Date: 2013-06-13
Type of information: Initiation of preclinical development
phase: 2a
Announcement: presentation of results at the European League Against Rheumatism (EULAR) Annual Congress in Madrid, Spain
Company: Galapagos (Belgium)
Product: GLPG0634
Action
mechanism: GLPG0634 is an orally-available, novel Janus kinase (JAK) inhibitor with selectivity for JAK1 developed by Galapagos. JAKs are critical components of signaling mechanisms utilized by a number of cytokines and growth factors, including those that are elevated in rheumatoid arthritis patients. JAK inhibitors have shown long-term efficacy in rheumatoid arthritis studies with an early onset of action. GLPG0634 differentiates from other JAK inhibitors in development by specifically targeting JAK1, a strategy which could result in a better efficacy and safety profile.
Disease: rheumatoid arthritis
Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases
Country: Hungary, Moldova, Russia, and Ukraine
Trial
details: The Phase 2A trial for GLPG0634 enrolled 91 patients with active RA (rheumatoid arthritis), showing an insufficient response to the standard-of-care treatment, methotrexate (MTX). The aim was to evaluate the efficacy, safety, tolerability and pharmacokinetics of once-daily dosing of 30 to 300mg of GLPG0634 in treating rheumatoid arthritis. Five groups of patients with active disease took the once-daily regimen of GLPG0634 or placebo for a period of four weeks, while all continued to take their stable background therapy of MTX. Efficacy endpoints included the ACR20 and ACR50 response rates, the disease activity score DAS28, and the reduction in C-reactive protein (CRP), the primary blood marker of inflammation. Galapagos conducted the study in 19 test centers in Hungary (4 sites), Moldova (1), Russia (5), and Ukraine (9).
Latest
news: * On June 13, 2013, Galapagos has announced that the company is presenting three posters on its selective JAK1 inhibitor GLPG0634 at the European League Against Rheumatism (EULAR) Annual Congress in Madrid, Spain. The posters and main results are:
• Safety and efficacy of GLPG0634, a selective JAK1 inhibitor, in patients with rheumatoid arthritis: results of a 4-week Phase IIA dose ranging, multi-center trial.
Selective inhibition of JAK1 by once-daily dosing of GLPG0634 from 75 - 300 mg was well tolerated and efficacious in this 4-week study. A favourable safety profile was observed, with an absence of the typical findings reported for other JAK inhibitors. GLPG0634 caused no anemia, no overall change to LDL or ALT, and no neutropenia. Regarding efficacy, a dose trend for improvement in RA disease parameters was found: 30 mg QD was sub-optimal, while doses of 75, 150 and 300 mg showed promising efficacy, with similar response rates in CRP, TJC, SJC and DAS28.
An imbalance in baseline characteristics of two patient groups may have influenced the study outcome:
- the placebo group showed a relatively high response rate correlating with a short history of RA
- the 150 mg group was most severely diseased. The 150 mg group showed a robust response in CRP, TJC, and SJC. However, the 4-week duration of the trial was too short to reach the full potential on patient-reported scores (pain assessment, global assessment, HAQ-DI).The encouraging short term efficacy and favourable safety profile in this study supports the potential of selective inhibition of JAK1 as a future RA treatment option, and confirms data from a previous Proof of Concept study at a 200 mg daily dose.
• Once-daily dosing of GLPG0634, a selective JAK1 inhibitor, is supported by its active metabolite
An active and JAK1-selective metabolite supports the activity of GLPG0634. The lower potency of the metabolite is compensated by its high exposure in humans. The long half-life of the metabolite and the resulting high plasma levels when parent GLPG0634 is at trough, provides a lasting effect. Because of the 7-hour half-life of GLPG0634, both BID and QD regimens were studied. However, the metabolite contribution to JAK1 inhibition now provides a potential explanation for the sustained efficacy results observed with once daily dosing of GLPG0634, adding to convenience for patients.
• Biological effects of the JAK1 selective inhibitor GLPG0634 on inflammation markers in arthritic mice
Oral administration of the selective JAK1 inhibitor GLPG0634 in arthritic mice demonstrates a selective engagement of the JAK1 target by GLPG0634 in vivo. Progression of established arthritis in the CIA model is blocked by selective inhibition of JAK1. GLPG0634 administration inhibits inflammation and confers structural protection at the level of bone and cartilage in a therapeutic CIA model. A single administration of GLPG0634 is sufficient to block CIA-induced inflammatory signalling.
* On November 8, 2012, Galapagos has announced that a second Phase 2A clinical trial with GLPG0634 repeated the excellent safety of the drug, as well as the clinical benefit to RA patients within 4 weeks. Clinical improvements were seen in RA patients with once-daily dosages of 75-300mg. In February 2012, Galapagos and Abbott announced a global collaboration for GLPG0634 to treat autoimmune diseases. In this four week, multi-center, Phase 2A trial in 91 RA patients, GLPG0634 was administered in five study arms at a wide range of once-daily dosages of placebo, 30, 75, 150 or 300 mg. Despite the fact that the study was not powered for statistical significance, GLPG0634 did achieve statistically significant improvement in CRP (C-reactive protein), DAS28, HAQ-DI and ACR response rates at the 300mg dose. Efficacy endpoints showed a rapid onset and sustained effect until the end of the study. GLPG0634 was well-tolerated, with none of the patients discontinuing the trial for safety reasons. No serious adverse events were reported. The safety profile of GLPG0634 was confirmed: an absence of the typical findings reported with other JAK inhibitors such as anemia, increases in blood lipids (LDL) and effects on liver enzymes (ALT/AST). An improvement rather than a decrease in hemoglobin was observed in patients receiving GLPG0634. The company expects that these results will enable it to move rapidly forward into global Phase 2B trials early next year.
