Ustekinumab in treatment of Crohn’s disease: design, development, and potential place in therapy

Figures & data

Figure 1 Ustekinumab binds to the p40 subunit of IL-12 and IL-23, preventing binding with the NK- or T-cell surface IL-12Rβ1, and inhibiting IL-12 signaling and further activation of Th1 subset of T cells as well as IL-23 signaling and further activation of Th17 subset of T cells.

Note: Image not drawn to scale; Adapted by permission from Macmillan Publishers Ltd: Nat Biotechnol. Benson JM, Sachs CW, Treacy G, et al. Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab. 2011;29(7):615–624. Copyright (2011).²⁴
Abbreviations: IL, interleukin; IL-12Rβ1, IL-12 receptor β1; NK, natural killer.

Table 1 Summary of RCTs on ustekinumab in Crohn’s disease

Name of the study	Type of RCT	Number of patients	Primary endpoint	Relevant secondary endpoints	Results	Serious adverse eventsa
Sandborn et al^Citation14	Phase IIa, (crossover), moderate-to-severe Crohn’s	104	Clinical response at week 8		USTb: 49% PBO: 40%	USTb: 4%
				Clinical response at week 4 and 6	USTb: 53% PBO: 30%	PBO: 6%
		49 (subgroup: previous exposure to IFX)		Clinical response at week 8	USTb: 59% PBO: 26%
CERTIFI^Citation13	Phase IIb, moderate- to-severe Crohn’s: resistant to anti-TNF	526	Clinical response at week 6		UST: 39.7% (6 mg/kg dose IV) PBO: 23.5%	USTc: 5.8%
						PBO: 8.3%
		145 (subgroup: responders put on maintenance)		Clinical response at week 22	UST: 69.4% (90 mg SC) PBO: 42.5%	UST: 12.5%d
				Clinical remission at weeks 22	UST: 41.7% (90 mg SC) PBO: 27.4%	PBO:16.4%
UNITI-1^Citation38,Citation39	Phase III, moderate-to- severe Crohn’s: failed/intolerant to anti-TNF	741	Clinical response at week 6		UST: 33.7% (6 mg/kg IV), 34.3% (130 mg IV) PBO: 21.5%	UST: 7.2% (6 mg/kg IV), 4.9% (130 mg IV)
				Clinical remission at week 8	UST: 20.9% (6 mg/kg IV), 15.9% (130 mg IV) PBO: 7.3%
				Clinical response at week 8	UST: 37.8% (6 mg/kg IV), 33.5% (130 mg IV) PBO: 20.2%
						PBO: 6.1%
UNITI-2^Citation38,Citation40	Phase III, moderate-to- severe Crohn’s	628	Clinical response at 6 weeks		UST: 55.5% (6 mg/kg IV), 51.7% (130 mg IV) PBO: 28.7%	UST: 2.9% (6 mg/kg IV), 4.7% (130 mg IV)
				Clinical remission at week 8	UST: 40.2% (6 mg/kg IV), 30.6% (130 mg IV) PBO: 19.6%
				Clinical response at week 8	UST: 57.9% (6 mg/kg IV), 47.4% (130 mg IV) PBO: 32.1%
						PBO: 5.8%
IM-UNITI^Citation38,Citation41	Phase III maintenance, UNITI-1 and UNITI-2 responders	397	Clinical remission at week 44		UST: 53.1% (90 mg SC q8w), 48.8% (90 mg SC q12w)	UST: 9.9% (q8w), 12.2% (q12w)
					PBO: 35.9%
				Clinical response at week 44	UST: 59.4% (90 mg SC q8w), 58.1% (90 mg SC q12w)	PBO: 15.0%
					PBO: 44.3%
				Corticosteroid-free remission at week 44	UST: 46.9% (90 mg SC q8w), 42.6% (90 mg SC q12w)
					PBO: 29.8%
				Continued remission at week 44 among those in remission at inclusion	UST: 66.7% (90 mg SC q8w), 56.4% (90 mg SC q12w)
					PBO: 45.6%
				Clinical remission at 44 anti-TNF refractory/intolerant	UST: 41.1% (90 mg SC q8w), 38.6% (90 mg SC q12w)
					PBO: 26.2%
				Clinical remission at 44 conventional therapy failures	UST: 62.5% (90 mg SC q8w), 56.9% (90 mg SC q12w)
					PBO: 44.2%
				Clinical remission at 44 anti-TNF naïve	UST: 65.4% (90 mg SC q8w), 56.6% (90 mg SC q12w)
					PBO: 49.0%

Notes:

a Through week 8 unless specified.

b Combined subcutaneous and intravenous group.

c Combined data for 1, 3, and 6 mg/kg IV induction groups.

d Through week 22.

Abbreviations: IFX, infliximab; PBO, placebo; TNF, tumor necrosis factor; UST, ustekinumab; RCTs, randomized control trials; IV, intravenous; SC, subcutaneous; q8w, every 8 weeks; q12w, every 12 weeks.

Figure 2 Overall structure of UNITI phase III program.

Note: ^aSubjects randomized to placebo and subjects who are non-responders to ustekinumab are eligible for non-randomized maintenance dosing after completion of the induction study.
Abbreviations: LTE, long-term extension; TNF, tumor necrosis factor; UST, ustekinumab; IV, intravenous; SC, subcutaneous; q8 wks, every 8 weeks; q12 wks, every 12 weeks.

Figure 3 Proposed algorithm for use of UST in moderate-to-severe Crohn’s disease.

Abbreviations: UST, ustekinumab; VDZ, vedolizumab; AEs, adverse events; TNF, tumor necrosis factor; CD, Crohn’s disease.

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