vs 29.4% (n ¼ 10) of placebo patients (Figure 1B). The model-predicted Response-100 rates at week 4 were
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Table 1. Demographic and Baseline Disease Characteristics Placebo (n ¼ 34) Female, n (%) Age, mean, y (SD) Race, white, n (%) Body weight, mean, kg (SD) Body mass index, mean, kg/m2 (SD) Smoking status, n (%) Never smoked Smoker Ex-smoker Geographic region United States Europe South Africa Duration since first diagnosis, mean, y (range) Disease location, n (%) Ileal Colonic Ileocolonic Upper disease CDAI scorea Mean Median SD CDAI category, n (%) <330 330 CRP level,b mg/L Mean Median SD CRP level 5 mg/mL, n (%) Fecal calprotectin level, mg/kg Mean Median SD Fecal calprotectin level 250 mg/kg, n (%) Open draining enterocutaneous fistulas, n (%) Immunosuppressant use within the previous 12 months, n (%) Patients remaining on immunosuppressant at screening, n (%) Steroid use within the previous 12 months, n (%) Anti-TNFa use within the previous 12 months, n (%)
22 35.7 32 74.8 26.6
(64.7) (12.7) (94.1) (17.8) (7.2)
17 (50.0) 10 (29.4) 7 (20.6) 13 18 3 8.2
(38.2) (52.9) (8.8) (0.1–35.6)
9 (26) 14 (41) 16 (47) 0
Tofacitinib 1 mg BID (n ¼ 36) 11 36.6 34 74.5 24.8
(30.6) (12.2) (94.4) (15.4) (5.1)
19 (52.8) 8 (22.2) 9 (25.0) 15 19 2 11.1 6 20 15 1
(41.7) (52.8) (5.6) (0.1–28.5) (17) (56) (42) (3)
Tofacitinib 5 mg BID (n ¼ 34) 20 38.7 28 70.4 25.0
(58.8) (10.2) (82.4) (20.6) (6.5)
18 (52.9) 11 (32.4) 5 (14.7) 16 16 2 10.9
(47.1) (47.1) (5.9) (0.3–29.3)
3 (9) 18 (53) 11 (32) 0
Tofacitinib 15 mg BID (n ¼ 35) 17 38.1 31 70.1 24.3
(48.6) (11.7) (88.6) (15.7) (5.2)
23 (65.7) 8 (22.9) 4 (11.4) 13 19 3 11.2
(37.1) (54.3) (8.6) (1.5–36.3)
10 (29) 17 (49) 17 (49) 0
306.4 293 62.6
300.3 286 76.7
297.7 293 63.7
308.0 303 50.8
22 (64.7) 12 (35.3)
26 (72.2) 10 (27.8)
22 (64.7) 12 (35.3)
24 (68.6) 11 (31.4)
17.1 8.9 23.1 22 (64.7)
18.3 6.3 28.8 17 (47.2)
17.5 7.2 22.4 19 (57.6)
26.1 11.8 34.9 25 (71.4)
1422 641 2274 19 (55.9) 3 (8.8) 7 (20.6) 0 15 (44.1) 1 (2.9)
1409 438 3386 24 (66.7) 8 (22.2) 8 (22.2) 0 16 (44.4) 4 (11.1)
482 362 453.5 20 (60.6) 5 (15.2) 9 (26.5) 0 14 (41.2) 1 (2.9)
1175 519 1964 20 (57.1) 10 (28.6) 15 (42.9) 2 (5.7) 16 (45.7) 4 (11.4)
BID, twice daily. a The range for the CDAI score is 0 to approximately 600. b The normal range for CRP concentration is 0–3 mg/L.
33.7% (80% CI vs placebo, 26.0–41.4; P ¼ .483), 38.8% (80% CI, 32.1–45.6; P ¼ .250), and 40.8% (80% CI, 32.0–49.6; P ¼ .223) for tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 28.1% (80% CI, 18.7–37.5) for placebo (Figure 1B). Clinical remission at week 4 occurred in 30.6% (n ¼ 11; P ¼ .417), 24.2% (n ¼ 8; P ¼ .776), and 14.3% (n ¼ 5; P ¼ .540) of patients receiving tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 20.6% (n ¼ 7) for placebo. Because of the failure to fit the Emax model, no predicted clinical remission rates from this model were available. CDAI scores decreased in each treatment group; the observed mean change from baseline ( standard
deviation) to week 4 was -63.85 (108.37), -100.28 (96.08), and -67.19 (98.54) for tofacitinib 1, 5, and 15 mg twice daily, respectively, vs -78.38 (105.28) for placebo (Figure 2). At week 8, the mean change was -48.52 (129.73), -64.25 (112.33), and -78.53 (94.45) for tofacitinib 1, 5, and 15 mg twice daily, respectively, and -68.57 (93.59) for placebo. The median (range) changes from baseline to week 4 in total IBDQ score were 18.0 (-35 to 111), 17.0 (-14 to 97), and 18.0 (-38 to 99) for tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 3.1 (-33 to 63) for placebo. The proportion of patients with a 16-point or more reduction in IBDQ score from baseline to week 4 was
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Clinical improvement in fistula drainage was seen in 1 of 4 patients (25.0%) for tofacitinib 5 mg twice daily and in 2 of 9 patients (22.2%) for 15 mg twice daily at week 4. At week 8, 3 of 4 patients (75.0%, 5 mg twice daily) and 3 of 9 patients (33.3%, 15 mg twice daily) showed clinical improvement. No placebo or tofacitinib 1-mg twice-daily patients showed clinical improvement in drainage at weeks 4 or 8. The subgroup summaries performed to look at the responses in patients with different baseline characteristics (CRP level, fecal calprotectin level, prior immunosuppressant use, and prior anti-TNFa use) are shown (Supplementary Table 1). Because of the small number of patients in each group, no obvious conclusion could be made.
Biomarkers
Figure 1. Proportion of patients achieving (A) Response-70 and (B) Response-100 at week 4. P values are observed data vs placebo. P values for Emax modeled data (vs placebo) are as follows: Response-70: 1 mg twice daily, P ¼ .667; 5 mg twice daily, P ¼ .558; and 15 mg twice daily, P ¼ .527; and Response-100: 1 mg twice daily, P ¼ .483; 5 mg twice daily, P ¼ .250; and 15 mg twice daily, P ¼ .223. BID, twice daily.
53.3%, 70.4%, and 54.5% for tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 42.3% for placebo; 36.4%, 39.3%, and 27.3% of tofacitinib patients were complete responders (total IBDQ score 170) at week 4, vs 19.2% in the placebo group.
Dose-related decreases from baseline in mean CRP concentrations were observed for all tofacitinib groups as early as week 1, with some further decreases over time up to week 4 in the 15-mg twice-daily arm. At week 4, the observed mean change from baseline in log-transformed CRP level was -0.93 mg/L (95% CI, -1.53 to -0.33) for tofacitinib 15 mg twice daily and -0.07 mg/L (95% CI, -0.43 to 0.28) for placebo (Figure 3A). For patients with baseline CRP levels of 5 mg/L or higher, mean dose-related decreases in log-transformed CRP levels observed at week 4 were of a slightly larger magnitude: -1.11 mg/L (95% CI, -1.72 to -0.50) for tofacitinib 15 mg twice daily (Figure 3B) and -0.11 mg/L (95% CI, -0.59 to 0.37) for placebo. At week 4, the observed mean change from baseline in log-transformed fecal calprotectin concentration was -0.70 mg/kg (95% CI, -1.11 to -0.29) for tofacitinib 15 mg twice daily and .08 mg/kg (95% CI, -0.38 to 0.55) for placebo (Figure 3C). For patients with a baseline fecal calprotectin concentration of 250 mg/kg or higher, the observed mean change at week 4 from baseline in logtransformed fecal calprotectin level was -1.22 mg/kg (95% CI, -1.69 to -0.75) for tofacitinib 15 mg twice daily and -0.09 mg/kg (95% CI, -0.85 to 0.67) for placebo (Figure 3D).
Safety
Figure 2. Mean change from baseline in CDAI score over time. BID, twice daily; SD, standard deviation.
