Our Toledo program

Our inflammation franchise
CSR report

“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).

Restoring the immune balance

Restoring the immune balance (graphic)

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.

Optimization through innovative chemistry

Optimization through innovative chemistry (graphic)

Toledo portfolio

Toledo portfolio (graphic)

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.

Promising and broad in vivo activity

Promising and broad in vivo activity (graphic)

IBD: inflammatory bowel disease; Pso: psoriasis; PsA: psoriatic arthritis; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; OA: osteoarthritis; SSc: systemic sclerosis; IPF: idiopathic pulmonary fibrosis

GLPG3970: strong in vivo activity

The activity of GLPG3970 has been observed in vivo across different IBD models, as shown below.

Robust activity in vivo in 3 IBD models

Robust activity in vivo in 3 IBD models (graphic)

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).

Impacting both sides of the balance in vivo

Multiplex cytokine analysis in IBD colon tissue (T-cell transfer model)

Impacting both sides of the balance in vivo (graphic)

We also observed strong activity of GLPG3970 in RA and psoriasis models:

Robust activity across arthritis models

Robust activity across arthritis models (graphic)

GLPG3970 activity in psoriasis model

GLPG3970 activity in psoriasis model (graphic)

Source: internal data on file

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.

Dual activity confirmed ex vivo 

Mean per treatment

Dual activity confirmed ex vivo (graphic)

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.

Parallel Proof of Concept studies

Parallel Proof of Concept studies (graphic)

* Timelines subject to delays due to global COVID-19 pandemic