RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

Table 2 Efficacy profiles of RORγt inhibition versus launched and pipeline mechanisms of action in the mouse house dust mite model

Endpoint		RORγt	Anti-IL-5	Anti-IL4 / anti-IL-13	Anti-IgE	CysLT1	oCS	Anti-TSLP	Anti-IL-33
Phenotypic	Airway hyperreactivity	58%*	0%	0%	0%	15%	65%*	62%*	n/d
	Pulmonary mechanics	62%^#	6%	20%	29%	0%	22%	0%	n/d
Th2	Eosinophils	0%	78%	8%	43%*	10%	21%	53%^#	0%
	IL-4	0%	50%^#	49%*	92%^#	45%*	31%	0%	0%
	IL-5	0%	100%*	40%*	0%	0%	17%	46%*	30%
non-Th2	Neutrophils	79%^§	40%*	3%	0%	0%	59%^#	9%	0%
	Macrophages	0%	55%^#	17%	0%	0%	97%^§	13%	0%
	IL-1β	0%	21%	26%	0%	8%	56%^#	10%	0%
	IL-6	0%	60%*	50%*	0%	22%	43%	0%	0%
	IL-8	60%*	0%	25%	0%	14%	20%	0%	0%
	IL-17	90%^§	0%	0%	0%	0%	67%^#	0%	0%
	IFN-γ	0%	44%	58%	0%	0%	45%	0%	0%

The effect size of BIX119 in the HDM mouse model (RORγt) versus lung function (phenotypic endpoint), Th2 and non-Th2-associated endpoints was compared with other clinical relevant modes of action anti-IL-5 (rat-anti-mouse IL-5; TRFK-5; 300 µg i.p.), anti-IL4 + anti-IL-13 (as a surrogate for anti-IL-4R; rat anti-mouse IL-4; MAB; 300 µg i.p. and rat anti-mouse IL-13; MAB413; 300 µg i.p.), anti-IgE (rat anti-mouse IgE; antibody1-5; 300 µg i.p.), CysLT1 (monteleukast; 25 mg/kg/day p.o.), oral corticosteroids (oCS; prednisolone; 4 mg/kg/day p.o.), anti-TSLP (rat anti-mouse TSLP; MAB555; 300 µg i.p.) and anti-IL-33R (rat anti-mouse IL-33R; MAB10041; 250 µg i.p.) in the same model. All treatments were administered on day 13, 24 h prior to challenge. Antibodies were dosed just once on day 13, small molecule inhibitors were dosed on days 13, 14 and 15. n/d not determined, *P < 0.05, ^#P < 0.01, ^§P < 0.005

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