Introduction

Current treatment options for IBD are limited by low clinical remission rates and loss of response. Most therapies target single pathogenic pathways and while combinations of biologics targeting different pathogenic cytokines can increase clinical remission rates, dosing schedules are inconvenient. JAK inhibitors, target multiple cytokine pathways, but are limited by safety concerns.
Salt-inducible kinases (SIKs) are a subfamily of serine/threonine kinases in the AMP-activated protein kinase (AMPK) family and act as key regulators of immune cell signaling. SIK inhibitors have been shown to target multiple cytokine pathways.
Three SIK isoforms exist: SIK1, SIK2 and SIK3. SIK inhibitors targeting multiple isoforms have been investigated in clinical trials. Although there have been signals of activity in patients with ulcerative colitis and psoriasis, limited efficacy and safety concerns related to SIK1 and 2 inhibition have hampered their development.

Aims & Methods

We performed structure based drug design to identify highly potent and selective SIK3 inhibitors that could offerbest in class efficacy and safety for the treatment of various auto-immune diseases. Our effort led to to the discovery of 100s of compounds spanning SIK3 binding sites. Compounds were tested in protein and cell-based assays to evaluate potency and selectivity against SIK3 and in a phenotypic human whole blood TNFα assay. Lead optimization involving rigorous testing in safety and pharmacology panels, resulted in the selection of lead candidates that were tested in a variety of translational models to identify the most efficacious compounds. Human PK predictions were performed using non-clinical in vivo PK assessments and allometric scaling leading to the selection of the drug candidate, which entered GLP toxicology studies.

Results

O3R-5671 is a highly potent and specific SIK3 inhibitor with sub-nanomolar potency for SIK3 and low activity against SIK1 and 2 and over all human kinases. It demonstrated potent activity in a panel of human primary phenotypic cell assays inhibiting TNFα, IL-12, and IL-23 release in LPS-stimulated myeloid cells, and inhibiting TNFa release in LPS-stimulated human whole blood. O3R-5671 also inhibited activation of TCR-stimulated human primary T cells and induced IL-10 secretion from myeloid cells.
In vivo, O3R-5671 demonstrated dose-dependent activity in a mouse LPS challenge model, dose-dependent efficacy in two distinct mouse models of IBD, and dose-dependent efficacy in mouse models of IL-23-induced psoriasis and psoriatic arthritis. Cross-species PK and allometric scaling were used to predict O3R-5671’s human PK profile- which is expected to be conducive to potent SIK3 inhibition and clinical efficacy in patients with IBD.
O3R-5671 demonstrated a highly attractive profile in ADME and in vitro safety panels. Six-week GLP toxicity studies in rats and dogs established no observed adverse effect levels (NOAELs) which support dosing in humans with doses that are predicted to be pharmacologically active with a large safety margin.

Conclusion

O3R-5671 is a highly specific and potent SIK3 inhibitor that is predicted to have a flat PK profile in humans. These properties should allow O3R-5671 to apply strong drug pressure on SIK3 while sparing SIK1 and 2. This is expected to result in the inhibition of multiple pathogenic cytokines including TNFa and IL-23, both of which have been validated as IBD targets. A clinical trial is ongoing to establish the safety and PK profile of O3R-5671 and understand its effect on pharmacodynamic biomarkers.

Disclosure

All authors were employed by Galapagos who discovered O3R-5671 or Novalix, a CRO that was employed by Galapagos. Some authors are employed by Onco3R therapeutics, who are currently developing O3R-5671

Introduction

Prospective evidence of the long-term efficacy of endoscopic submucosal dissection (ESD) for T1 colorectal cancer (CRC) is insufficient.

Aims & Methods

We aimed to evaluate long-term ESD outcomes for T1 CRC, focusing on the risk stratification criteria and necessity of additional surgery.
This large-scale, multicenter, prospective cohort study was conducted by Hiroshima GI Endoscopy Research Group. All consecutive patients who underwent colorectal ESD between January 2014 and December 2018 were included, and those with pathologically confirmed T1 CRC were analyzed. Patients were classified into low-risk and high-risk groups based on histopathological risk factors for lymph node metastasis in JSCCR guidelines. High-risk patients were categorized into those who underwent additional surgery (surgery group) and those who were followed up without surgery (follow-up group).

Results

Among 2357 patients who underwent ESD for 2478 early colorectal neoplasms, 431 were diagnosed with T1 CRC. Ten recurrences (2.6%) and five T1 CRC-associated deaths (1.3%) occurred in the high-risk group, with none in the low-risk group. Five-year cumulative overall and local recurrence rates were significantly higher in the follow-up versus surgery group (7.7% and 1.9%; P=0.019 versus 6.4% and 0%; P<0.001), with no local recurrence in the surgery group. Five-year overall survival was significantly worse in the follow-up group (79.5% and 95.2%; P<0.001), while no significant difference was found in 5-y disease-specific survival (98.5% and 98.5%; P=0.447).

Conclusion

No recurrence or mortality occurred in the low-risk group, suggesting that intensive surveillance may be unnecessary for these patients after curative ESD. Additional surgery could prevent local recurrence for high-risk T1 CRC, supporting a risk-based treatment approach.