Background/Purpose:

GLPG0634 is an oral, selective inhibitor of Janus kinase 1 (JAK1). JAKs signal for cytokines and growth factors, including those involved in rheumatoid arthritis (RA). Non-selective JAK inhibitors have demonstrated efficacy in patients with RA, but also dose-limiting toxicity. In a prior 4-week Proof-of-Concept (PoC) study, GLPG0634 showed promising efficacy and safety at a daily dose of 200 mg.

The objective of this study is to evaluate short-term safety and efficacy of a dose range of GLPG0634 administered as once-daily regimen in RA patients with insufficient response to methotrexate (MTX) alone.

Methods:

4-week, double-blind Phase IIA study, comparing GLPG0634 at 30, 75, 150 and 300 mg once-daily (QD) versus placebo in a total of 91 patients. Patients had active RA (mean DAS28 of 6.0) with insufficient response to MTX and naïve to biological therapies, and continued their stable background therapy of MTX.

Results:

GLPG0634 treatment was generally well tolerated; most adverse events (AEs) were mild and no serious AEs were reported. No patient discontinued due to AEs. No anemia was observed but rather a dose related improvement in hemoglobin. There was a limited decrease in absolute neutrophil count, no neutropenia, and no impact on lymphocyte subsets. No consistent changes in LDL were observed. ALT/AST was stable with no elevations >1.5 times ULN.

 

After 4 weeks treatment		Once-daily GLPG0634
	Placebo	30 mg	75 mg	150 mg	300 mg
CRP: mean change (mg/L)	-5.7	-13.3	-15.1	-20.5	-17.4
–  CRP shift high to normal (% pts)	0	24	32	47	60
Mean change DAS28(CRP)	-1.2	-1.1	-1.7	-1.8	-2.3
–  Low disease, <3.2 (% pts)*	18	12	32	13	45
* includes patients achieving remission (<2.6)

Within 4 weeks, GLPG0634 showed an encouraging dose trend in efficacy. There was a limited improvement with the 30 mg dose whereas good anti-inflammatory (CRP) response and change in disease activity (DAS28) was apparent for doses of 75 through 300 mg QD (table). The results achieved at 300 mg are similar to those with 200 mg QD in the prior PoC study (DAS28: -2.2, with 33% <3.2 at week 4). The improvement in RA disease parameters was similar for doses of 75 mg through 300 mg, with highest response rates (at 150 or 300mg) for TJC68: -15, SJC: -11, physician’s global: -29, patient’s global: -26, patient’s pain: -30, and HAQ-DI: -0.7. A high response rate in the placebo group may be related to a lower disease activity at baseline. For the 150 mg group, having the highest level of disease, 4 weeks treatment was too short to obtain good patient-reported outcomes. For ACR scores, best results were obtained for the 300mg group (65% ACR20, 45% ACR50). In spite of the small study, statistically significant improvements were obtained for CRP, DAS28, HAQ-DI and ACR50 at the high dose.

Conclusion:

These early clinical results demonstrate that selective JAK1 inhibition by GLPG0634 at daily doses of 75 to 300 mg QD is efficacious and generally well tolerated after 4 weeks in patients with RA. Safety and efficacy findings were consistent for two Phase IIA studies. A dose trend was found and current data suggest that a maximum level of efficacy is attained at 200 mg/day. Larger 24-week studies in RA patients are ongoing to evaluate optimal doses for efficacy and safety.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-jak1-selective-inhibitor-glpg0634-is-safe-and-rapidly-reduces-disease-activity-in-patients-with-moderate-to-severe-rheumatoid-arthritis-results-of-a-4-week-dose-ranging-study/