Ustekinumab Is Effective and Safe for Ulcerative Colitis Through 2 Years of Maintenance Therapy

Remo Panaccione; Silvio Danese; William J. Sandborn; Christopher D. O'Brien; Yiying Zhou; Hongyan Zhang; Omoniyi J. Adedokun; Ilia Tikhonov; Stephan Targan; Maria T. Abreu; Tadakazu Hisamatsu; Ellen J. Scherl; Rupert W. Leong; David S. Rowbotham; Ramesh P. Arasaradnam; Bruce E. Sands; Colleen Marano

Disclosures

Aliment Pharmacol Ther. 2020;52(11-12):1658-1675. 

In This Article

Results

Patient Demographics and Disease Characteristics

A total of 588 patients who completed safety and efficacy evaluations at Week 44 and, in the opinion of the investigator, would benefit from continued treatment were treated in the long-term extension. Among these, 399 patients were from the maintenance randomised population and 189 patients were from the non-randomised population (Figure 1A,B, respectively).

Demographics, UC medication history, concomitant UC medication and UC disease characteristics among patients who were treated in the long-term extension are summarised in Table 2. Among randomised patients, 58.1% were male, 74.4% were white, and the mean age was 40.9 years (Table 2). At Week 44 of maintenance, measures of UC disease activity (eg Mayo scores) were generally comparable among patients randomised to ustekinumab q12w and q8w (Table S1), with 46.1% and 52.4% in clinical remission and 56.7% and 61.5% with endoscopic improvement respectively. Among Week 16 ustekinumab induction responders treated in the long-term extension, measures of disease activity indicated benefit from ustekinumab maintenance therapy; across measures these patients tended to have somewhat higher disease activity and inflammatory burden at Week 44 of maintenance accompanied by lower rates of clinical remission (38.8%) and endoscopic improvement (47.4%) relative to those patients in response 8 weeks after a single induction dose of IV ustekinumab and randomised to ustekinumab q8w (Table S1).

Of the patients randomised in maintenance who were treated in the long-term extension, 55.9% (223/399) had no history of biologic failure of whom 95.1% (212/223) were biologic naïve and 4.9% (11/223) were biologic experienced without documentation of failure (Table 2). Among 44.1% (176/399) patients with a history of biologic failure, 99.4% (175/176) failed ≥1 TNF antagonist (regardless of vedolizumab) and 26.7% (47/176) failed both vedolizumab and a TNF antagonist at induction baseline (Table 2).

Among all patients receiving ustekinumab during the long-term extension, 338/399 (84.7%) of randomised patients and 112/120 (93.3%) of non-randomised ustekinumab induction Week 16 responders completed study participation through Week 96. Through Week 96, the placebo group (ie ustekinumab IV induction responders randomised to placebo SC maintenance therapy) had 12 fewer weeks of follow-up on average (37.1 weeks) as compared to the combined ustekinumab groups (49.1 weeks), which is primarily attributed to the protocol-specified discontinuation of placebo-treated patients at the time of study unblinding. The proportions of patients from the randomised and non-randomised populations who discontinued ustekinumab prior to Week 96 were 8.5% (24 patients) and 4.3% (5 patients) respectively (Table 3).

Of 399 randomised patients who entered the long-term extension, 43.5% (50/115), 46.8% (66/141) and 46.9% (67/143) of placebo, and ustekinumab q12w, and q8w groups, respectively completed Week 96 assessments before study unblinding.

Efficacy

Because 95.1% of the biologic non-failure population was comprised of biologic naïve patients, only results for subgroups of patients who were biologic naïve and those with a history of biologic failure are presented for each analysis population.

All Patients Randomised to Maintenance Treatment at Week 0 (Intent-to-treat Population): Non-responder Imputation Analysis. Symptomatic remission rates were generally sustained through Week 92 among patients who initially responded to ustekinumab induction and were randomised to ustekinumab maintenance (Figure 2A). At Week 44, 62.2% of patients randomised to 90 mg q12w and 67.6% of patients randomised to 90 mg q8w were in symptomatic remission. At Week 92, 64.5% and 67.6% of randomised patients, respectively, were in symptomatic remission. Proportions of patients in symptomatic remission were also sustained in biologic naïve patients (70.5% and 73.4% at Week 92 respectively) and in those with a history of biologic failure (55.7% and 61.5% at Week 92 respectively) (Figure 2B). Figure S1 summarises proportions of patients in symptomatic remission over time when dose adjustment was considered a treatment failure.

Figure 2.

Non-responder imputation analysis of all patients randomised in maintenance study (intent-to-treat population) for symptomatic remission†,‡,§,¶,††,‡‡ through Week 92 (A) and by biologic treatment history subgroup (B)

As steroids were tapered per protocol, proportions of patients achieving corticosteroid-free symptomatic remission increased during the maintenance study and were 61.6% and 65.9% at Week 92 for patients randomised to ustekinumab 90 mg q12w and q8w respectively (Figure 3).