The overall incidence of AEs and serious AEs (SAEs) was similar across all treatment groups (Table 2). A total of 83 patients experienced 1 or more treatment-emergent AEs, 40 of which were considered by the investigator to be related to study medication. The most commonly reported treatment-emergent AEs were nausea (8.6% of patients), abdominal pain (7.9%), worsening of Crohn’s disease (6.5%), and vomiting (6.5%). Fourteen patients experienced 26 SAEs; the SAEs of 2 patients were considered by the investigator to be treatment-related (worsening of Crohn’s disease in 1 patient in the 1-mg twice-daily group; severe abdominal pain, diarrhea, ileus, chills, and pyrexia in 1 patient in the 5-mg twicedaily group). The most commonly reported SAE was
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Figure 3. Mean change from baseline in log-transformed CRP (mg/L) in (A) all patients and (B) patients with baseline CRP levels of 5 mg/L or greater. Mean change from baseline in log-transformed fecal calprotectin (mg/kg) in (C) all patients, and (D) patients with baseline fecal calprotectin levels of 250 mg/kg or greater. BID, twice daily.
worsening of Crohn’s disease (15.4%). A total of 26 patients reported 31 treatment-emergent infection AEs, the most common of which were nasopharyngitis (4.3%) and urinary tract infection (2.9%). Five infection events were considered to be severe: anal abscess (placebo, 1.4%), pneumonia (placebo, 0.7%), sepsis (placebo, 0.7%), and vulval abscess (5 mg twice daily, 0.7%). Thirteen patients discontinued study participation, 6 owing to AEs: decreased weight (1-mg twice-daily group,
n ¼ 1), subileus (5-mg twice-daily group, n ¼ 1), worsening of Crohn’s disease (15-mg twice-daily group, n ¼ 1), and intestinal obstruction, anal abscess, vomiting and worsening of Crohn’s disease (placebo group, n ¼ 3). One death was reported in a patient receiving placebo who experienced a fatal SAE of ventricular fibrillation as a result of sepsis. Dose-related mean increases from baseline to week 4 in total cholesterol, low-density lipoprotein (LDL)
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Table 2. Summary of Safety Findings Tofacitinib 1 mg BID (n ¼ 36)
Placebo (n ¼ 34) Patients with all-causality TEAE, n (%) Patients with treatment-related TEAEs, n (%) Patients with all-causality SAEs, n (%) Patients with treatment-related SAEs, n (%) Patients with all-causality infection AEs, n (%) Patients who discontinued because of AEs, n (%) Deaths, n (%) Most commonly reported all-causality TEAEs, n (%)a Nausea Abdominal pain Crohn’s disease (worsening of) Vomiting Asthenia Diarrhea Fatigue Headache Pyrexia Insomnia Lipid assays at week 4, mg/dL Total cholesterol Mean change from baseline (SD) Mean at week 4 Median at week 4 LDL cholesterol Mean change from baseline (SD) Mean at week 4 Median at week 4 HDL cholesterol Mean change from baseline (SD) Mean at week 4 Median at week 4 Triglycerides at week 4 Mean change from baseline (SD) Mean at week 4 Median at week 4
Tofacitinib 5 mg BID (n ¼ 34)
22 9 5 0 8 3 1
(64.7) (26.5) (14.7) (2.9) (23.5) (8.8) (2.9)
18 (50.0) 10 (27.8) 4 (11.1) 1 (2.8) 5 (13.9) 1 (2.8) 0
21 10 4 1 8 1
2 4 1 3 3 1 3 1 1 2
(5.9) (11.8) (2.9) (8.8) (8.8) (2.9) (8.8) (2.9) (2.9) (5.9)
4 (11.1) 3 (8.3) 3 (8.3) 2 (5.6) 3 (8.3) 2 (5.6) 4 (11.1) 2 (5.6) 0 2 (5.6)
3 1 3 1 1 2
-3.8 (24.6) 176.6 181.0
-2.1 (20.1) 170.9 166.0
8.7 (25.3) 179.0 177.0
16.5 (29.2) 183.1 183.0
-1.0 (21.0) 96.3 100.0
1.5 (14.3) 90.0 80.5
3.8 (21.6) 92.1 95.5
11.3 (22.2) 89.7 78.0
0.85 (8.1) 52.8 50.5
6.0 (11.1) 59.1 57.9
8.3 (12.4) 57.7 57.0
-18.6 (49.3) 102.7 94.0
15.1 (138.5) 140.8 78.3
-0.1 (59.4) 116.8 100.0
2.6 (12.1) 52.7 51.2 -17.5 (43.8) 134.3 118.4
(61.8) (29.4) (11.8) (2.9) (23.5) (2.9) 0
Tofacitinib 15 mg BID (n ¼ 35)
(8.8) (2.9) (8.8) (2.9) (2.9) (5.9) 0 2 (5.9) 3 (8.8) 0
22 (62.9) 11 (31.4) 1 (2.9) 0 5 (14.3) 1 (2.9) 0 3 3 2 3 1 3 1 3 3 2
(8.6) (8.6) (5.7) (8.6) (2.9) (8.6) (2.9) (8.6) (8.6) (5.7)
BID, twice daily; SD, standard deviation; TEAE, treatment-emergent adverse event. a The 10 most commonly reported all-causality TEAEs are shown, as reported by the Medical Dictionary for Regulatory Activities preferred term (v12.1; McLean, VA).
cholesterol, and high-density lipoprotein (HDL) cholesterol were reported for the tofacitinib 5- and 15-mg twicedaily groups. Triglyceride levels decreased from baseline to week 4 for the placebo and the tofacitinib 1-mg twicedaily groups by -17.5 and -18.6 mg/dL, respectively, increased in the 5-mg twice-daily group by 15.1 mg/dL, and remained relatively unchanged in the 15-mg twicedaily group (-0.1 mg/dL) (Table 2). No clinically significant changes from baseline to week 4 in other laboratory tests, including liver and renal function tests and hematology parameters, were reported. No patients had an ANC less than 1.0 109/L at any time during treatment.
Discussion In this 4-week, phase 2 trial in patients with moderateto-severe active Crohn’s disease, a proportion of whom
had failed conventional therapy, tofacitinib did not show efficacy in the induction of a clinical response, as measured by Response-70/-100 or clinical remission rates; however, placebo response and remission rates were greater than expected. Tofacitinib 15 mg twice daily reduced CRP and fecal calprotectin concentrations, and numeric improvements from baseline in IBDQ score were observed in all groups. No statistical comparisons were made. The observed screening failure rate was 41%. This was a relatively high screen failure rate for a trial in which patients were not screened for objective markers of inflammation. The selection of an early (4-week) end point was expected to result in low placebo response rates11; however, the week 4 placebo response was higher than expected, and much higher than that observed in previous studies of anti-TNFa.12–15 One possible explanation for the high placebo response was an inadvertent
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selection bias toward the enrollment of patients with a more benign natural history. A number of factors could have contributed toward this selection bias, including the fact that the study was placebo-controlled, only 4 weeks’ duration, without an extension phase in which patients could receive open-label tofacitinib therapy, as well as the requirement to discontinue azathioprine, 6-mercaptopurine, and methotrexate before the start of the study. Only 21% of placebo patients previously had received azathioprine or 6-mercaptopurine, 44% were receiving corticosteroids, and only 2% previously failed anti-TNFa therapy. At baseline, 65% of placebo patients had increased CRP concentrations (5 mg/L), and 56% had increased fecal calprotectin concentrations (250 mg/kg). A recently reported 6-week induction trial of certolizumab pegol in Crohn’s disease failed to show efficacy in an anti-TNFa–naive patient population, in which approximately 40% of patients did not have CRP increases at baseline.16 The week 6 remission rate in the placebo arm of this study also was unexpectedly high.16 The currently ongoing tofacitinib Crohn’s disease study requires a demonstration of the presence of terminal ileal or colonic ulcers by endoscopy as an inclusion criterion and a long-term treatment option also is available. It is unclear whether the failure of tofacitinib to show induction efficacy for Crohn’s disease was owing to the high placebo response rate discussed previously or whether it was a true negative result. A likely biologic effect of tofacitinib 15 mg twice daily, as measured by reductions from baseline CRP and fecal calprotectin concentrations, was observed in this study. A phase 2b induction trial (NCT01393626) of tofacitinib in Crohn’s disease is underway to address this issue. Confirmation of the diagnosis in the present study was based on a visualization of the gastrointestinal tract by radiology, scintigraphy, or endoscopy within 24 months before screening. The lack of histologic confirmation of the diagnosis was a limitation of this study. Although it is possible that some patients were misdiagnosed, taking into account that patients were diagnosed with Crohn’s disease for a mean period of 8 to 11 years, it is unlikely that this had a significant effect on study results. An 8-week phase 2 trial of tofacitinib in patients with moderate-to-severe ulcerative colitis7 also was conducted; tofacitinib (10 and 15 mg twice daily) was more effective in the induction of clinical response, clinical remission, and mucosal healing, as well as the reduction of CRP and fecal calprotectin concentrations, vs placebo. Whether the failure of tofacitinib to show clinical efficacy in Crohn’s disease represents a real difference from the efficacy seen in ulcerative colitis remains unclear. If this is indeed the case, then additional mechanistic studies to determine the reasons for this difference would be warranted. The short duration of the trial and small sample size did not allow for a comprehensive evaluation of the safety and tolerability of tofacitinib in Crohn’s disease. In rheumatoid arthritis, tofacitinib has been associated with mean increases in serum creatinine, LDL and HDL
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cholesterol, and mean decreases in ANC.5 Serious infections and malignancies including lymphomas also have been observed.5,8 The clinical importance of these laboratory abnormalities require further evaluation. In this study, we observed a dose-dependent increase in LDL and HDL cholesterol. A dose-dependent treatment effect on lipid levels vs placebo is consistent with that seen in rheumatoid arthritis trials. We observed no difference between active treatment and placebo as measured by clinical end points; thus, changes in lipids as a predictor of efficacy was not tested. In clinical trials with tofacitinib in which efficacy was observed, no relationship with changes in lipid profiles has been shown.
