Following successful induction with ustekinumab, a secondary loss of response to ustekinumab maintenance therapy administered every 8 weeks develops in some patients with CD.1-3 The doubleblind, multicenter, phase 3b POWER study evaluated the safety and efficacy of a single intravenous dose of ustekinumab vs continuous maintenance with the subcutaneous administration of ustekinumab in patients who had CD with a secondary loss of response to ustekinumab maintenance therapy.4 The 36-week study enrolled patients with moderately to severely active CD who initially responded to induction therapy with ustekinumab administered intravenously and who experienced a secondary loss of response to maintenance therapy with ustekinumab (90 mg, every 8 weeks) administered subcutaneously. Loss of response was defined as a CDAI higher than 220 to 450 plus either elevated C-reactive protein (CRP), elevated fecal calprotectin, or endoscopic evidence of active CD. Following randomization, 108 patients in arm 1 received reinduction therapy with intravenous ustekinumab (6 mg/kg) plus a subcutaneous placebo, and 107 patients in arm 2 received an intravenous placebo plus continued maintenance therapy with subcutaneous ustekinumab (90 mg, every 8 weeks).
A post hoc analysis was conducted to evaluate pharmacokinetics, pharmacodynamics, and immunogenicity in patients from the POWER trial.3 Baseline characteristics were well balanced between the 2 arms. The patients had a median age of approximately 41 years and a mean CDAI of 289. Most of the patients (~90%) had previously been exposed to anti-TNF therapy, with or without vedolizumab. Endoscopy in a subset of patients (~60% in each arm) showed relatively mild disease. Most of the patients in each arm (86%-93%) completed treatment at week 16. The serum concentration of ustekinumab reached a median level of 105.62 μg/ mL among the patients who received a single intravenous reinduction dose of ustekinumab vs 1.47 μg/mL among the patients who received the intravenous placebo, and it was also higher after intravenous reinduction at week 16. The change in CDAI was evaluated in patients on the basis of the ustekinumab trough concentration at baseline, and the CDAI reduction was superior for ustekinumab reinduction vs intravenous placebo in all groups. At week 16, the proportions of patients in clinical response were similar in the 2 arms among the patients with a trough concentration of ustekinumab at week 16 of at least 1.3 μg/mL (Figure 4). Among the patients with a ustekinumab serum trough concentration of at least 1.3 μg/mL, a greater proportion of those in arm 1 than in arm 2 achieved endoscopic remission (23.8% vs 8.3%). Immunogenicity was not a concern.
Figure 4.
Clinical responsea at week 16 by ustekinumab trough concentrations at week 16b from the POWER trial.
aClinical response: ≥100-point reduction from baseline in CDAI or CDAI <150.
bPatients with insufficient data to calculate CDAI, a prohibited CD-related surgery, prohibited concomitant medication changes, or discontinuation of study agent due to lack of efficacy or due to an adverse event indicated to be of worsening CD before the designated analysis timepoint are considered not to be in clinical response.
CD, Crohn’s disease; CDAI, Crohn's Disease Activity Index; IV, intravenous; SC, subcutaneous; UST, ustekinumab.
Adapted from Feagan et al. Abstract 32. Presented at: ACG 2023; October 20-25, 2023; Vancouver, British Columbia, Canada.3
A related study investigated baseline characteristics that correlated with a clinical response to reinduction with ustekinumab.5 Parameters associated with an increased likelihood of achieving a clinical response at week 16 with ustekinumab vs placebo included duration of disease of less than 5 years (P=.029), both ileal and colonic involvement (P=.002), elevated baseline level of CRP (P=.029) or fecal calprotectin (P=.045), no more than 1 prior failure with a biologic therapy (P=.042), and prior perianal CD-related surgery (P=.013).
References
- Feagan BG, Sandborn WJ, Gasink C et al. UNITIIM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946–1960. doi: 10.1056/NEJMoa1602773. [DOI] [PubMed] [Google Scholar]
- Sandborn WJ, Rebuck R, Wang Y et al. Five-year efficacy and safety of ustekinumab treatment in Crohn’s disease: the IM-UNITI trial. Clin Gastroenterol Hepatol. 2022;20(3):578–590.e4. doi: 10.1016/j.cgh.2021.02.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Feagan B, Lee S, van der Woude CJ Pharmacokinetics, exposure-response relationships, and immunogenicity in Crohn’s disease patients with Ustekinumab secondary loss of response following Ustekinumab iv reintroduction: week 16 results from the POWER study. Abstract 32. 2023. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25. Vancouver, Canada.
- Schreiber SW, Lee S, van der Woude CJ et al. Efficacy and safety of intravenous ustekinumab reinduction therapy in Crohn’s disease patients with secondary loss of response to ustekinumab maintenance therapy: week 16 results from the POWER trial (ECCO abstract P436). J Crohns Colitis. 2023;17(suppl 1) [Google Scholar]
- Wolf D, Lee S, Schreiber S Analysis of baseline characteristics associated with clinical response to ustekinumab iv re-induction strategy in patients with Crohn’s disease in the POWER trial. Abstract P2174. 2023. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25. Vancouver, Canada.