Figure 3.

Non-responder imputation analysis of corticosteroid-free symptomatic remission through Week 92†,‡,§,¶,††,‡‡ for all patients randomized to ustekinumab in the maintenance study (intent-to-treat population)

Randomised Patients Treated in the Long-term Extension: Non-responder Imputation Analysis. Proportions of patients in symptomatic remission were generally sustained through Week 92 (Figure 4A). At Week 44, 83.0% of patients in the q12w group and 83.2% of patients in the q8w group were in symptomatic remission. At Week 92, 78.7% and 83.2%, respectively, were in symptomatic remission. Proportions of patients in symptomatic remission were also sustained in biologic naïve patients (81.7% and 86.6% at Week 92 respectively) and in those with a history of biologic failure (73.6% and 78.9% at Week 92, respectively; Figure 4B). Figure S2 summarises the proportions of patients who were in symptomatic remission from Week 44 through Week 92 when dose adjustment was considered a treatment failure.

Figure 4.

Non-responder imputation analysis of symptomatic remission†,‡,§,¶ from Week 44 through Week 92 for all patients randomised to ustekinumab in the maintenance study and treated in the long-term extension (A) and by biologic treatment history subgroup (B)

The proportions of patients from the ustekinumab q12w and q8w groups who had achieved symptomatic clinical remission at Week 44 were 83.0% and 83.2% respectively. Among these patients, 72.6% and 70.6%, respectively, maintained symptomatic remission at Week 92.

Maintenance baseline median partial Mayo scores (2.0 in the ustekinumab q12w and q8w groups) were generally maintained from Week 44 (median change, −1.0 and −1.0 in the ustekinumab q12w and q8w groups respectively) through Week 92 (median change, 0.0 and −1.0 in the ustekinumab q12w and q8w groups respectively).

Greater than 95% of patients who were in symptomatic remission at Week 92 were corticosteroid free (Figure 5).

Figure 5.

Non-responder imputation analysis of symptomatic remission and corticosteroid-free symptomatic remission†,‡,§,¶ at Week 92; patients randomised to ustekinumab in the maintenance study and treated in the long-term extension

The mean daily prednisone-equivalent (P.Eq.) corticosteroid dose (excluding budesonide and beclomethasone dipropionate) among patients receiving corticosteroids at maintenance baseline was 15.4 mg/day in both ustekinumab groups. At Week 44, the mean daily doses in the ustekinumab q12w and q8w groups were 1.2 mg/day and 1.7 mg/day respectively. Reductions observed by Week 44 were generally maintained through Week 92 (Figure S3). Among patients receiving corticosteroids at maintenance baseline (including budesonide and beclomethasone dipropionate), 91.2% (62/68) and 94.4% (67/71) in the ustekinumab q12w and q8w groups, respectively, were not receiving corticosteroids at Week 92 on the basis of the non-responder imputation analysis with dose adjustment as a treatment failure.

C Reactive Protein and Faecal Calprotectin: At maintenance baseline, median CRP concentrations were 1.5 and 1.8 mg/L in the ustekinumab q12w and q8w groups respectively. Over time through Week 92, the median CRP concentrations at Week 44 were generally maintained (mean change 0.1 and 0.0 mg/L for the q12w and q8w groups, respectively; Figure S4).

At maintenance baseline, median faecal calprotectin concentrations were 431.0 and 450.5 mg/kg in the ustekinumab q12w and q8w groups respectively. Through Week 92, median faecal calprotectin concentrations observed at Week 44 were generally maintained (Figure S5).

Dose Adjustment of Patients Randomised to Ustekinumab and Treated in the Long-term Extension: Patients randomised to ustekinumab maintenance who in the opinion of the investigator had a worsening of disease activity during the long-term extension could receive a dose adjustment after Week 56 as follows: ustekinumab q12w → ustekinumab q8w (n = 40) and ustekinumab q8w → ustekinumab q8w (sham dose adjustment; n = 37). Of these, 20 and 28 patients, respectively, had ≥16 weeks of follow-up. The majority of these patients were in symptomatic remission at the time of dose adjustment, 55.0% (11/20 patients) and 64.3% (18/28 patients) respectively (Table S2). The proportion of patients in symptomatic remission ≥16 weeks after dose adjustment was 70.0% (14/20 patients) and 71.4% (20/28 patients) respectively. Among patients who were not in symptomatic remission at the time of dose adjustment, 44.4% (4/9 patients) and 60.0% (6/10 patients), respectively, were in symptomatic remission after dose adjustment. Among biologic naïve patients and those with a history of biologic failure, ≥70% of patients were in symptomatic remission after dose adjustment. Partial Mayo scores, and CRP and faecal calprotectin concentrations generally improved among patients who received dose adjustment although the sample sizes were limited (Table S2).