Conclusions In conclusion, patients with moderate-to-severe active Crohn’s disease treated with tofacitinib were not more likely to achieve clinical response or clinical remission vs those receiving placebo; however, the placebo response and remission rates were unexpectedly high. The reductions in CRP and fecal calprotectin values in the tofacitinib 15-mg twice-daily group suggest biologic activity. Further studies are needed to determine whether tofacitinib is effective for the treatment of Crohn’s disease.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2014.01.029.
References 1. Baumgart D, Sandborn WJ. Crohn’s disease. Lancet 2012; 380:1590–1605. 2. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130:940–987. 3. Karaman MW, Herrgard S, Treiber DK, et al. A qualitive analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26:127–132. 4. Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP690,550, in rat adjuvant-induced arthritis. J Inflamm 2010;7:41. 5. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012;367:495–507. 6. Papp K, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol 2012;167:668–677. 7. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012; 367:616–624. 8. Vincenti F, Tedesco SH, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant
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2014 patients: efficacy, renal function and safety at 1 year. Am J Transplant 2012;12:2446–2456.
9. Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70:439–444. 10. Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology 1994;106:287–296. 11. Su C, Lichtenstein GR, Krok K, et al. A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn’s disease. Gastroenterology 2004;126:1257–1269. 12. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029–1035. 13. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human antitumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006; 130:323–333. 14. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007; 357:228–238. 15. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829–838. 16. Sandborn WJ, Schreiber S, Feagan BG, et al. Certolizumab pegol for active Crohn’s disease: a placebo-controlled, randomized trial. Clin Gastroenterol Hepatol 2011;9:670–678.
Reprint requests Address requests for reprints to: William J. Sandborn, MD, Division of Gastroenterology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0956. e-mail: [email protected]; fax: (858) 657-5022. Acknowledgements The authors would like to thank the patients who were involved in this study, and the A3921043 investigators and study team. Conflicts of interest The authors disclose the following: William Sandborn has received consulting fees from Abbott, ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corp, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys, Inc, Atlantic Healthcare, Ltd, Aptalis, BioBalance Corp, BoehringerIngelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen, Diagnostics, Inc, Ferring Pharmaceuticals, Flexio Therapeutics, Inc, Funxional Therapeutics, Ltd, Genzyme Corp, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, Janssen Pharmaceutical Research & Development, LLC, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millennium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer Inc, Procter and Gamble, Prometheus Laboratories, ProtAb, Ltd, Purgenesis Technologies, Inc, Relypsa, Inc,
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Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma, Ltd, Sirtris Pharmaceuticals, SLA Pharma UK, Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tilliotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics, Ltd, Warner Chilcott UK, Ltd, and Wyeth; has received research grants from Abbott, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen Pharmaceutical Research & Development, LLC, Millennium Pharmaceuticals, Novartis, Pfizer Inc, Procter and Gamble, Shire Pharmaceuticals, and UCB Pharma; has received payments for lectures and speakers bureau fees from Abbott, Bristol-Myers Squibb, and Janssen Pharmaceutical Research & Development, LLC; and holds stock/stock options in Enteromedics. Subrata Ghosh has received consulting fees from Abbott, Pfizer Inc, Merck, Shire, Centocor, and BMS; has received research grants from Merck and Abbott; has received payment for lectures from Abbott, Merck, Shire, Millennium, Centocor, and Ferring; and has received payment for the development of an educational presentation from Abbott. Julian Panes has received speaker fees from AbbVie, MSD, Shire Pharmaceuticals, and UCB; has acted as a scientific consultant for AbbVie, Bristol-Myers Squibb, Ferring, MSD, Novartis, Pfizer Inc, Shire Pharmaceuticals, Tygenics, and UCB; and has received research grants from AbbVie and MSD. Ivana Vranic, Wenjin Wang, and Wojciech Niezychowski are employees of, and hold stock/stock options in, Pfizer Inc. Funding This study was sponsored by Pfizer Inc. Editorial support was provided by Karen Irving at Complete Medical Communications, funded by Pfizer Inc.
Appendix 1 The following investigators participated in this study: Europe: Professor Severine A. R. A. Vermeire, Dr Olivier Dewit, Dr Harald Peeters, Dr Jiri Stehlik, Dr Tomas Vanasek, Dr David Laharie, Professor Jean Frederic Colombel, Professor Marc-André Bigard, Dr Marta Varga, Professor Margit Zeher, Dr Janos Novak, Professor Bela Hunyady, Dr Agnes Salamon, Professor Istvan Racz, Professor Paolo Gionchetti, Dr Anna Kohn, Professor Cosimo Prantera, Dr P. C. F. Stokkers, Professor Maria Slomka, Professor Leszek Paradowski, Dr Tomasz Arlukowicz, Dr Ladislav Kuzela, Dr Boris Baricky, Dr Tibor Hlavaty, Dr Maria Isabel Vera, Dr Julian Panes, Dr Jordi Guardiola, Professor Christopher Probert, and Dr Jonathan Lionel Shaffer; United States: Dr Mark Fleisher, Dr Ronald Edward Pruitt, Dr William J. Sandborn, Dr John Sawyer Goff, Dr John Weber, Dr Raymond Lloyd Bell, Dr Andrew Harrison Zwick, Dr Alexandra Gutierrez, Dr Robert H. Levine, Dr Stephen Brett Hanauer, Dr Lori Ann Lavelle, Dr Ravindranath K. Kottoor, Dr Gerald Wayne Dryden Jr, Dr Robert Hardi, Dr David Vaughn Glorioso, Dr Prabhakar Swaroop, Dr Scott D. Lee, Dr Teressa Joan Patrick, Dr Sheldon Scheinert, Dr Charles A. Sninsky, Dr Seymour Katz, Dr Mark D. Noar, Dr Michael Marion Gaspari, Dr Glenn L. Gordon, Dr Thomas A. Dalton, Dr Douglas Edward Homoky, Dr William Ransom Kilgore III, and Dr Joel A. Levien; and South Africa: Dr Herbert R. Schneider, Dr Suleman Abdul Moola, Dr Frederik Cornelius Kruger, Dr John P. Wright, and Dr Nazimuddin Aboo.
