Background/Purpose: Baricitinib (formerly LY3009104/INCB028050), a novel, oral inhibitor of JAK1 and JAK2 in the JAK-STAT signaling pathway, has been evaluated in a 24 week blinded phase 2b study in patients (pts) with moderate to severe RA with inadequate response to methotrexate (MTX).The primary endpoint after 12 weeks of treatment was met¹. The 24 week safety and efficacy findings are reported here.

Methods: Pts with active RA (defined as at least 8 swollen and 8 tender joints based on the 66/68 joint assessment) on stable MTX were randomized 2:1:1:1:1 to receive placebo (PBO) or 1of 4 once-daily baricitinib doses (1, 2, 4, or 8 mg) for 12 wks. Pts assigned to 2 mg, 4 mg or 8 mg continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg were reassigned to an exploratory 4 mg daily or 2 mg twice daily group between weeks 12-24 and were excluded from the primary 24-week analysis.

Results: Three hundred one pts entered the study. After 12 weeks of treatment, significant differences versus placebo (p<0.05) were observed in the proportion of patients achieving ACR20, ACR50 and ACR70, DAS28CRP<2.6 and CDAI≤2.8, and for DAS28CRP, HAQ-DI and CDAI (Table1). At week 24, patients receiving 2 mg, 4 mg or 8 mg baricitinib maintained or improved in all measures. Over 12 weeks in the PBO and combined baricitinib groups, there were similar incidence rates of TEAEs (44% vs 41%), infections (12% vs 14%) and SAEs (2% vs 2%, respectively) over 12 weeks.  Over 24 weeks in the combined 2 mg, 4 mg and 8 mg groups, the rate of TEAEs was 64% (36% mild, 23% moderate, 5% severe) , the rate of infections was 27% (16% mild, 9% moderate, 1% severe), and the rate of SAEs was 5%. There were no opportunistic infections and no deaths.  Decreases in hemoglobin and small increases in serum creatinine were seen. Increases were seen in LDL and HDL (Table 2).

Conclusion: Significant improvements in the signs and symptoms of RA versus placebo were observed over 12 weeks. These responses were maintained or improved for an additional 12 weeks of blinded treatment with 2 mg, 4 mg and 8 mg. In addition, safety signals observed over 12 and 24 weeks were consistent with previously conducted studies of baricitinib.

¹Keystone et al. Ann Rheum Dis 2012;71(Suppl3):152

Table 1:  Primary and Selected Secondary Efficacy Endpoints at 12-and 24 weeks

	PBO (N=98)	1 mg QD (N=49)	2mg QD (N=52)	4 mg QD (N=52)	8 mg QD (N=50)
12 weeks
% ACR20†	41	57*	54	75*	78*
% ACR50†	10	31*	17	35*	40*
% ACR70†	2	12*	8	23*	20*
% DAS28CRP<2.6†	4	14*	15*	37*	22*
%CDAI ≤2.8†	1	2	6	21*	12*
DAS28-CRP§	4.5	4.0*	4.0*	3.2*	3.6*
CDAI§	23.7	20.8	20.7	13.7*	16.3*
HAQ-DI Δfrom baseline§	-0.10	-0.35*	-0.18	-0.33*	-0.39*
24 weeks
% ACR20†	—	—	63	78	73
% ACR50†	—	—	20	48	55
% ACR70†	—	—	10	28	24
% DAS28CRP<2.6†	—	—	16	34	37
%CDAI ≤2.8†	—	—	8	23	22
DAS28-CRP	—	—	3.9	3.0	3.3
CDAI	—	—	19.4	11.1	12.9
HAQ-DI Δ from baseline	—	—	-0.19	-0.33	-0.45

^†non-responder imputation and 1-sided p-value from Fisher’s exact test;  ^§2-sided p-value from LY dose vs. PBO contrast from ANCOVA with treatment as fixed factor and baseline (Week 0) value as covariate (Mean, LOCF);  *p<0.05 vs. PBO

Table 2:  Summary of Laboratory Data at Week 24:  Change from Baseline

Mean (SD)	2 mg QD	4 mg QD	8 mg QD
Hemoglobin (g/dL)	-0.28 (1.1)	-0.24 (0.9)	-0.44 (1.0)
Neutrophil count (103/mm3)	-0.25 (2.2)	-0.21 (2.0)	-1.37 (2.3)
Creatinine (mg/dL)	0.04 (0.10)	0.05 (0.08)	0.07 (0.13)
HDL cholesterol (mg/dL)	5.63 (12.21)	5.40 (10.62)	8.24 (13.05)
LDL cholesterol (mg/dL)	11.52 (22.80)	8.75 (32.60)	13.98 (30.87)

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