Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy

Abstract

Background: In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported.

Methods: UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding.

Results: A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed.

Conclusions: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Figure 1

Study design for IM‐UNITI phase 3 Crohn's disease program*. R, randomisation; IV, intravenous; SC, subcutaneous; q8w, every 8 weeks; q12w, every 12 weeks; PE, primary endpoint; LTE, long‐term extension; DBL, database lock. *Unblinding occurred when the final patients reached Week 44

Figure 2

Clinical remission from Week 44 through Week 92 of treatment among (A) all randomised patients entering the long‐term extension and (B) by induction study subgroups. SC, subcutaneous; TNF, tumour necrosis factor; q8w, every 8 weeks; q12w, every 12 weeks

Figure 3

Proportions of patients with normalised CRP (≥3 mg/L) from Week 44 through Week 92; randomised patients who entered the long‐term extension. CRP, C‐reactive protein; SC, subcutaneous; q8w, every 8 weeks; q12w, every 12 weeks

Figure 4

Patients in clinical remission from Week 44 through Week 92 of IM‐UNITI long‐term extension: observed data

Figure 5

Long‐term rates of remission for patients responding to ustekinumab induction through Week 92 (intent‐to‐treat analysis of IM‐UNITI primary population from Week 0). SC, subcutaneous; q8w, every 8 weeks; q12w, every 12 weeks