Efficacy and Safety of Maintenance Ustekinumab for Ulcerative Colitis Through 3 Years: UNIFI Long-term Extension

Abstract

Background and aims: The UNIFI long-term extension [LTE] study reports the efficacy and safety of subcutaneous 90 mg ustekinumab through 3 years of maintenance therapy.

Methods: Patients randomised to ustekinumab every 12 weeks [q12w] or every 8 weeks [q8w] at maintenance baseline [N = 348] and randomised ustekinumab-treated patients in the LTE [N = 284] were evaluated. Symptomatic remission [Mayo stool frequency = 0/1, rectal bleeding = 0] was assessed. Safety included all LTE patients [N = 188 placebo and N = 457 ustekinumab].

Results: Among patients randomised to the ustekinumab q12w and q8w groups at maintenance baseline, 54.1% and 56.3% achieved symptomatic remission at Week 152, respectively. Overall, 20% of patients discontinued ustekinumab, 10% of biologic-naïve and 30% of biologic-exposed patients. Among patients in symptomatic remission at Year 3, 94.6% and 98.0% of patients were also corticosteroid free, respectively. Corticosteroid-free symptomatic remission rates in the ustekinumab q12w and q8w groups were 51.2% and 55.1% at Week 152, respectively. Remission rates were higher for biologic-naïve patients than for those with a history of biologic failure. Biochemical evidence of response was demonstrated by stable, decreased C-reactive protein and faecal calprotectin measurements over 3 years. From Weeks 96 to 156, no deaths, major adverse cardiovascular events, or tuberculosis occurred. Nasopharyngitis, ulcerative colitis, and upper respiratory tract infection were most frequently reported. One ustekinumab-treated patient with a history of basal cell carcinoma [BCC] reported two BCCs. One patient in the q8w ustekinumab group, who was receiving concomitant 6-mercaptopurine, experienced serious adverse events of neutropenic sepsis and oral herpes.

Conclusions: Efficacy of ustekinumab in patients with ulcerative colitis was confirmed through 3 years. No new safety signals were observed.

Keywords: Ustekinumab; symptomatic remission; ulcerative colitis.

Graphical abstract

Figure 1.

Study flow. a. Patients who were assigned to placebo SC during the maintenance study were discontinued after study unblinding, which occurred after analysis of the maintenance study. R, patients who responded 8 weeks after ustekinumab intravenous induction were re-randomised in the maintenance study; SC, subcutaneous; q8w, every 8 weeks; q12w, every 12 weeks.

Figure 2.

Symptomatic remission through Week 152 for all ustekinumab IV induction responders who were randomised in the maintenance study [intent-to-treat population with missing data and treatment failure rules applied]: overall population [A], and biologic treatment history subgroups [B]; data are displayed according to the patients’ randomised treatment group. AE, adverse event; IV, intravenous; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous; UC, ulcerative colitis.a. Data are displayed by randomised group at maintenance Week 0 regardless of whether patients had a dose adjustment during the LTE. Between Weeks 56 and 152, 60 patients in the q12w group received dose adjustment to q8w. b. Symptomatic remission is defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0. c. Patients who had both stool frequency and rectal bleeding subscores missing at a visit were considered not to be in symptomatic remission for that visit. d. Patients who had a prohibited change in UC medication, an ostomy or colectomy, or used a rescue medication after clinical flare, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC prior to the Week 44 visit were considered not to be in symptomatic remission. e. Patients who had an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC after Week 44 and prior to the designated visit, were considered not to be in symptomatic remission. f. Patients who maintained symptomatic remission are defined as those who had achieved symptomatic remission at least 80% of all visits from Week 4 to Week 140 [at least 16 out of 19 visits] and were in symptomatic remission at Week 152.

Figure 3.

Corticosteroid-free symptomatic remission through Week 152 for all ustekinumab IV induction responders who were randomised in the maintenance study [intent-to-treat population with missing data and treatment failure rules applied]: overall population [A], and biologic treatment history subgroups [B]; data are displayed according to the patients’ randomised treatment group. AE, adverse event; IV, intravenous; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous; UC, ulcerative colitis.a. Patients who had both stool frequency and rectal bleeding subscores missing at a visit were considered not to be in symptomatic remission for that visit. b. Data are displayed by randomised group at maintenance Week 0 regardless of whether patients had a dose adjustment during the LTE. Between Weeks 56 and 152, 60 patients in the q12w group received dose adjustment to q8w. c. Patients who had a prohibited change in UC medication, an ostomy or colectomy, or used a rescue medication after clinical flare, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC prior to the Week 44 visit were considered not to be in symptomatic remission. d. Patients who had a missing value in corticosteroid use at a visit had their last observation carried forward.

Figure 4.