Randomised Patients Treated in the Long-term Extension: Observed Case Analysis: Among randomised patients with data at Week 44, 83.0% and 83.9% of patients in the ustekinumab q12w and q8w groups, respectively, were in symptomatic remission. Over time, proportions of patients in symptomatic remission were sustained from Week 44 through Week 92 in both ustekinumab groups and were 86.0% and 88.9% in the ustekinumab q12w and q8w groups at Week 92 respectively (Figure S6A).

Proportions of patients in symptomatic remission were sustained from Week 44 through Week 92 in the ustekinumab q12w and q8w groups at similar rates using modified observed case analysis (Figure S7A).

In the biologic treatment history subgroups, proportions of patients in symptomatic remission were sustained from Week 44 through Week 92 in both ustekinumab groups in biologic naïve patients and patients with a history of biologic failure for the observed case and modified observed case analyses (Figures S6B and S7B respectively).

Non-randomised Patients: Non-responder Imputation Analysis. Week-16 Ustekinumab Induction Responders: Patients who received ustekinumab IV induction, who were not in clinical response 8 weeks later, received a single dose of SC ustekinumab 90 mg at induction Week 8, and were in clinical response 8 weeks later (induction Week 16) were identified as Week 16 responders and continued to receive 90 mg ustekinumab q8w through the maintenance study and long-term extension (Figure 1B). Among all ustekinumab Week 16 responders (n = 157) enrolled at maintenance Week 0, the proportions of patients in symptomatic remission were sustained from Weeks 44 through Week 92, with 58.6% in symptomatic remission at Week 92. Of ustekinumab Week 16 responders treated in the long-term extension (n = 116), the proportions of patients in symptomatic remission were sustained from Week 44 through Week 92 with 79.3% in symptomatic remission at Week 92.

Treatment Interruption After Ustekinumab IV Induction: Patients who were ustekinumab IV induction responders, re-randomised to SC placebo at maintenance baseline, and treated with placebo during the long-term extension were eligible for dose adjustment to ustekinumab 90 mg q8w after Week 56 if according to the investigator's judgement they had worsening disease (Figure 1B). Among placebo-treated patients, 46.1% (53/115) (Figure 1A) had a dose adjustment to ustekinumab q8w, and 42 patients had data ≥16 weeks after dose adjustment (Table S3). Overall, 71.4% (30/42 patients) were in symptomatic remission at the first visit ≥16 weeks after dose adjustment, including 82.4% (14/17 patients) and 64.0% (16/25 patients) with and without symptomatic remission at the time of dose adjustment respectively. Mean partial Mayo score (3.2, 1.5), and median CRP (3.6 mg/L, 2.0 mg/L) and median faecal calprotectin (1016.5 mg/kg, 355.0 mg/kg) concentrations at the time of treatment interruption improved ≥16 weeks after treatment re-introduction respectively (Table S3).

Pharmacokinetics and Immunogenicity. Randomised patients who continued receiving either the ustekinumab q12w or q8w dose regimen in the long-term extension had sustained and consistent levels of ustekinumab through Week 92 of the long-term extension that were generally comparable with serum ustekinumab levels observed during the maintenance phase of the study (Table S4).

Between induction Week 0 and maintenance Week 96 of the long-term extension, 5.5% (22/400) of patients who received ustekinumab in maintenance and continued on ustekinumab in the long-term extension were positive for ADAs, including patients who were Week 8 responders to ustekinumab IV induction and randomised to ustekinumab SC maintenance, and those who were Week 16 responders who received SC maintenance thereafter; 18.2% (4/22) of these patients were positive for neutralising antibodies. The proportions of randomised patients in symptomatic remission at Week 92 were comparable between those who were positive and those who were negative for antibodies to ustekinumab (Table S5).

Safety

Among all patients treated in the long-term extension from maintenance Week 0 through long-term extension Week 96, the PY of follow-up was nearly 2.5 times greater for those receiving ustekinumab than placebo. The average duration of follow-up was comparable for those receiving placebo and ustekinumab. Rates of AEs, SAEs, AEs leading to discontinuation, serious infections, malignancies (excluding non-melanoma skin cancer [NMSC]), and deaths per 100 PY of follow-up were generally similar for combined ustekinumab vs placebo (Table 4).

From Week 44 through Week 96, the average duration of follow-up for patients in the placebo group (37.1 weeks) was shorter than that in the ustekinumab q12w (44.5 weeks) and q8w (45.3 weeks) groups, largely due to patients on placebo being discontinued at the time of study unblinding; duration of follow-up was comparable in the ustekinumab groups (Table S6). The number of AEs per 100 PY of follow-up were 267.93, 223.82 and 268.17 in the placebo, ustekinumab q12w and ustekinumab q8w groups respectively. Ulcerative colitis, nasopharyngitis, upper respiratory tract infection, influenza and headache were the most frequently reported AEs (Table S6). There was no increase in the overall rates of AEs, SAEs, AEs leading to discontinuation, serious infections, malignancies (excluding NMSC), or deaths from Week 44 through Week 96 with increased exposure to ustekinumab (Figure 6).

