Beyond Infliximab: Other Anti-TNF Therapies for Ulcerative Colitis

Clinical trials

ACT1/ACT2

ULTRA1/ULTRA2

PURSUIT-SC

Placebo (n = 121/123)

IFX 5 mg/kg (n = 121/121)

IFX 10 mg/kg (n = 122/120)

Placebo (n = 130/246)

ADA 80/40 (n = 130/–)

ADA 160/80 (n = 130/248)

Placebo (n = 331)

GLM 100/50 (n = 72)

GLM 200/100 (n = 331)

GLM 400/200 (n = 331)

Study design

ACT1: moderate-to-severe active UC despite concurrent CS alone or CS + AZA/6-MP; randomized to placebo or IFX (5 or 10 mg/kg) at week 0, 2, and 6 then every 8 week through week 46

ACT2: moderate-to-severe active UC despite concurrent CS alone or CS + AZA/6-MP and 5-ASA; randomized to placebo or IFX (5 or 10 mg/kg) at week 0, 2, and 6 then every 8 week through week 22

ULTRA1: moderate-to-severe active UC despite CS and/or AZA/6-MP; anti-TNF naïve; randomized to placebo or ADA (80/40: 80 mg at week 0, 40 mg at week 2, 4 and 6; 160/80: 160 mg at week 0, 80 mg at week 2, 40 mg at week 4 and 6) through week 8

ULTRA2: moderate-to-severe active UC with concurrent CS and/or AZA/MP; 40 % had previous treatment of anti-TNF; randomized to placebo or ADA (160 mg at week 0, 80 mg at week 2, 40 mg every other week) through week 52

Pursuit-SC induction: moderate-to-severe active UC despite CS and/or AZA/6-MP, or CS dependent; anti-TNF naïve; randomized to placebo or GLM (100/50: 100 mg at week 0, 50 mg at week 2; 200/100: 200 mg at week 0, 100 mg at week 2; 400/200: 400 mg at week 0, 200 mg at week2) through week 6

Pursuit-SC maintenance: patients who responded to induction therapy with GLM were randomized to placebo, GLM 50 mg, GLM 100 mg every 4 weeks through week 52

Clinical response

Week 8^a

37.2 %/29.3 %

69.4 %/64.5 %

61.5 %/69.2 %

44.6 %/34.6 %

52.5 %/–

54.6 %/50.4 %

29.7 %

–

51.8 %

55.0 %

Week 54^b

19.8 %/–

45.5 %/–

44.3 %/–

–/18.3 %

–/–

–/30.2 %

31 %

47 %

51 %

–

Clinical remission

Week 8^a

14.9 %/5.7 %

38.8 %/33.9 %

32.0 %/27.5 %

9.2 %/9.3 %

10.0 %/–

18.5 %/16.5 %

6.3 %

–

18.7 %

17.8 %

Week 54^b

16.5 %/–

34.7 %/–

34.4 %/–

–/8.5 %

–/–

–/17.3 %

15 %

24 %

29 %

–

Mucosal healing

Week 8^a

33.9 %/30.9 %

62.0 %/60.3 %

59.0 %/61.7 %

41.5 %/31.7 %

37.7 %/–

46.9 %/41.1 %

28.5 %

–

43.2 %

45.3 %

Week 54^b

18.2 %/–

45.5 %/–

46.7 %/–

–/15.4 %

–/–

–/25 %

27 %

42 %

44 %

–

Adverse event

Any AE (%)

103 (85.1)/90 (73.2)

106 (87.6)/99 (81.8)

111 (91.0)/96 (80.0)

108 (48.4)/218 (83.8)

70 (53.8)/–

112 (50.2)/213 (82.9)

126 (38.3 %)/103 (66.0 %)

34 (47.9 %)/112 (72.7 %)

124 (37.5 %)/113 (73.4)

129 (38.9 %)/–

Any serious AE (%)

31 (25.6)/24 (19.5)

26 (21.5)/13 (10.7)

29 (23.8)/11 (9.2)

17 (7.6)/32 (12.3)

5 (3.8 %)/–

9 (4.0 %)/31 (12.1)

20 (6.1 %)/12 (7.7 %)

2 (2.8 %)/13 (8.4 %)

9 (2.7 %)/22 (14.3 %)

5 (1.5 %)/–

Serious infection (%)

5 (4.1)/1 (0.8)

3 (2.5)/2 (1.7)

8 (6.6)/3 (2.5)

3 (1.3)/5 (1.9)

2 (1.5)/–

0 (0)/4 (1.6)

6 (1.8 %)/3 (1.9 %)

0 (0.0 %)/5 (3.2 %)

1 (0.3 %)/5 (3.2 %)

3 (0.9 %)/–

Malignancies (%)

0 (0)/1 (0.3)

2 (0.6)/1 (0.3)

1 (0.3)/0 (0)