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Supplementary Table 1. Post Hoc Subgroup Analysis: Response-70, Response-100, and Remission Rates at Week 4
Response-70, % (n/N) Baseline CRP level, mg/mL <5 5 Baseline fecal calprotectin level, mg/kg <250 250 Prior immunosuppressant use Yes No Prior anti-TNFa use Yes No Response-100, % (n/N) Baseline CRP level, mg/mL <5 5 Baseline fecal calprotectin level, mg/kg <250 250 Prior immunosuppressant use Yes No Prior anti-TNFa use Yes No Remission, % (n/N) Baseline CRP level, mg/mL <5 5 Baseline fecal calprotectin level, mg/kg <250 250 Prior immunosuppressant use Yes No Prior anti-TNFa use Yes No
Placebo
Tofacitinib 1 mg BID
Tofacitinib 5 mg BID
Tofacitinib 15 mg BID
44.4 (4/9) 45.5 (10/22)
35.7 (5/14) 41.2 (7/17)
66.7 (6/9) 52.6 (10/19)
50.0 (3/6) 48.0 (12/25)
33.3 (4/12) 63.2 (12/19)
37.5 (3/8) 41.7 (10/24)
33.3 (4/12) 75.0 (15/20)
15.4 (2/13) 70.0 (14/20)
28.6 (2/7) 51.9 (14/27)
25.0 (2/8) 39.3 (11/28)
44.4 (4/9) 62.5 (15/24)
60.0 (9/15) 31.6 (6/19)
0 (0/1) 48.5 (16/33)
25.0 (1/4) 37.5 (12/32)
0 (0/1) 59.4 (19/32)
50.0 (2/4) 43.3 (13/30)
44.4 (4/9) 27.3 (6/22)
35.7 (5/14) 29.4 (5/17)
44.4 (4/9) 42.1 (8/19)
50.0 (3/6) 36.0 (9/25)
8.3 (1/12) 47.4 (9/19)
25.0 (2/8) 37.5 (9/24)
25.0 (3/12) 60.0 (12/20)
0 (0/7) 37.0 (10/27)
12.5 (1/8) 35.7 (10/28)
44.4 (4/9) 45.8 (11/24)
53.3 (8/15) 26.3 (5/19)
0 (0/1) 30.3 (10/33)
0 (0/4) 34.4 (11/32)
0 (0/1) 46.9 (15/32)
50.0 (2/4) 36.7 (11/30)
33.3 (3/9) 13.6 (3/22)
35.7 (5/14) 29.4 (5/17)
33.3 (3/9) 21.1 (4/19)
16.7 (1/6) 16.0 (4/25)
16.7 (2/12) 26.3 (5/19)
37.5 (3/8) 33.3 (8/24)
33.3 (4/12) 20.0 (4/20)
7.7 (1/13) 20.0 (4/20)
0 (0/7) 25.9 (7/27)
25.0 (2/8) 32.1 (9/28)
33.3 (3/9) 20.8 (5/24)
20.0 (3/15) 10.5 (2/19)
0 (0/1) 21.2 (7/33)
25.0 (1/4) 31.3 (10/32)
0 (0/1) 25.0 (8/32)
25.0 (1/4) 13.3 (4/30)
7.7 (1/13) 60 (12/20)
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Supplementary Figure 1. Patient disposition and treatment through week 8.
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A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients With Crohn’s Disease William J. Sandborn,* Subrata Ghosh,‡ Julian Panes,§ Ivana Vranic,k Wenjin Wang,¶ and Wojciech Niezychowski,# on behalf of the Study A3921043 Investigators *Division of Gastroenterology, University of California San Diego, La Jolla, California; ‡Department of Medicine, University of Calgary, Calgary, Alberta, Canada; §Gastroenterology Department, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain; k Global Medicine Development, Pfizer Inc, Sandwich, United Kingdom; ¶Global Innovative Pharma Division, and #Global Medicine Development, Pfizer Inc, Collegeville, Pennsylvania BACKGROUND & AIMS:
Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through g-chain– containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn’s disease.
METHODS:
Patients (N [ 139; age, ‡18 y) with moderate-to-severe active Crohn’s disease were assigned randomly to groups given 1 mg (n [ 36), 5 mg (n [ 34), or 15 mg (n [ 35) tofacitinib or placebo (n [ 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn’s Disease Activity Index score of ‡70 points [Response-70]). Secondary end points included clinical remission (Crohn’s Disease Activity Index score of <150 points) at week 4.
RESULTS:
A clinical response was observed in 36% (P [ .467), 58% (P [ .466), and 46% (P ‡ .999) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 47% of patients given placebo. Clinical remission was observed in 31% (P [ .417), 24% (P [ .776), and 14% (P [ .540) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 21% of patients given placebo. The 15-mg dose of tofacitinib reduced levels of C-reactive protein and fecal calprotectin from baseline. Adverse and serious adverse events were similar among groups. Dose-dependent increases in low- and high-density lipoprotein cholesterol were observed in patients given the 5- or 15-mg doses of tofacitinib.
CONCLUSIONS:
There were no significant differences in the percentage of patients with moderate-to-severe active Crohn’s disease who achieved clinical responses (Response-70) or clinical remission after 4 weeks’ administration of tofacitinib (1, 5, or 15 mg) or placebo twice daily. However, a large percentage of patients given placebo achieved Response-70 or remission. Reductions in C-reactive protein and fecal calprotectin levels among patients given the 15-mg dose of tofacitinib indicate its biologic activity. ClinicalTrials.gov number: NCT00615199.
Keywords: Tofacitinib; CP-690,550; Crohn’s Disease; Randomized Control Trial.
rohn’s disease is a chronic inflammatory disease of the small intestine and colon characterized by alternating periods of relapse and remission.1 Proven medications for Crohn’s disease include budesonide, corticosteroids, azathioprine, 6-mercaptopurine, methotrexate, and anti–tumor necrosis factor (TNF)a antibodies; not all patients respond to these medications, and serious toxicities are associated with many of them.2 An unmet need exists for novel therapies with alternative mechanisms of action. Tofacitinib is a novel, oral, small-molecule Janus kinase (JAK) inhibitor that is being investigated as a targeted immunomodulator for inflammatory bowel
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disease. It is a highly selective inhibitor of the JAK family of kinases and competes with adenosine triphosphate for binding to the adenosine triphosphate binding site of the kinase domain within JAK enzymes.3,4 In vitro, tofacitinib Abbreviations used in this paper: AE, adverse event; ANC, absolute neutrophil count; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; IBDQ, Inflammatory Bowel Disease Questionnaire; JAK, Janus kinase; LDL, lowdensity lipoprotein; SAE, serious adverse event; TNF, tumor necrosis factor. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.01.029
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preferentially inhibits signaling by receptors associated with JAK3 and JAK1, while showing reduced inhibition for JAK2- and TYK2-associated signaling.4 Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common g-chain–containing receptors for several cytokines, including interleukins 2, 4, 7, 9, 15, and 21, which are integral to lymphocyte activation, proliferation, and function; inhibition of their signaling thus may result in modulation of multiple aspects of the immune response. In addition, inhibition of JAK1 will result in attenuation of signaling by additional proinflammatory cytokines, such as interleukin 6 and interferon-g.4 At higher exposures, inhibition of erythropoietin signaling could occur via inhibition of JAK2 signaling. Many of these pathways have been implicated in the pathogenesis of Crohn’s disease and ulcerative colitis. Tofacitinib has been shown to be beneficial in the treatment of rheumatoid arthritis,5 psoriasis,6 and ulcerative colitis,7 and for the prevention of organ allograft rejection8; the efficacy of tofacitinib for the treatment of Crohn’s disease is unknown. We conducted a 4-week treatment study of tofacitinib in patients with moderate-to-severe active Crohn’s disease.
Methods The study (A3921043, ClinicalTrials.gov NCT00615199) was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines established by the International Conference on Harmonisation. The protocol was approved by the Institutional Review Board at each center. All patients provided written informed consent. The study investigators were responsible for adhering to the study procedures described in the protocol. The study was patient-, investigator-, and sponsorblinded. Electronically generated blinded codes could be broken only in emergency situations for reasons of patient safety. All authors had access to the study data and reviewed and approved the final manuscript.
Patients This 4-week, phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted at 48 centers in 12 countries (Belgium, Czech Republic, France, Hungary, Italy, The Netherlands, Poland, Slovakia, South Africa, Spain, United Kingdom, and United States) between January 9, 2008, and October 29, 2009. Eligible patients, aged 18 years and older, had Crohn’s disease for 3 months or longer, with moderateto-severe disease at baseline defined by a Crohn’s Disease Activity Index (CDAI)9 score of 220 to 450. Confirmation of the diagnosis and extent of disease must have been obtained by endoscopy and/or cross-sectional imaging within 24 months before screening. Exclusion criteria included the following: hemoglobin level less than 9.0 g/dL, hematocrit less than 30%, white
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blood cell count less than 3.0 109/L, absolute neutrophil count (ANC) less than 1.2 109/L, or platelet count less than 100 109/L; estimated glomerular filtration rate less than 50 mL/min; total bilirubin, aspartate aminotransferase, or alanine aminotransferase level greater than 2 the upper limit of normal; a history of symptomatic obstructive strictures or short-bowel syndrome; an ostomy, extensive bowel resection (>100 cm), or bowel surgery within 6 months before baseline; chronic or recurrent infections, including latent or inadequately treated Mycobacterium tuberculosis infection; malignancy or history of malignancy, with the exception of adequately treated or excised nonmetastatic basal cell or squamous cell cancer of the skin, or cervical carcinoma in situ. Patients with a positive stool culture for bacterial pathogens and/or a stool test for Clostridium difficile toxin were excluded. Cytomegalovirus disease was not specifically evaluated and excluded because it would require gastrointestinal tissue sample analysis; endoscopy was not part of the baseline procedure.
