TYK2 Identified as a Key Genetic Mechanism of Critical Illness in Covid-19 and as an Important Potential Target for Therapy
Findings published in Nature support scientific rationale for Sareum’s SDC-1801 development programme in Covid-19 and its recent grant award from UKRI
Cambridge, UK, 14 December 2020 – Sareum Holdings plc (AIM: SAR), the specialist drug development company delivering targeted small molecule therapeutics to improve the treatment of cancer and autoimmune diseases, is pleased to note that a multi-centre analysis of DNA samples from patients with severe forms of Covid-19, including symptoms caused by the over-active inflammatory response (“cytokine storm”), has identified TYK2 as a key causative genetic mechanism and a potential target for therapy.
This observation, which was published online as an Accelerated Article Preview by Nature on 11 December 2020 (*Pairo-Castineira, E. et al.) is consistent with the scientific rationale supporting Sareum’s recent successful UK Research & Innovation (UKRI) grant application for its proprietary TYK2/JAK1 inhibitor, SDC-1801.
The funding from this grant (announced by the Company on 3 December 2020) will be used to investigate the therapeutic potential of SDC-1801 in severe phase Covid-19, in a six-month research project, with results expected around mid-2021. This research will treat cells infected with the SARS-CoV-2 virus with SDC-1801 to evaluate its potential to block the immune pathway that leads to the cytokine storm in this life-threatening disease.
Sareum also intends to investigate if treatment with SDC-1801 in disease models can re-establish protection against bacterial pneumonia following SARS-CoV-2 infection.
Sareum’s CSO, Dr John Reader, commented:
“The important findings of this extensive DNA analysis, which were highlighted in this Nature Article Preview, provide strong support for our hypothesis that TYK2 inhibition could be a significant contributor to the fight against the life-threatening cytokine storm effects of severe Covid-19. We are very pleased to have recently received a UKRI grant to test this hypothesis and look forward to working closely with others in the field to evaluate the potential of this new approach to bring a much-needed treatment option to patients with severe Covid-19.”
*Pairo-Castineira, E. et al. Genetic mechanisms of critical illness in Covid-19. Nature https://doi.org/10.1038/s41586-020-03065-y (2020).
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About SDC-1801 and its potential to treat severe-phase Covid-19
SDC-1801 was designed by Sareum to be a potent and selective dual inhibitor of tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1), which are part of the JAK family of proteins. These are important in cytokine-mediated cell signalling, which is a key component of the inflammatory response seen in autoimmune diseases and potentially the cytokine-release syndrome (CRS) associated with severe Covid-19. JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in Covid-19 and other viral infections.
SDC-1801 has demonstrated a potent anti-inflammatory effect in multiple disease models and is currently in preclinical development with the potential to become a new therapeutic targeting a wide range of inflammatory diseases, such as psoriasis, systemic lupus erythematosus (SLE) and Crohn’s disease. It has demonstrated an encouraging safety profile in initial toxicity studies.
Covid-19 is caused by the virus SARS-CoV-2 and usually results in a mild disease that resolves on its own. However, some patients develop a potentially fatal severe disease due to inflammation arising from an overreaction of the immune system, known as CRS or a ‘cytokine storm’, leading to Acute Respiratory Distress Syndrome (ARDS), requiring intensive care. A major inflammatory pathway mediated by TYK2/JAK1 – the Interferon Type 1 pathway (Type 1 IFN) – is over-activated in severe Covid-19 patients and this pathway may be able to be blocked by SDC-1801.
Recently, researchers have observed the similarity between severe Covid-19 and the acute flares of lupus, an autoimmune disease characterised by overproduction of Type I IFN1. As Sareum reported in July 2020, SDC-1802, a close analogue of SDC-1801, demonstrated encouraging results in a disease model of lupus. The Company believes that SDC-1801 could potentially benefit severe-phase Covid-19 patients by blocking signalling along this inflammatory pathway and therefore reducing the ‘cytokine storm’.
Furthermore, disease model studies have reported that specifically inhibiting TYK2 activity restores the body’s ability to protect against bacterial pneumonia following influenza infection2, suggesting that a TYK2 inhibitor, such as SDC-1801, may have the same effect in Covid-19 patients. Serious bacterial infections have been reported in up to 50% of critically ill Covid-19 patients.
Positive results in its Covid-19 studies might lead to further opportunities for the Company to investigate SDC-1801 in treating severe and life-threatening inflammation that occurs as a result of other viral infections.
1 Woodruff M, et al. Critically ill SARS-CoV-2 patients display lupus-like hallmarks of extrafollicular B cell activation. medRxiv [Preprint]. (2020) May 3:2020.04.29.20083717. doi: 10.1101/2020.04.29.20083717. PMID: 32511635; PMCID: PMC7276991.
2 Berg J, et al. Tyk2 as a target for immune regulation in human viral/bacterial pneumonia. Eur. Respir. J. 2017; 50: 1601953 https://doi.org/10.1183/13993003.01953-2016.
Sareum is a specialist drug development company delivering targeted small molecule therapeutics to improve the treatment of cancer and autoimmune diseases. The Company aims to generate value through licensing its candidates to international pharmaceutical and biotechnology companies at the preclinical or early clinical trials stage.
Sareum is advancing internal programmes focused on distinct dual tyrosine kinase 2 (TYK2) / Janus kinase 1 (JAK1) inhibitors through preclinical development as therapies for autoimmune diseases, including the “cytokine storm” immune system overreaction to Covid-19 and other viral infections, (SDC-1801) and cancer immunotherapy (SDC-1802).
The Company’s preclinical FLT3+Aurora inhibitor programme targeting haematological cancers is licensed to a China-based specialty pharma company.
Sareum also has an economic interest in SRA737, a clinical-stage oral, selective Checkpoint kinase 1 (Chk1) inhibitor that targets cancer cell replication and DNA damage repair mechanisms. Preliminary Phase 2 and comprehensive preclinical data suggest SRA737 may have broad application in combination with other oncology and immune-oncology drugs in genetically defined patients.
SRA737 was discovered and initially developed by scientists at The Institute of Cancer Research in collaboration with Sareum, and with funding from Sareum and Cancer Research UK. SRA737 was licensed by CRT Pioneer Fund (CPF) to Sierra Oncology Inc. Sierra is currently exploring options to obtain the funding or support necessary to advance the future development of SRA737.
Sareum Holdings plc is listed on the AIM market of the London Stock Exchange, trading under the ticker SAR. For further information, please visit the Company’s website at www.sareum.com.
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