Our SIK program
The Salt-Inducible Kinases (SIKs) belong to a novel target class in inflammation which we discovered with our proprietary target discovery platform. The search for this novel target class started with the ambition to find new anti-inflammatory drug candidates with a favorable efficacy and safety profile relative to existing therapies. Although significant progress has been made with novel therapies in recent years, for instance in psoriasis, there remains a high unmet need for diseases related to overactive inflammation in joints, the bowel, and other organs.
Molecules discovered by us and which inhibit the different members of the SIK family have shown the potential to modulate anti-inflammatory cytokines and pro-inflammatory cytokines. Targeted and selective inhibition of SIK proteins brings an opportunity to restore the immune balance that is typically out of balance in autoimmune diseases. This approach brings potential differentiation from existing therapies that predominantly act by suppressing the immune system (see figure below).
The family of SIKs contains three targets: SIK1, SIK2 and SIK3. In our search for compounds acting on these targets, over 5,000 molecules were synthesized leading to more than 11 different chemical series with multiple selectivity profiles. Our first efforts in the space led to compound GLPG3312, a pan-SIK inhibitor, that was tested in Phase 1 and soon thereafter replaced by a more selective SIK2/3 compound, GLPG3970. We initiated a series of early-stage clinical trials with GLPG3970 and reported the first topline results in July 2021. These initial results resulted in proof-of-mechanism data, elucidating the role of SIKs in inflammation. GLPG4399, a selective SIK3 inhibitor, is in Phase 1, whereas tissue selective SIK2/3 inhibitor GLPG4605 and other SIK inhibitors are advancing preclinically (see figure below). Several other compounds with different profiles are being explored in discovery.
GLPG3970: encouraging Phase 1 data
Following positive results across a range of preclinical models, we evaluated GLPG3970 in a Phase 1 single and multiple ascending dose study which demonstrated that GLPG3970 was well tolerated. In addition, GLPG3970 had a dose-dependent effect on two key cytokines representative for its dual mode of action (see figure below). The pro-inflammatory cytokine, TNFα, decreased with increased compound dosing (left). The anti-inflammatory cytokine, IL-10, increased (right) with increasing compound dosing.
Pioneering role of SIKi in inflammation
We evaluated GLPG3970 in three randomized, placebo-controlled, double-blind studies: i) a Phase 1b study in patients with moderate to severe psoriasis and ii) two Phase 2a studies in patients with moderate to severely active UC and RA. GLPG3970 or placebo were administered orally once-daily for 6 weeks. The main objectives of the studies were to evaluate the safety and tolerability of GLPG3970 as well as early signs of biological and clinical activity.
Across the three studies, GLPG3970 was generally safe and well tolerated. There were no deaths nor serious adverse events, and the majority of treatment emergent adverse events (TEAEs) were mild or moderate in nature.
CALOSOMA Phase 1b study in psoriasis
This randomized placebo-controlled study enrolled 26 patients with moderate to severe psoriasis.
At week 6, four out of 13 patients on GLPG3970 had a PASI 50 response, defined as at least a 50% improvement of baseline PASI, compared to none on placebo. Specifically, the four responders achieved 50%, 50%, 56%, and 77% improvement in their PASI scores from baseline, reaching statistical significance compared to placebo (p=0.002) at week 6. Positive signals of clinical activity were also consistently observed for other endpoints, including affected Body Surface Area and physician and patient global assessment, versus placebo at week 6.
SEA TURTLE Phase 2a study in UC
This randomized placebo-controlled study enrolled 31 biologic-naïve patients with moderate to severely active UC.
At week 6, positive signals on objective parameters such as endoscopy, histology, and fecal calprotectin were observed in patients treated with GLPG3970. These findings did not translate in a differentiation from placebo on change from baseline in the total Mayo Clinical Score (MCS), the primary endpoint of this 6-week study (GLPG3970 -2.7, placebo -2.6). Seven out of 18 patients on GLPG3970 who underwent endoscopy at week 6 met the criteria for Endoscopic Improvement, defined as a score of 0 or 1 on the endoscopic response score, compared to one out of 9 patients on placebo. The robustness of these signals will be further examined by assessing the correlation to histological endpoints and tissue biomarker data.
LADYBUG Phase 2a study in RA
This randomized placebo-controlled study enrolled 28 patients with moderate to severely active RA and an inadequate response to methotrexate.
At week 6, patients on GLPG3970 showed no differentiation from placebo on change from baseline in DAS28 (CRP) response (GLPG3970 -1.29, placebo -1.24), nor on most other efficacy endpoints.
Outlook SIK portfolio
From these three clinical studies we learned that the SIK pathway has the potential to play an important role in inflammation and confirms the therapeutic potential of SIK inhibitors in inflammatory diseases. Although we will not progress GLPG3970 into clinical development, the study results are an essential part of the broad evidence package that we are assembling on our SIK program. This strengthens our understanding of the best approach going forward. Today, we have several molecules targeting SIK2 and SIK3 with higher potency, as well as more selective molecules acting on SIK2 and SIK3 combined, that we aim to advance. Generating data with relative inhibition of SIK2 versus SIK3 will deepen our knowledge of the safety profile and inform us which isoforms best match with specific inflammatory conditions. We are currently finalizing a Phase 1 study with our SIK3 inhibitor GLPG4399 in healthy volunteers.