TYK2/JAK1 - Viral Infections

The aim of Sareum’s Covid-19 research programme is to investigate the effects of SDC-1801 on cytokine signalling after human cells are infected with SARS-CoV-2, to confirm whether an over-active inflammatory response (known as a ‘cytokine storm’) via the Interferon Type 1 pathway can be blocked in this disease. The Company will also investigate whether treatment with SDC-1801 in disease models can re-establish protection against bacterial pneumonia following SARS-CoV-2 infection.

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.

Sareum has been awarded a grant of approximately £174,000 by UK Research & Innovation (“UKRI”) to investigate the therapeutic potential of SDC-1801 in preclinical models of severe phase Covid-19.

This six-month project was completed on schedule, generating promising results. The project found that SDC-1801 reduced the levels of cytokines associated with ARDS in human lung cells infected with SARS-CoV-2 and demonstrated a profile that was superior to the anti-inflammatory steroid dexamethasone and similar to baricitinib, a JAK1/JAK2 inhibitor.

The design and timing of the clinical trials for Covid-19 applications will be determined following consultations with experts in the field. The trial may be eligible for further UK government funding from the recently launched AGILE clinical development platform, or equivalent programmes, which have been established to fund Phase 1 trials and fast-track the development of potentially ground-breaking Covid-19 treatments.

Further details can be made available to potential funding, collaboration and/or licensing partners on request.

References

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.