Our Toledo program
“Toledo” is our program name for a novel target class, the Salt-Inducible Kinases (SIKs), which we discovered with our 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 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 are expected to effectuate a dual mode of action on inflammation by stimulating anti-inflammatory cytokines and inhibiting pro-inflammatory cytokines. This potential master switch brings an opportunity to restore the immune balance that is typically out of control in auto-immune diseases and is potentially differentiated from existing therapies that predominantly act by suppressing the immune system (see figure below).
Extensive Toledo portfolio
The family of SIKs contains three targets: SIK1, SIK2 and SIK3. In our search for compounds acting on these targets, over 3,000 molecules were synthesized leading to more than 10 different chemical series with multiple selectivity profiles. The lead molecule, GLPG3970, a SIK2/3 inhibitor, was prioritized over the first-generation compound GLPG3312, a pan-SIK inhibitor, following Phase 1 completion, given its more suitable pharmacological profile. GLPG3970 is currently being tested in five Phase 2 Proof of Concept trials. GLPG4399, a selective SIK3 inhibitor, is in Phase 1, whereas GLPG4876 and GLPG4605 are advancing preclinically (see figure below). Several other compounds with different profiles are being explored in discovery.
The developed compounds were extensively tested in a broad panel of animal models for different inflammatory diseases. Based on the collected data including cytokine profile analysis, we discovered that these SIK compounds were able to modulate several aspects of the innate and adaptive immune system opening up a wide spectrum of potential disease indications. Based on this information, combined on the findings on SIK selectivity as well as individual compound profiles, we were able to match each compound with a set of potential disease indications. The figure below describes the Toledo family of compounds with demonstrated activity in relevant preclinical disease models for inflammation and fibrosis.
The discovery strategy for the Toledo program is to continue to advance multiple candidates across different selectivity profiles. The broad panel of in vivo disease models guides clinical development.
GLPG3970: strong in vivo activity
The activity of GLPG3970 has been observed in vivo across different IBD models, as shown below.
As shown below, the analysis of diseased IBD colon tissue brings out the dual mode of action of GLPG3970, reducing the pro-inflammatory cytokines (such as a decrease in TNFα levels), and inducing the anti-inflammatory cytokines (such as an increase in IL-10 levels).
We also observed strong activity of GLPG3970 in RA and psoriasis models:
GLPG3970: encourgaging data from a healthy volunteer study
Following these successful encouraging results across a range of preclinical models, we evaluated GLPG3970 in a healthy volunteer study. The results from this Phase 1 single and multiple ascending dose study demonstrated that GLPG3970 was well tolerated, with an encouraging pharmacokinetics (PK) profile. For pharmacodynamics (PD) analysis, blood was drawn from the healthy volunteers on Day 1 and on Day 14 after administration of different doses of GLPG3970 or placebo, after which the blood was stimulated ex vivo to measure effects on cytokine release. The figure below shows a dose-dependent effect between GLPG3970 and two cytokines. The pro-inflammatory cytokine, TNFα, decreased with increased compound dosing (left). The anti-inflammatory cytokine, IL-10, increased (right) with increasing compound dosing, confirming the dual activity of GLPG3970.
GLPG3970: five PoC signal detection studies currently ongoing
Following the completion of the first part of a Phase 1 trial, GLPG3970 progressed into a Phase 1b in psoriasis and safety and “signal seeking” Phase 2 Proof of Concept trials in four additional indications, with the first three topline readouts (CALOSOMA, SEA TURTLE, LADYBUG) expected in 2021.