Study Design and Treatment The study comprised a screening visit within 3 weeks of baseline, a 4-week double-blind treatment period, and a 4-week follow-up period. Patients completed a daily diary of their symptoms from screening onward, and data from the last week before randomization were used to assess baseline symptoms and calculate the baseline CDAI score. Outpatients were randomized 1:1:1:1 to receive the following: oral tofacitinib 1 mg twice daily, 5 mg twice daily, 15 mg twice daily, or placebo twice daily. These doses for this phase 2 study were selected based on the efficacy and safety results from studies in patients with renal allograft, psoriasis, or rheumatoid arthritis to identify the lowest effective dose while including the maximum proposed therapeutic dose.5,6,8 Patients were stratified according to disease activity at baseline (CDAI score, <330 vs 330 points) and randomized (concealed allocation) into the study. The cut-off value of 330 was chosen as a midpoint of the CDAI score inclusion criteria. The planned total number of 136 patients was based on the assumptions of a 30% clinical response rate (Response-70) for placebo and a difference from placebo of 25% in clinical response rate in 1 or more active doses over placebo. Under these assumptions, there was a greater than 84% probability to have an observed difference in Response-70 greater than 15% and have the lower bound of the 80% two-sided confidence interval (CI) for the difference greater than 0.
Concomitant Medications Patients who previously had not received any treatment for Crohn’s disease were excluded from this study. The following concomitant therapies were prohibited: azathioprine, 6-mercaptopurine, methotrexate
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(within 7 days of baseline); cyclosporine, mycophenolate, tacrolimus (within 4 weeks); interferon, and anti-TNFa therapy (within 8 weeks). The following therapies at stable doses were permitted (but not required): 5-acetylsalicylic acid or sulfasalazine (3 weeks before baseline and during treatment); prednisolone 30 mg or less per day or budesonide 9 mg or less per day (2 weeks before baseline); and chronic treatment with antibiotics and rectally administered corticosteroids or 5-acetylsalicylic acid (2 weeks before baseline and during treatment).
Efficacy and Safety Evaluations The primary efficacy end point was the proportion of clinical responders at week 4, defined as a decrease in CDAI score of 70 or more points from baseline (Response70). At the time of finalizing the design, both Response-70 and Response-100 were used in Crohn’s disease trials. Taking into account the short duration of this trial, a lower hurdle of Response-70 was considered appropriate as a primary end point for this proof-of-concept study. Secondary efficacy end points at week 4 included Response-100, and the clinical remission rate (a reduction in CDAI score to <150 points). Patients who withdrew from the study or who required rescue medications were analyzed as nonresponders. Other parameters measured included improvement in quality of life, as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ)10 (range, 0–224 points; score 170 points indicates clinically inactive disease) at baseline and weeks 4 and 8; improvement (a decrease from baseline in the number of open draining fistulas of 50% for 2 consecutive visits) or remission (closure of all fistulas that were draining at baseline for 2 consecutive visits) of enterocutaneous fistulas measured by the Fistula Drainage Assessment; and a change from baseline in C-reactive protein (CRP) and fecal calprotectin levels at every visit. A colonoscopy for assessment of mucosal healing was not permitted during the trial. The frequency and severity of all adverse events (AEs) were recorded throughout. Blood and urine samples for standard hematology and chemistry assessments, urine samples for urinalysis, and fecal samples for calprotectin were collected at baseline and weeks 1, 2, 4, and 8.
Statistical Analysis The planned primary analysis was to explore the dose-response relationship for Response-70 by fitting a 3-parameter Emax model to the log-odds of the observed rates. A term was included for baseline CDAI score. Estimates of the treatment differences from the fitted response function and associated 80% CIs for each active dose vs placebo were calculated. Results were backtransformed to give point estimates of the difference in proportions and associated 80% CIs. In addition, the observed response rates and the pairwise 2-sided P values
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from the Fisher exact test for comparisons vs placebo also were obtained. Similar methods were planned for Response-100 and clinical remission. No adjustments for multiple comparisons were made because of the exploratory nature of the study. The population for the analyses of efficacy parameters included all randomized patients who had either withdrawn as a treatment failure or had completed 1 or more weeks of dosing and had 1 or more valid CDAI scores during the active double-blind phase. Safety data were summarized descriptively. A post hoc summary was performed to look at the response in patients with different baseline CRP levels, baseline fecal calprotectin levels, prior immunosuppressant use, and prior anti-TNFa use.
Results Patient Disposition and Demographics In total, 236 patients were screened; 139 (58.9%) patients were randomized to receive tofacitinib 1 (n ¼ 36), 5 (n ¼ 34), or 15 mg twice daily (n ¼ 35), or placebo twice daily (n ¼ 34); 126 (90.6%) patients completed the study (Supplementary Figure 1). One patient with a baseline CDAI score of less than 150 from the 5-mg twice-daily group was excluded from all efficacy analyses. Baseline demographic characteristics were similar between groups (Table 1). Steroids (meprednisone, prednisone, prednisolone, or methylprednisolone) were used at baseline by 41.2%, 38.9%, 35.3%, and 34.3% of patients in the placebo and tofacitinib 1-, 5-, and 15-mg twice-daily groups, respectively; the median prednisone equivalent dose was 15.0 mg in the placebo group and 20.0 mg in each of the tofacitinib groups.
Efficacy At week 4, the observed rates for the primary end point of Response-70 were 36.1% (n ¼ 13; P ¼ .467), 57.6% (n ¼ 19; P ¼ .466), and 45.7% (n ¼ 16; P .999) of patients receiving tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 47.1% (n ¼ 16) of placebo patients. The model-predicted Response-70 rates at week 4 were 44.8% (80% CI, 38.2–51.5; P ¼ .667), 48.0% (80% CI, 41.3–54.7; P ¼ .558), and 49.9% (80% CI, 40.7–59.0; P ¼ .527) for patients in the tofacitinib 1-, 5-, and 15-mg twice-daily groups, respectively, vs 42.9% (80% CI, 33.8–52.0) for placebo patients (Figure 1A).
Secondary End Points At week 4, the observed rates for Response-100 were 30.6% (n ¼ 11; P .999), 45.5% (n ¼ 15; P ¼ .212), and 37.1% (n ¼ 13; P ¼ .611) of patients in the tofacitinib 1-, 5-, and 15-mg twice-daily groups, respectively, vs 29.4% (n ¼ 10) of placebo patients (Figure 1B). The model-predicted Response-100 rates at week 4 were
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Table 1. Demographic and Baseline Disease Characteristics Placebo (n ¼ 34) Female, n (%) Age, mean, y (SD) Race, white, n (%) Body weight, mean, kg (SD) Body mass index, mean, kg/m2 (SD) Smoking status, n (%) Never smoked Smoker Ex-smoker Geographic region United States Europe South Africa Duration since first diagnosis, mean, y (range) Disease location, n (%) Ileal Colonic Ileocolonic Upper disease CDAI scorea Mean Median SD CDAI category, n (%) <330 330 CRP level,b mg/L Mean Median SD CRP level 5 mg/mL, n (%) Fecal calprotectin level, mg/kg Mean Median SD Fecal calprotectin level 250 mg/kg, n (%) Open draining enterocutaneous fistulas, n (%) Immunosuppressant use within the previous 12 months, n (%) Patients remaining on immunosuppressant at screening, n (%) Steroid use within the previous 12 months, n (%) Anti-TNFa use within the previous 12 months, n (%)
22 35.7 32 74.8 26.6
(64.7) (12.7) (94.1) (17.8) (7.2)
17 (50.0) 10 (29.4) 7 (20.6) 13 18 3 8.2
(38.2) (52.9) (8.8) (0.1–35.6)
9 (26) 14 (41) 16 (47) 0
Tofacitinib 1 mg BID (n ¼ 36) 11 36.6 34 74.5 24.8
(30.6) (12.2) (94.4) (15.4) (5.1)
19 (52.8) 8 (22.2) 9 (25.0) 15 19 2 11.1 6 20 15 1
(41.7) (52.8) (5.6) (0.1–28.5) (17) (56) (42) (3)
Tofacitinib 5 mg BID (n ¼ 34) 20 38.7 28 70.4 25.0
(58.8) (10.2) (82.4) (20.6) (6.5)
18 (52.9) 11 (32.4) 5 (14.7) 16 16 2 10.9
(47.1) (47.1) (5.9) (0.3–29.3)
3 (9) 18 (53) 11 (32) 0
Tofacitinib 15 mg BID (n ¼ 35) 17 38.1 31 70.1 24.3
(48.6) (11.7) (88.6) (15.7) (5.2)
23 (65.7) 8 (22.9) 4 (11.4) 13 19 3 11.2
(37.1) (54.3) (8.6) (1.5–36.3)
10 (29) 17 (49) 17 (49) 0
306.4 293 62.6
300.3 286 76.7
297.7 293 63.7
308.0 303 50.8
22 (64.7) 12 (35.3)
26 (72.2) 10 (27.8)
22 (64.7) 12 (35.3)
24 (68.6) 11 (31.4)
17.1 8.9 23.1 22 (64.7)
18.3 6.3 28.8 17 (47.2)
17.5 7.2 22.4 19 (57.6)
26.1 11.8 34.9 25 (71.4)
1422 641 2274 19 (55.9) 3 (8.8) 7 (20.6) 0 15 (44.1) 1 (2.9)
1409 438 3386 24 (66.7) 8 (22.2) 8 (22.2) 0 16 (44.4) 4 (11.1)
482 362 453.5 20 (60.6) 5 (15.2) 9 (26.5) 0 14 (41.2) 1 (2.9)
1175 519 1964 20 (57.1) 10 (28.6) 15 (42.9) 2 (5.7) 16 (45.7) 4 (11.4)
BID, twice daily. a The range for the CDAI score is 0 to approximately 600. b The normal range for CRP concentration is 0–3 mg/L.