Figure 6.

All adverse events (A) and key safety events (B) during ustekinumab exposure†,‡,§,¶,††. Number of treatment-emergent adverse events per 100 patient-years of follow-up and 95% confidence interval (rates by each year of follow-up) in the pooled ustekinumab ulcerative colitis safety cohort. Confidence intervals based on an exact method assuming that the observed number of events follows a Poisson distribution. Infection as assessed by the investigator. §Placebo (First Year) includes 1) Patients who were in clinical response to ustekinumab IV induction dosing and were randomised to placebo SC on entry into this maintenance study and were followed after Week 8; and 2) Patients who were in clinical response to placebo IV induction dosing and received placebo SC on entry into this maintenance study. Only includes data from Week 8 onward for patients who were in clinical response to ustekinumab IV induction dosing and were randomised to placebo SC on entry into this maintenance study. All Ustekinumab (First Year) includes 1) patients who received ustekinumab SC (q8w or q12w) in this maintenance study; and 2) patients who were in clinical response to ustekinumab IV induction dosing and received placebo SC on entry into this maintenance study; 2) data from Week 0 to Week 8 for patients who were in clinical response to ustekinumab IV induction dosing and were randomised to placebo SC on entry into this maintenance study. ††All Ustekinumab treated in the LTE (Second Year) includes: 1) Patients who were in clinical response to ustekinumab IV induction dosing and were randomised to receive ustekinumab 90 mg SC q12w or q8w on entry into the maintenance study, with data from Week 44 through Week 96; 2) Patients who were in clinical response to ustekinumab IV induction dosing, randomised to receive placebo SC on entry into the maintenance study, and had a dose adjustment to ustekinumab 90 mg SC q8w, with data from the time of dose adjustment onward; 3) Patients who were not in clinical response to ustekinumab at I-8 but were in clinical response at I-16 after a SC administration of ustekinumab at I-8 and received ustekinumab 90 mg SC q8w on entry into the maintenance study with data from Week 44 through Week 96. Key: CI, confidence interval; IV, intravenous; NMSC, nonmelanoma skin cancer; q8w, every 8 weeks; 12w, every 12 weeks; SC, subcutaneous

As previously reported,[2] one patient died during the long-term extension. The patient had responded to ustekinumab IV induction, was randomised to placebo SC maintenance, and received one 90 mg ustekinumab dose after dose adjusting from placebo. The immediate cause of death was attributed to cardiac arrest, but the patient had previously reported multiple AEs including cytomegalovirus (CMV) colitis, worsening UC, and failure to thrive. The patient also had multiple comorbidities, including prior myocardial infarction and coronary artery disease with placement of two stents.

Among patients treated with ustekinumab from Week 44 through Week 96, three patients had NMSCs. One patient each receiving ustekinumab q12w or q8w had basal cell carcinoma (BCC), one patient receiving ustekinumab q8w had a concurrent squamous cell carcinoma and BCC. Two patients who received placebo had one each: BCC and lentigo malignant melanoma. No other malignancies were reported.

Among all treated patients, serious major adverse cardiovascular events from Week 44 through Week 96 were reported in three patients: non-fatal myocardial infarction in one ustekinumab IV Week 16 responder, non-fatal stroke in one ustekinumab IV induction responder randomised to placebo SC maintenance therapy who dose adjusted to ustekinumab q8w, and one cardiovascular death (reported above).

Two serious infections considered to be opportunistic were reported between Week 44 and Week 96. One patient was hospitalised for diarrhoea secondary to UC complicated by CMV colitis as identified by the presence of CMV inclusion bodies on biopsy (>60 years old, ustekinumab IV induction responder randomised to placebo SC maintenance therapy who dose adjusted to ustekinumab q8w); this patient as reported above expired due to cardiac arrest. Another patient (>60 years old, placebo SC maintenance therapy who dose adjusted to ustekinumab q8w) was hospitalised for symptoms associated with worsening UC and fever, received treatment including ceftriaxone and tacrolimus, and had a blood culture positive for Listeria monocytogenes.

Among ustekinumab-treated patients from Week 44 through Week 96, proportions of injections with injection site reactions were 0.5% among all ustekinumab injections and 0.3% among all placebo injections administered. There were no cases of anaphylactic or delayed hypersensitivity reactions reported from Week 44 through Week 96. No relationship between the development of ADAs and injections with injection-site reactions was identified in this study (Table S7).

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