Symptomatic remission and corticosteroid-free symptomatic remission at Week 152 for all ustekinumab IV induction responders who were randomised in the maintenance study and treated in the LTE [with missing data and treatment failure rules applied]: overall population [A], and biologic treatment history subgroups [B]; data are displayed according to the patients’ randomised treatment group. AE, adverse event; IV, intravenous; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous; UC, ulcerative colitis.a. Randomised group at maintenance Week 0 regardless of whether patients had a dose adjustment during the LTE. b. Patients who had a missing value in corticosteroid use at a time point had their last available value carried forward to that time point. c. Patients who had both stool frequency and rectal bleeding subscores missing at a visit were considered not to be in symptomatic remission for that visit. d. Patients who had an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC prior to the designated visit were considered not to be in symptomatic remission.

Figure 5.

Daily prednisone-equivalent [P.Eq] corticosteroid dose [mg/day] through Week 152 for all ustekinumab IV induction responders randomised in the maintenance study and treated in the LTE who were receiving corticosteroids at maintenance baseline [excluding budesonide and beclomethasone] [with missing data and treatment failure rules applied]; data are displayed according to the patients’ randomised maintenance treatment group. AE, adverse event; IV, intravenous; LTE, long-term extension; PEq, prednisone equivalent; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous; UC, ulcerative colitis.a. Patients who had an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC, or were dose adjusted [only occurred from Week 56 onward] prior to the Week 152 visit had their Week 0 value of the induction study carried forward from the time of the event onward. b. Analysis of patients who were receiving corticosteroid at baseline. Corticosteroid includes prednisone only; excludes budesonide and beclomethasone dipropionate. c. Data are displayed by randomised group at maintenance Week 0 regardless of whether patients had a dose adjustment during the LTE. Between Weeks 56 and 152, 20 patients in the q12w group received dose adjustment to q8w. d. Patients who had a missing value in corticosteroid use at a time point had their last available value carried forward to that time point.

Figure 6.

Median CRP [mg/L] [A] and faecal calprotectin [mg/kg] concentrations [B] during the LTE for all ustekinumab IV induction responders who were randomised in the maintenance study and treated in the LTE; data are displayed according to the patients’ randomised treatment group. AE, adverse event; CRP, C-reactive protein; IV, intravenous; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous; UC, ulcerative colitis.a. Patients who had an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC prior to the Week 152 visit had their Week 0 value of the induction study carried forward from the time of the event onward. b. Patients who had a missing CRP or faecal calprotectin value at the designated analysis time point had their last observation carried forward.

Figure 7.

Key safety events per 100 patient-years of exposure during the first, second, and third year of ustekinumab maintenance therapy. AE, adverse events; CI, confidence interval; IV, intravenous; LTE, long-term extension; NMSC, nonmelanoma skin cancer; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous.a. Number of AEs 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. b. Infection as assessed by the investigator. c. All ustekinumab [first year] includes: 1] patients who received ustekinumab SC [q8w or q12w] in this maintenance study; 2] patients who were in clinical response to ustekinumab IV induction dosing and received placebo SC on entry into this maintenance study; and 3] 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. d. All ustekinumab-treated in the LTE [second year] includes: 1] data from Week 44 through Week 96 for patients who were in clinical response to ustekinumab IV induction dosing and were randomised to ustekinumab 90 mg SC q12w on entry into the maintenance study; 2] patients who were in clinical response to ustekinumab IV induction dosing and were randomised to receive ustekinumab 90 mg SC q8w on entry into the maintenance study, with data from Week 44 through Week 96; 3] 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 prior to Week 96 to ustekinumab 90 mg SC q8w, with data from the time of dose adjustment onward; and 4] patients who were not in clinical response to ustekinumab at induction Week 8 but were in clinical response at induction Week 16 after an SC administration of ustekinumab at induction Week 8 and received ustekinumab 90 mg SC q8w on entry into the maintenance study with data from Week 44 through Week 96. e. All ustekinumab in the LTE [third year] includes: 1] data from Week 96 through Week 156 for patients who were in clinical response to ustekinumab IV induction dosing and were randomised to ustekinumab 90 mg SC q12w on entry into the maintenance study; 2] patients who were in clinical response to ustekinumab IV induction dosing and were randomised to receive ustekinumab 90 mg SC q8w on entry into the maintenance study, with data from Week 96 through Week 156; 3] 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 at or after Week 96 to ustekinumab 90 mg SC q8w, with data from the time of dose adjustment onward; and 4] patients who were not in clinical response to ustekinumab at induction Week 8 but were in clinical response at induction Week 16 after an SC administration of ustekinumab at induction Week 8 and received ustekinumab 90 mg SC q8w on entry into the maintenance study with data from Week 96 through Week 156.