Memorial Sloan Kettering Cancer Center: Potential treatment of COVID-19 using inhalable camostat/nafamostat formulated with HPBCD or SBECD

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Memorial Sloan Kettering Cancer Center (MSKCC) has filed a patent application on an inhalational therapeutic composition of camostat solubilized by HPBCD or SBECD which was recently published (WO2021188815).

Camostat mesylate is a protease inhibitor approved for clinical use in Japan for the treatment of chronic pancreatitis and postoperative esophagitis. Camostat mesylate was recently shown to be an inhibitor of a cellular protease (TMPRSS2) required for entry of the SARS-CoV-2 virus into lung cells in a study by Hoffmann et al. entitled “SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. ” See Hoffmann et al., Cell, (2020), Vol. 181, pp. 1-10 (published online March 5, 2020). Hoffman et al. found that camostat mesylate had only modest potency for blocking SARS-CoV-2 virus entry into lung cells – having an apparent EC90 of 5-10 mM. This led the research group at MSKCC to hypothesize: (a) that systemic administration of camostat mesylate may cause significant off-target side effects at the doses required to block SARS-CoV-2 entry, and (b) that localized delivery of camostat (e.g., camostat mesylate) directly to affected lung tissue may provide therapeutic efficacy with reduced side-effects (inhalational delivery directly to the lung typically requires about 400 times less drug than is required for systemic delivery).

The researchers also hypothesized that direct administration of camostat mesylate to the lungs in combination with systemic (e.g. oral or IV) delivery of camostat mesylate might be even more effective – with possible synergistic effects resulting from targeting both the lung and upper GI tract pathologies associated with COVID-19 disease.

Nafamostat mesylate is an analog of camostat mesylate, suggested to have similar activity against SARS-CoV-2 that has also been approved for use in human subjects. Therefore, it was hypothesized that inhibition of SARS-CoV-2 viral entry via inhalational administration of nafamostat (e.g., nafamostat mesylate or nafamostat bismesylate) may also be clinically beneficial for treating COVID-19 disease.

An exemplary formulation proposed for the administration via inhalational route was prepared in water for injections (WFI) having final SBECD concentration of 12.5 % and 38.8 mg/mL content of camostat mesylate. Another example showed that 10% (w/v) HPBCD in WFI enabled camostat mesylate level of 45.0 mg/ml.

Preclinical studies were performed in which luciferase (or fluorescent reporter protein) had a protease cleavable sequence (from SARS-CoV-2 spike protein) and activity of cellular protease TMPRSS2 inactivated the luciferase (or fluorescent reporter). These biosensor proteins (and substrates, in the case of a luciferase system) were delivered at the time of, or together with, or before the delivery of the compositions of the invention. If the composition reached the protease at a therapeutic concentration, then the protease cleavage site was blocked through protease inhibition, and the luciferase (or fluorescent reporter) signal was increased – as observed by whole-body luciferase imaging (or whole-body fluorescent imaging, in the fluorescent reporter version).

Even though the actual testing of antiviral efficacy of the studied complexes did not involve any functional SARS-CoV-2 virus (at the date of the provisional application dated back to March 18, 2020), the preclinical results were encouraging enough conducting further research, moreover there are currently 5 ongoing/planned clinical studies involving Camostat in the fight against COVID-19 according to database.

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