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Acute Respiratory Distress Syndrome (ARDS) in COVID-19BC201 Combination therapy
SARS-CoV-2
o Novel 2019 Corona virus –highly contagious
o Pandemic declared March 2020
o Severe COVID-19 disease in some patients
o >15M cases, 600k deaths (July 2020)
Ø SARS-CoV - 8098 Cases, 774 deaths (2002)
Ø MERS-CoV – 2495 Cases, 858 deaths (2012)
Complex disease requires a multifaceted approach:
1. Target SARS-CoV 2 cell entry AND reproduction (Val201)
o Src Kinase-Androgen Receptor Inhibitor (Src-ARi - ValiRx)
(Phase 1/2 data in clinical trials for prostate cancer)
o Decapeptide selectively inhibits non genomic AR signalling
Ø Block TMPRSS2 spike protein activator expression
Ø Block Src mediated viral capsid and RNA synthesis
2. Mitigate host directed NETopathy and hyperinflammation
o Src-ARi inhibits kinase dependant transcription (in NETosis)
o Niacin – available as extended release formulation (AbbVie)
(Clinically prescribed for hyperlipidemia - ⇩ LDL and ⇧ HDL)
o Vitamin B3 – Nicotine Adenine dinucleoside (NAD) substrate
Ø Depletion increases NADPH level/activity, ROS* and NETosis
Ø Protection against oxidative stress* (NET bystander effect)
Ø Reduces neutrophil infiltration, edema, and cytokine levels
o Dornase Alfa (Recombinant DNAse) (Genentech/Roche)
(clinical NET digester used in cystic fibrosis patients)
o Pulmozyme® or generic Tigeraze® mucolytic agent
Ø Improved lung function/oxygenation
Ø Reduced cytokine production
BC201: Benefits of combined therapyo less severe disease – lower hospital admissionso shorter disease time course – faster dischargeo less invasive treatment - lower ICU straino reduced long term damage – less ongoing support
Broad applicability to viral and bacterial sepsis
BC 201 COVID-19 targets -
1-2 weeks ICU
Home1-2 weeks
Home1 week
Hospital1-2 days
30-40% ICU mortality
A
B
C
D
Infection
Cell binding and entry
Reproduction
Cytokine storm
Systemic disease
Death
Asymptomatic
Mild Disease
Pneumonia
ARDS
40%
15%
5%
40%
Impaired oxygenation
Long term damage
Improved oxygenation
Reduced Hypoxia
US provisional filing June 2020 by Black Cat Bio Ltd
⇩ NETosis, cytokines ⇧⇧ Gas exchange ⇩⇩ Lung injury ⇧⇩ Edema ⇧
Neutrophil recruitment to diseased lung
Dr Mark Eccleston: [email protected] Suzanne Dilly: [email protected] Wolstenhulme: [email protected]
Neutrophil Extracellular Traps
Toxic histonesOxidising enzymes*
