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

Discussion

The objectives of this long-term extension study were to assess the efficacy, PK and immunogenicity, and safety, of one additional year of ustekinumab maintenance treatment in patients originally manifesting moderate-to-severe UC activity who had completed the 44-week maintenance study. Of the 523 randomised patients who participated in the maintenance study, 399 (76.3%) patients continued treatment in the long-term extension. Greater than 90% of patients with no history of biologic failure were biologic naïve. Approximately 25% of patients with a history of biologic failure had failed both vedolizumab and a TNF antagonist.

In the long-term extension, a majority of randomised patients who continued to receive ustekinumab completed study participation through Week 96. Additionally, among all ustekinumab-treated randomised patients and Week 16-responder nonrandomized patients, 95.3% (388/400) of patients completed study participation through Week 96.

Our findings show that among all ustekinumab induction responders who were randomised to ustekinumab in the maintenance study (intent-to-treat population), approximately two thirds were in symptomatic remission at Week 92. Among randomised patients who continued treatment in the long-term extension, greater than 80% were in symptomatic remission at Week 92. Rates of symptomatic remission were maintained from Week 44 through Week 92. Rates for symptomatic remission over time are supported by sustained improvements in partial Mayo scores, and reductions in CRP and faecal calprotectin concentrations. The majority (>95%) of patients who achieved symptomatic remission at Week 92 were also not receiving corticosteroids. Similar and consistent efficacy was observed for ustekinumab q12w and q8w dosing.

Sustained efficacy was observed under varying clinical scenarios including biologic treatment history (eg those with documented biologic failure or those naïve to biologic therapy), when dose adjustment was considered part of the treatment regimen, and with those patients with a delayed response to their initial treatment with ustekinumab. Also, in a limited subset of patients who responded to the ustekinumab IV induction dose but delayed initiation of the SC ustekinumab maintenance therapy (ie were randomised to placebo maintenance and dose adjusted to ustekinumab maintenance), ustekinumab was still effective after dose interruption.

Following continued treatment with ustekinumab q12w or q8w, sustained serum ustekinumab concentrations were observed through Week 92 that were generally consistent with serum ustekinumab concentrations observed during the maintenance study. Through 2 years of ustekinumab maintenance therapy, rates of ADAs were low with no notable impact on proportions of patients in symptomatic remission at Week 92 or injections with injection-site reactions.

Nasopharyngitis was the most frequently reported infection and UC flare was the most frequently reported gastrointestinal AE. Malignancy rates were low and similar between groups, and primarily NMSC. Age, prior immunomodulator use and sun exposure were confounding factors in these patients. One death due to cardiac arrest occurred in the long-term extension and was reported previously.[2] No cases of tuberculosis were reported in ustekinumab-treated patients. Two patients developed serious infections considered to be opportunistic infections (CMV colitis and L. monocytogenes infection detected by blood culture). Proportions of injections with injection-site reactions remained low from Week 44 through Week 96, with no reports of serious reactions, anaphylaxis or serum sickness-like reactions.

The efficacy and safety findings reported here are consistent with those reported in patients with moderately-to-severely active Crohn's disease who also had their clinical benefits maintained through 2 years with ustekinumab 90 mg q12w and q8w.[5]

With the introduction of biologic therapies including TNF-α,[6–9] α4β7 integrin–MAdCAM-1[10] and Janus kinase antagonists,[11] management of UC has greatly improved. Efficacy and safety reported from study extensions of phase 3, randomised clinical trials, showed that an additional year of treatment with infliximab,[12] golimumab,[13] adalimumab,[14] vedolizumab[15] or tofacitinib[16] maintained efficacy and safety profiles of the respective therapies.

It should be noted that the patients receiving placebo in the long-term extension originated from both randomised and non-randomised populations with different treatment histories in the study. Patients randomised to placebo maintenance had responded to IV ustekinumab induction, and efficacy shown by these patients in the maintenance study extension may reflect an as yet identified prolonged pharmacodynamic effect as median serum ustekinumab levels in this group were below the level of detection 20 weeks following the single IV administration. Patients who were in clinical response after IV placebo induction received SC placebo in the maintenance study and were followed in the non-randomised population. All patients and investigators were blinded to induction and maintenance study treatments into the long-term extension, including placebo, until the Week 44 database was locked, and the study was unblinded. Patients who were still receiving placebo at the time of unblinding were discontinued from the long-term extension per protocol. Because patients were enrolled in the study at different times but stopped the study at the same time, their treatment duration during the long-term extension varied. Of note, from Week 44 through Week 96, the placebo groups had 12 fewer weeks of follow-up on average (37.1 weeks) as compared with the combined ustekinumab groups (49.1 weeks). Therefore, we did not use efficacy data from the placebo group after Week 44 for efficacy comparisons; however, they were included in the safety analyses that were normalised by summarising events per 100 PY of follow-up.

Placebo-treated patients in the randomised maintenance population who dose adjusted to ustekinumab maintenance provided an opportunity to evaluate ustekinumab treatment interruption, since they responded to ustekinumab IV induction and started ustekinumab maintenance after initially being randomised to placebo maintenance for at least 1 year. The results showed that patients improved after starting ustekinumab maintenance. While delaying the start of ustekinumab maintenance after induction may not be a recommended treatment regimen in patients with inflammatory bowel diseases, these results suggest that patients may still show benefit if such a delay is unavoidable.

Our results should be interpreted in light of the limitations associated with the design of the long-term extension. Patients were selected by the investigator to participate because, in their opinion, they might benefit from continued treatment, which may limit the generalisability of the results of analyses based solely on the cohort of patients treated in the long-term extension. Unlike the rigorously controlled maintenance study where concomitant UC medication dosages except for oral corticosteroids remained constant through Week 44, during the long-term extension patients could change concomitant medications at any time which mimics real world practice. Also, when considering the data for dose adjustment within the randomised population, it should be noted that the decision to dose adjust was based on the clinical judgement of the investigator regarding a patient's disease activity; no protocol-specified criteria (eg clinical flare based on partial Mayo score) were applied and some patients were in symptomatic remission at the time of the dose adjustment, thereby limiting the interpretability of these data.

The results reported here in patients with moderately-to-severely active UC, together with both clinical trial and registry data confirm the positive long-term efficacy and safety profile of ustekinumab-treated patients with other immune-mediated inflammatory diseases such as psoriasis[17–19] and Crohn's disease.[5,20] In summary, patients with moderately-to-severely active UC treated with ustekinumab 90 mg SC q12w or q8w maintained symptomatic remission measured through the second year of maintenance treatment (Week 44 through Week 96). The safety profile observed for ustekinumab in the second year of maintenance treatment was consistent with that reported through the first year during the maintenance study and with the established ustekinumab safety profile; no new safety signals were identified.

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