33.7% (80% CI vs placebo, 26.0–41.4; P ¼ .483), 38.8% (80% CI, 32.1–45.6; P ¼ .250), and 40.8% (80% CI, 32.0–49.6; P ¼ .223) for tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 28.1% (80% CI, 18.7–37.5) for placebo (Figure 1B). Clinical remission at week 4 occurred in 30.6% (n ¼ 11; P ¼ .417), 24.2% (n ¼ 8; P ¼ .776), and 14.3% (n ¼ 5; P ¼ .540) of patients receiving tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 20.6% (n ¼ 7) for placebo. Because of the failure to fit the Emax model, no predicted clinical remission rates from this model were available. CDAI scores decreased in each treatment group; the observed mean change from baseline ( standard
deviation) to week 4 was -63.85 (108.37), -100.28 (96.08), and -67.19 (98.54) for tofacitinib 1, 5, and 15 mg twice daily, respectively, vs -78.38 (105.28) for placebo (Figure 2). At week 8, the mean change was -48.52 (129.73), -64.25 (112.33), and -78.53 (94.45) for tofacitinib 1, 5, and 15 mg twice daily, respectively, and -68.57 (93.59) for placebo. The median (range) changes from baseline to week 4 in total IBDQ score were 18.0 (-35 to 111), 17.0 (-14 to 97), and 18.0 (-38 to 99) for tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 3.1 (-33 to 63) for placebo. The proportion of patients with a 16-point or more reduction in IBDQ score from baseline to week 4 was
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Clinical improvement in fistula drainage was seen in 1 of 4 patients (25.0%) for tofacitinib 5 mg twice daily and in 2 of 9 patients (22.2%) for 15 mg twice daily at week 4. At week 8, 3 of 4 patients (75.0%, 5 mg twice daily) and 3 of 9 patients (33.3%, 15 mg twice daily) showed clinical improvement. No placebo or tofacitinib 1-mg twice-daily patients showed clinical improvement in drainage at weeks 4 or 8. The subgroup summaries performed to look at the responses in patients with different baseline characteristics (CRP level, fecal calprotectin level, prior immunosuppressant use, and prior anti-TNFa use) are shown (Supplementary Table 1). Because of the small number of patients in each group, no obvious conclusion could be made.
Biomarkers
Figure 1. Proportion of patients achieving (A) Response-70 and (B) Response-100 at week 4. P values are observed data vs placebo. P values for Emax modeled data (vs placebo) are as follows: Response-70: 1 mg twice daily, P ¼ .667; 5 mg twice daily, P ¼ .558; and 15 mg twice daily, P ¼ .527; and Response-100: 1 mg twice daily, P ¼ .483; 5 mg twice daily, P ¼ .250; and 15 mg twice daily, P ¼ .223. BID, twice daily.
53.3%, 70.4%, and 54.5% for tofacitinib 1, 5, and 15 mg twice daily, respectively, vs 42.3% for placebo; 36.4%, 39.3%, and 27.3% of tofacitinib patients were complete responders (total IBDQ score 170) at week 4, vs 19.2% in the placebo group.
Dose-related decreases from baseline in mean CRP concentrations were observed for all tofacitinib groups as early as week 1, with some further decreases over time up to week 4 in the 15-mg twice-daily arm. At week 4, the observed mean change from baseline in log-transformed CRP level was -0.93 mg/L (95% CI, -1.53 to -0.33) for tofacitinib 15 mg twice daily and -0.07 mg/L (95% CI, -0.43 to 0.28) for placebo (Figure 3A). For patients with baseline CRP levels of 5 mg/L or higher, mean dose-related decreases in log-transformed CRP levels observed at week 4 were of a slightly larger magnitude: -1.11 mg/L (95% CI, -1.72 to -0.50) for tofacitinib 15 mg twice daily (Figure 3B) and -0.11 mg/L (95% CI, -0.59 to 0.37) for placebo. At week 4, the observed mean change from baseline in log-transformed fecal calprotectin concentration was -0.70 mg/kg (95% CI, -1.11 to -0.29) for tofacitinib 15 mg twice daily and .08 mg/kg (95% CI, -0.38 to 0.55) for placebo (Figure 3C). For patients with a baseline fecal calprotectin concentration of 250 mg/kg or higher, the observed mean change at week 4 from baseline in logtransformed fecal calprotectin level was -1.22 mg/kg (95% CI, -1.69 to -0.75) for tofacitinib 15 mg twice daily and -0.09 mg/kg (95% CI, -0.85 to 0.67) for placebo (Figure 3D).
Safety
Figure 2. Mean change from baseline in CDAI score over time. BID, twice daily; SD, standard deviation.
The overall incidence of AEs and serious AEs (SAEs) was similar across all treatment groups (Table 2). A total of 83 patients experienced 1 or more treatment-emergent AEs, 40 of which were considered by the investigator to be related to study medication. The most commonly reported treatment-emergent AEs were nausea (8.6% of patients), abdominal pain (7.9%), worsening of Crohn’s disease (6.5%), and vomiting (6.5%). Fourteen patients experienced 26 SAEs; the SAEs of 2 patients were considered by the investigator to be treatment-related (worsening of Crohn’s disease in 1 patient in the 1-mg twice-daily group; severe abdominal pain, diarrhea, ileus, chills, and pyrexia in 1 patient in the 5-mg twicedaily group). The most commonly reported SAE was
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Figure 3. Mean change from baseline in log-transformed CRP (mg/L) in (A) all patients and (B) patients with baseline CRP levels of 5 mg/L or greater. Mean change from baseline in log-transformed fecal calprotectin (mg/kg) in (C) all patients, and (D) patients with baseline fecal calprotectin levels of 250 mg/kg or greater. BID, twice daily.