2 (0.9)/0 (0)

0 (0)/–

0 (0)/2 (0.8)

–/1 (0.4 %)

–/0 (0 %)

–/1 (0.3 %)

–/–

^aWeek 6 for PURSUIT-SC induction trial

^bWeek 52 for ULTRA1/2 trials; CS corticosteroids, AZA azathioprine, 6-MP 6-mercaptopurine

ADA treatment was generally well tolerated and the overall safety profile was comparable with placebo. Malignancies occurred in two ADA-treated patients (one skin squamous cell carcinoma and one gastric cancer) compared to none in the placebo group. There was no significant difference in serious adverse events between the ADA- (12.3 %) and placebo-treated (12.1 %) groups. Greater proportions of reported injection site reactions (12.1 % in ADA group vs. 3.8 % in placebo group, p <0.001) and hematological-related adverse events (1.9 % in ADA group vs. 0 % in placebo group, p = 0.03) were observed in ADA-treated patients. The development of antibodies to ADA was detected in 2.9 % (7 of 245) of patients in the ADA 160/80 treatment group; all seven patients had received ADA monotherapy. Similar to reports with other anti-TNF antibodies, the development of anti-ADA antibodies was lower in patients receiving combination therapy with ADA and an immunosuppressive agent [25]. Serum trough ADA concentrations for remitters were numerically higher than those for non-remitters throughout the duration of the study. This correlation is consistent with observations in other studies [26].

Of note, in the ULTRA2 trial, greater proportions of ADA-treated patients achieved almost all secondary endpoints at week 8 (clinical response, mucosal healing, physician global assessment, rectal bleeding subscore, corticosteroid-free remission, IBDQ score). This is in contrast to the ULTRA1 trial in which only rectal bleeding and physician global assessment subscores were significantly better in ADA-treated patients. This discrepancy might be due to the relatively high placebo response rates observed in ULTRA1 as noted above. In summary, evidence from these trials demonstrates that ADA is effective in inducing and maintaining clinical remission and clinical response in patients with moderate to severe UC failing conventional treatment with corticosteroids and/or immunomodulators.

Golimumab (SIMPONI) for UC

Golimumab (GLM) is a human IgG1κ monoclonal antibody specific for human TNF-α which was genetically engineered using mice immunized with human TNF. It was approved by the FDA in May 2013 for the induction and maintenance of clinical response and remission in UC as well as for improving endoscopic mucosal appearance during induction therapy. The approved dosing is induction with a 200 mg subcutaneous injection at week 0 followed by a 100 mg injection at week 2 and then maintenance therapy dosed at 100 mg every 4 weeks.

A combined phase 2 and phase 3 placebo-controlled randomized trial [27] called the “PURSUIT-SC” trial was conducted to assess the dosing and dose-response relationship of GLM and to evaluate the safety and efficacy of GLM induction therapy in patients with moderate to severe UC. Patients included in this study had active UC with failure to respond to or inability to tolerate treatment with oral mesalamine, oral corticosteroids, 6-mercaptopurine, and/or azathioprine, or were corticosteroid dependent; all patients were naïve to anti-TNF therapy. In the phase 2 portion of the study, 169 patients were randomized and an additional 122 patients were enrolled while the phase 2 data were analyzed. Based on findings of a trend to a dose-response relationship and a correlation between higher GLM serum concentrations and clinical response parameters, the phase 3 portion of this study randomized 774 patients to treatment at weeks 0 and 2 with placebo (n = 258), GLM 200/100 (n = 258, 200 mg at week 0 and 100 mg at week 2), or GLM 400/200 (n = 258, 400 mg at week 0 and 200 mg at week 2). The primary endpoint was clinical response at week 6, defined as a decrease in Mayo score of both ≥30 % and ≥3 points along with an improvement in the rectal bleeding subscore. Secondary endpoints included clinical remission, mucosal healing, and change from baseline IBDQ. At week 6, patients who received GLM did significantly better than placebo-treated patients in terms of clinical response rates (51.8 % in GLM 200/100 and 55.0 % in GLM 400/200 vs. 29.7 % in placebo; p <0.0001 for both GLM group comparisons to placebo), clinical remission rates (18.7 % in GLM 200/100 and 17.8 % in GLM 400/200 vs. 6.3 % in placebo, p <0.0001 for both GLM group comparisons to placebo), mucosal healing rates (43.2 % in GLM 200/100 vs. 28.5 % in placebo, p = 0.0005; 45.3 % in GLM 400/200 vs. 28.5 % in placebo, p <0.0001), and improvement in IBDQ scores from baseline (27.4 points in GLM 200/100 and 27.0 points in GLM 400/200 vs. 14.6 points in placebo; p <0.0001 for both GLM group comparisons to placebo). Similar to the phase 2 findings, there was a correlation between higher serum GLM concentrations and clinical response parameters.

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