worsening of Crohn’s disease (15.4%). A total of 26 patients reported 31 treatment-emergent infection AEs, the most common of which were nasopharyngitis (4.3%) and urinary tract infection (2.9%). Five infection events were considered to be severe: anal abscess (placebo, 1.4%), pneumonia (placebo, 0.7%), sepsis (placebo, 0.7%), and vulval abscess (5 mg twice daily, 0.7%). Thirteen patients discontinued study participation, 6 owing to AEs: decreased weight (1-mg twice-daily group,
n ¼ 1), subileus (5-mg twice-daily group, n ¼ 1), worsening of Crohn’s disease (15-mg twice-daily group, n ¼ 1), and intestinal obstruction, anal abscess, vomiting and worsening of Crohn’s disease (placebo group, n ¼ 3). One death was reported in a patient receiving placebo who experienced a fatal SAE of ventricular fibrillation as a result of sepsis. Dose-related mean increases from baseline to week 4 in total cholesterol, low-density lipoprotein (LDL)
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Table 2. Summary of Safety Findings Tofacitinib 1 mg BID (n ¼ 36)
Placebo (n ¼ 34) Patients with all-causality TEAE, n (%) Patients with treatment-related TEAEs, n (%) Patients with all-causality SAEs, n (%) Patients with treatment-related SAEs, n (%) Patients with all-causality infection AEs, n (%) Patients who discontinued because of AEs, n (%) Deaths, n (%) Most commonly reported all-causality TEAEs, n (%)a Nausea Abdominal pain Crohn’s disease (worsening of) Vomiting Asthenia Diarrhea Fatigue Headache Pyrexia Insomnia Lipid assays at week 4, mg/dL Total cholesterol Mean change from baseline (SD) Mean at week 4 Median at week 4 LDL cholesterol Mean change from baseline (SD) Mean at week 4 Median at week 4 HDL cholesterol Mean change from baseline (SD) Mean at week 4 Median at week 4 Triglycerides at week 4 Mean change from baseline (SD) Mean at week 4 Median at week 4
Tofacitinib 5 mg BID (n ¼ 34)
22 9 5 0 8 3 1
(64.7) (26.5) (14.7) (2.9) (23.5) (8.8) (2.9)
18 (50.0) 10 (27.8) 4 (11.1) 1 (2.8) 5 (13.9) 1 (2.8) 0
21 10 4 1 8 1
2 4 1 3 3 1 3 1 1 2
(5.9) (11.8) (2.9) (8.8) (8.8) (2.9) (8.8) (2.9) (2.9) (5.9)
4 (11.1) 3 (8.3) 3 (8.3) 2 (5.6) 3 (8.3) 2 (5.6) 4 (11.1) 2 (5.6) 0 2 (5.6)
3 1 3 1 1 2
-3.8 (24.6) 176.6 181.0
-2.1 (20.1) 170.9 166.0
8.7 (25.3) 179.0 177.0
16.5 (29.2) 183.1 183.0
-1.0 (21.0) 96.3 100.0
1.5 (14.3) 90.0 80.5
3.8 (21.6) 92.1 95.5
11.3 (22.2) 89.7 78.0
0.85 (8.1) 52.8 50.5
6.0 (11.1) 59.1 57.9
8.3 (12.4) 57.7 57.0
-18.6 (49.3) 102.7 94.0
15.1 (138.5) 140.8 78.3
-0.1 (59.4) 116.8 100.0
2.6 (12.1) 52.7 51.2 -17.5 (43.8) 134.3 118.4
(61.8) (29.4) (11.8) (2.9) (23.5) (2.9) 0
Tofacitinib 15 mg BID (n ¼ 35)
(8.8) (2.9) (8.8) (2.9) (2.9) (5.9) 0 2 (5.9) 3 (8.8) 0
22 (62.9) 11 (31.4) 1 (2.9) 0 5 (14.3) 1 (2.9) 0 3 3 2 3 1 3 1 3 3 2
(8.6) (8.6) (5.7) (8.6) (2.9) (8.6) (2.9) (8.6) (8.6) (5.7)
BID, twice daily; SD, standard deviation; TEAE, treatment-emergent adverse event. a The 10 most commonly reported all-causality TEAEs are shown, as reported by the Medical Dictionary for Regulatory Activities preferred term (v12.1; McLean, VA).
cholesterol, and high-density lipoprotein (HDL) cholesterol were reported for the tofacitinib 5- and 15-mg twicedaily groups. Triglyceride levels decreased from baseline to week 4 for the placebo and the tofacitinib 1-mg twicedaily groups by -17.5 and -18.6 mg/dL, respectively, increased in the 5-mg twice-daily group by 15.1 mg/dL, and remained relatively unchanged in the 15-mg twicedaily group (-0.1 mg/dL) (Table 2). No clinically significant changes from baseline to week 4 in other laboratory tests, including liver and renal function tests and hematology parameters, were reported. No patients had an ANC less than 1.0 109/L at any time during treatment.
Discussion In this 4-week, phase 2 trial in patients with moderateto-severe active Crohn’s disease, a proportion of whom
had failed conventional therapy, tofacitinib did not show efficacy in the induction of a clinical response, as measured by Response-70/-100 or clinical remission rates; however, placebo response and remission rates were greater than expected. Tofacitinib 15 mg twice daily reduced CRP and fecal calprotectin concentrations, and numeric improvements from baseline in IBDQ score were observed in all groups. No statistical comparisons were made. The observed screening failure rate was 41%. This was a relatively high screen failure rate for a trial in which patients were not screened for objective markers of inflammation. The selection of an early (4-week) end point was expected to result in low placebo response rates11; however, the week 4 placebo response was higher than expected, and much higher than that observed in previous studies of anti-TNFa.12–15 One possible explanation for the high placebo response was an inadvertent
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selection bias toward the enrollment of patients with a more benign natural history. A number of factors could have contributed toward this selection bias, including the fact that the study was placebo-controlled, only 4 weeks’ duration, without an extension phase in which patients could receive open-label tofacitinib therapy, as well as the requirement to discontinue azathioprine, 6-mercaptopurine, and methotrexate before the start of the study. Only 21% of placebo patients previously had received azathioprine or 6-mercaptopurine, 44% were receiving corticosteroids, and only 2% previously failed anti-TNFa therapy. At baseline, 65% of placebo patients had increased CRP concentrations (5 mg/L), and 56% had increased fecal calprotectin concentrations (250 mg/kg). A recently reported 6-week induction trial of certolizumab pegol in Crohn’s disease failed to show efficacy in an anti-TNFa–naive patient population, in which approximately 40% of patients did not have CRP increases at baseline.16 The week 6 remission rate in the placebo arm of this study also was unexpectedly high.16 The currently ongoing tofacitinib Crohn’s disease study requires a demonstration of the presence of terminal ileal or colonic ulcers by endoscopy as an inclusion criterion and a long-term treatment option also is available. It is unclear whether the failure of tofacitinib to show induction efficacy for Crohn’s disease was owing to the high placebo response rate discussed previously or whether it was a true negative result. A likely biologic effect of tofacitinib 15 mg twice daily, as measured by reductions from baseline CRP and fecal calprotectin concentrations, was observed in this study. A phase 2b induction trial (NCT01393626) of tofacitinib in Crohn’s disease is underway to address this issue. Confirmation of the diagnosis in the present study was based on a visualization of the gastrointestinal tract by radiology, scintigraphy, or endoscopy within 24 months before screening. The lack of histologic confirmation of the diagnosis was a limitation of this study. Although it is possible that some patients were misdiagnosed, taking into account that patients were diagnosed with Crohn’s disease for a mean period of 8 to 11 years, it is unlikely that this had a significant effect on study results. An 8-week phase 2 trial of tofacitinib in patients with moderate-to-severe ulcerative colitis7 also was conducted; tofacitinib (10 and 15 mg twice daily) was more effective in the induction of clinical response, clinical remission, and mucosal healing, as well as the reduction of CRP and fecal calprotectin concentrations, vs placebo. Whether the failure of tofacitinib to show clinical efficacy in Crohn’s disease represents a real difference from the efficacy seen in ulcerative colitis remains unclear. If this is indeed the case, then additional mechanistic studies to determine the reasons for this difference would be warranted. The short duration of the trial and small sample size did not allow for a comprehensive evaluation of the safety and tolerability of tofacitinib in Crohn’s disease. In rheumatoid arthritis, tofacitinib has been associated with mean increases in serum creatinine, LDL and HDL
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cholesterol, and mean decreases in ANC.5 Serious infections and malignancies including lymphomas also have been observed.5,8 The clinical importance of these laboratory abnormalities require further evaluation. In this study, we observed a dose-dependent increase in LDL and HDL cholesterol. A dose-dependent treatment effect on lipid levels vs placebo is consistent with that seen in rheumatoid arthritis trials. We observed no difference between active treatment and placebo as measured by clinical end points; thus, changes in lipids as a predictor of efficacy was not tested. In clinical trials with tofacitinib in which efficacy was observed, no relationship with changes in lipid profiles has been shown.
Conclusions In conclusion, patients with moderate-to-severe active Crohn’s disease treated with tofacitinib were not more likely to achieve clinical response or clinical remission vs those receiving placebo; however, the placebo response and remission rates were unexpectedly high. The reductions in CRP and fecal calprotectin values in the tofacitinib 15-mg twice-daily group suggest biologic activity. Further studies are needed to determine whether tofacitinib is effective for the treatment of Crohn’s disease.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2014.01.029.
References 1. Baumgart D, Sandborn WJ. Crohn’s disease. Lancet 2012; 380:1590–1605. 2. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130:940–987. 3. Karaman MW, Herrgard S, Treiber DK, et al. A qualitive analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26:127–132. 4. Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP690,550, in rat adjuvant-induced arthritis. J Inflamm 2010;7:41. 5. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012;367:495–507. 6. Papp K, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol 2012;167:668–677. 7. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012; 367:616–624. 8. Vincenti F, Tedesco SH, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant
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2014 patients: efficacy, renal function and safety at 1 year. Am J Transplant 2012;12:2446–2456.
9. Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70:439–444. 10. Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology 1994;106:287–296. 11. Su C, Lichtenstein GR, Krok K, et al. A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn’s disease. Gastroenterology 2004;126:1257–1269. 12. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029–1035. 13. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human antitumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006; 130:323–333. 14. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007; 357:228–238. 15. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829–838. 16. Sandborn WJ, Schreiber S, Feagan BG, et al. Certolizumab pegol for active Crohn’s disease: a placebo-controlled, randomized trial. Clin Gastroenterol Hepatol 2011;9:670–678.
Reprint requests Address requests for reprints to: William J. Sandborn, MD, Division of Gastroenterology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0956. e-mail: [email protected]; fax: (858) 657-5022. Acknowledgements The authors would like to thank the patients who were involved in this study, and the A3921043 investigators and study team. Conflicts of interest The authors disclose the following: William Sandborn has received consulting fees from Abbott, ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corp, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys, Inc, Atlantic Healthcare, Ltd, Aptalis, BioBalance Corp, BoehringerIngelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen, Diagnostics, Inc, Ferring Pharmaceuticals, Flexio Therapeutics, Inc, Funxional Therapeutics, Ltd, Genzyme Corp, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, Janssen Pharmaceutical Research & Development, LLC, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millennium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer Inc, Procter and Gamble, Prometheus Laboratories, ProtAb, Ltd, Purgenesis Technologies, Inc, Relypsa, Inc,
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Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma, Ltd, Sirtris Pharmaceuticals, SLA Pharma UK, Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tilliotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics, Ltd, Warner Chilcott UK, Ltd, and Wyeth; has received research grants from Abbott, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen Pharmaceutical Research & Development, LLC, Millennium Pharmaceuticals, Novartis, Pfizer Inc, Procter and Gamble, Shire Pharmaceuticals, and UCB Pharma; has received payments for lectures and speakers bureau fees from Abbott, Bristol-Myers Squibb, and Janssen Pharmaceutical Research & Development, LLC; and holds stock/stock options in Enteromedics. Subrata Ghosh has received consulting fees from Abbott, Pfizer Inc, Merck, Shire, Centocor, and BMS; has received research grants from Merck and Abbott; has received payment for lectures from Abbott, Merck, Shire, Millennium, Centocor, and Ferring; and has received payment for the development of an educational presentation from Abbott. Julian Panes has received speaker fees from AbbVie, MSD, Shire Pharmaceuticals, and UCB; has acted as a scientific consultant for AbbVie, Bristol-Myers Squibb, Ferring, MSD, Novartis, Pfizer Inc, Shire Pharmaceuticals, Tygenics, and UCB; and has received research grants from AbbVie and MSD. Ivana Vranic, Wenjin Wang, and Wojciech Niezychowski are employees of, and hold stock/stock options in, Pfizer Inc. Funding This study was sponsored by Pfizer Inc. Editorial support was provided by Karen Irving at Complete Medical Communications, funded by Pfizer Inc.
Appendix 1 The following investigators participated in this study: Europe: Professor Severine A. R. A. Vermeire, Dr Olivier Dewit, Dr Harald Peeters, Dr Jiri Stehlik, Dr Tomas Vanasek, Dr David Laharie, Professor Jean Frederic Colombel, Professor Marc-André Bigard, Dr Marta Varga, Professor Margit Zeher, Dr Janos Novak, Professor Bela Hunyady, Dr Agnes Salamon, Professor Istvan Racz, Professor Paolo Gionchetti, Dr Anna Kohn, Professor Cosimo Prantera, Dr P. C. F. Stokkers, Professor Maria Slomka, Professor Leszek Paradowski, Dr Tomasz Arlukowicz, Dr Ladislav Kuzela, Dr Boris Baricky, Dr Tibor Hlavaty, Dr Maria Isabel Vera, Dr Julian Panes, Dr Jordi Guardiola, Professor Christopher Probert, and Dr Jonathan Lionel Shaffer; United States: Dr Mark Fleisher, Dr Ronald Edward Pruitt, Dr William J. Sandborn, Dr John Sawyer Goff, Dr John Weber, Dr Raymond Lloyd Bell, Dr Andrew Harrison Zwick, Dr Alexandra Gutierrez, Dr Robert H. Levine, Dr Stephen Brett Hanauer, Dr Lori Ann Lavelle, Dr Ravindranath K. Kottoor, Dr Gerald Wayne Dryden Jr, Dr Robert Hardi, Dr David Vaughn Glorioso, Dr Prabhakar Swaroop, Dr Scott D. Lee, Dr Teressa Joan Patrick, Dr Sheldon Scheinert, Dr Charles A. Sninsky, Dr Seymour Katz, Dr Mark D. Noar, Dr Michael Marion Gaspari, Dr Glenn L. Gordon, Dr Thomas A. Dalton, Dr Douglas Edward Homoky, Dr William Ransom Kilgore III, and Dr Joel A. Levien; and South Africa: Dr Herbert R. Schneider, Dr Suleman Abdul Moola, Dr Frederik Cornelius Kruger, Dr John P. Wright, and Dr Nazimuddin Aboo.
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Supplementary Table 1. Post Hoc Subgroup Analysis: Response-70, Response-100, and Remission Rates at Week 4
Response-70, % (n/N) Baseline CRP level, mg/mL <5 5 Baseline fecal calprotectin level, mg/kg <250 250 Prior immunosuppressant use Yes No Prior anti-TNFa use Yes No Response-100, % (n/N) Baseline CRP level, mg/mL <5 5 Baseline fecal calprotectin level, mg/kg <250 250 Prior immunosuppressant use Yes No Prior anti-TNFa use Yes No Remission, % (n/N) Baseline CRP level, mg/mL <5 5 Baseline fecal calprotectin level, mg/kg <250 250 Prior immunosuppressant use Yes No Prior anti-TNFa use Yes No
Placebo
Tofacitinib 1 mg BID
Tofacitinib 5 mg BID
Tofacitinib 15 mg BID
44.4 (4/9) 45.5 (10/22)
35.7 (5/14) 41.2 (7/17)
66.7 (6/9) 52.6 (10/19)
50.0 (3/6) 48.0 (12/25)
33.3 (4/12) 63.2 (12/19)
37.5 (3/8) 41.7 (10/24)
33.3 (4/12) 75.0 (15/20)
15.4 (2/13) 70.0 (14/20)
28.6 (2/7) 51.9 (14/27)
25.0 (2/8) 39.3 (11/28)
44.4 (4/9) 62.5 (15/24)
60.0 (9/15) 31.6 (6/19)
0 (0/1) 48.5 (16/33)
25.0 (1/4) 37.5 (12/32)
0 (0/1) 59.4 (19/32)
50.0 (2/4) 43.3 (13/30)
44.4 (4/9) 27.3 (6/22)
35.7 (5/14) 29.4 (5/17)
44.4 (4/9) 42.1 (8/19)
50.0 (3/6) 36.0 (9/25)
8.3 (1/12) 47.4 (9/19)
25.0 (2/8) 37.5 (9/24)
25.0 (3/12) 60.0 (12/20)
0 (0/7) 37.0 (10/27)
12.5 (1/8) 35.7 (10/28)
44.4 (4/9) 45.8 (11/24)
53.3 (8/15) 26.3 (5/19)
0 (0/1) 30.3 (10/33)
0 (0/4) 34.4 (11/32)
0 (0/1) 46.9 (15/32)
50.0 (2/4) 36.7 (11/30)
33.3 (3/9) 13.6 (3/22)
35.7 (5/14) 29.4 (5/17)
33.3 (3/9) 21.1 (4/19)
16.7 (1/6) 16.0 (4/25)
16.7 (2/12) 26.3 (5/19)
37.5 (3/8) 33.3 (8/24)
33.3 (4/12) 20.0 (4/20)
7.7 (1/13) 20.0 (4/20)
0 (0/7) 25.9 (7/27)
25.0 (2/8) 32.1 (9/28)
33.3 (3/9) 20.8 (5/24)
20.0 (3/15) 10.5 (2/19)
0 (0/1) 21.2 (7/33)
25.0 (1/4) 31.3 (10/32)
0 (0/1) 25.0 (8/32)
25.0 (1/4) 13.3 (4/30)
7.7 (1/13) 60 (12/20)
-
2014
Trial of Tofacitinib for Crohn’s Disease
Supplementary Figure 1. Patient disposition and treatment through week 8.
9.e2