TITLE: Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis:
Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics
Tom M. Quinn
#1,2
, Erin E. Gaughan
#1,2
, Annya Bruce
1
, Jean Antonelli
1
, Richard O’Connor
1
, Feng Li
1
,
Sarah McNamara
1
, Oliver Koch
3
, Claire MacIntosh
3
, David Dockrell
1,3
, Timothy Walsh
1,2
, Kevin G.
Blyth
4
, Colin Church
5
, Jürgen Schwarze
1
, Cecilia Boz
1
, Asta Valanciute
1
, Matthew Burgess
1
, Philip
Emanuel
1
, Bethany Mills
1
, Giulia Rinaldi
1
, Gareth Hardisty
1
, Ross Mills
1
, Emily Findlay
1
, Sunny
Jabbal
2
, Andrew Duncan
3
, Sinéad Plant
3
, Adam D. L. Marshall
1,2
, Irene Young
1
, Kay Russell
1
, Emma
Scholefield
1
, Alastair F. Nimmo
2
, Islom B. Nazarov
6,7
, Grant C. Churchill
7
, James S.O. McCullagh
9
,
Kourosh H. Ebrahimi
13
, Colin Ferrett
8
, Kate Templeton
2
, Steve Rannard
10
, Andrew Owen
10
, Anne
Moore
1
, Keith Finlayson
1
, Manu Shankar-Hari
1
, John Norrie
11
, Richard A. Parker
11
, Ahsan R.
Akram
1,2
, Daniel C. Anthony
7
, James W. Dear
2,12
, Nik Hirani
1,2
, Kevin Dhaliwal*
1,2
#
contributed equally
*Correspondence to Kev.Dhaliwal@ed.ac.uk
1
Centre for Inflammation Research, Queen’s Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh,
UK
2
Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh
3
Regional Infectious Disease Unit, NHS Lothian
4
Institute of Cancer Sciences, University of Glasgow
5
Department of Respiratory Medicine, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde Health
Board, Glasgow, UK
6
Latus Therapeutics, Oxford, UK
7
Department of Pharmacology, University of Oxford, Oxford, UK
8
Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
9
Department of Chemistry, University of Oxford, Oxford, UK
10
Centre of Excellence for Long-acting Therapeutics, Materials Innovation Factory & Department of Pharmacology and
Therapeutics, University of Liverpool
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
11
Edinburgh Clinical Trials Unit (ECTU), Usher Institute, University of Edinburgh, Edinburgh, UK
12
Centre for Cardiovascular Science, Queen’s Medical Research Institute, Bioquarter, University of Edinburgh, Edinburgh,
UK
13
Institute of Pharmaceutical Science, King's College London, UK
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
TITLE: Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis:
Phase 2A Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics
ABSTRACT
Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a
global health problem and further chemotherapeutics are required. Many repurposed drugs have
progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics
(PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate
(Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory
properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-
2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell
entry.
Methods:
We present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT),
exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19
pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative
therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and
clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell
flow cytometry and viral load.
Results:
Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous
Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more
adverse events and a lower number of oxygen free days. There were no other statistically significant
differences in the primary or secondary endpoints between Nafamostat and SoC. PK data
demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We
observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no
differences in cytokine profile and immune cell phenotype and viral loads between the groups.
Conclusion
In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory,
anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials
with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to
selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat
delivered via a different route may be warranted. This trial demonstrates the importance of
experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
INTRODUCTION
COVID-19, caused by the coronavirus SARS-CoV-2, was declared a global pandemic on the 11
th
of
March 2020 [1] and an ongoing global health, social and economic crisis has ensued. Vaccination
programmes are at varying stages globally, with concerns in vaccinated populations regarding
resistant strains ever-present. Identifying effective treatments for preventing clinical deterioration is
therefore of paramount importance. At the time of writing, dexamethasone and interleukin-6 receptor
antagonists [2] are the only effective treatments available for COVID-19 [3] [4], however, the
mortality rate of unvaccinated COVID-19 in hospitalised patients remains high at 22.9% [2].
Further chemotherapeutics are therefore required, with the repurposing of pre-existing drugs, quicker
and more cost-effective than the development of new medications.
Nafamostat Mesylate (Nafamostat) is a synthetic protease inhibitor and directly inhibits the
transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry of MERS-CoV,
therefore, blocking human cell entry [5]. This method of cell entry is shared by other coronaviruses
including SARS-CoV-2, and in-vitro studies have confirmed activity against SARS-CoV-2 [6, 7].
Nafamostat has shown to significantly reduce weight loss and lung tissue SARS-CoV-2 titres in
murine models [8]. Nafamostat has a short half-life and poor oral bioavailability, which necessitates
intravenous administration, limiting the potential use of the current formulation outside of a hospital
setting. It has been used to treat disseminated intravascular coagulation (DIC), acute pancreatitis, and
as an anticoagulant in extracorporeal hemofiltration and dialysis since the 1980s. In addition to the
potential antiviral effects, Nafamostat inhibits platelet aggregation, inhibits thrombin, kallikrein,
plasmin and other complement factors and reduces endothelial activation [9]. Given the prominent
activation of thrombotic pathways and endothelial inflammation in COVID-19 immunopathogenesis,
these are potentially beneficial attributes.
In this context Nafamostat is a drug highlighted as a potential target due to its antiviral,
immunomodulatory and anticoagulant effects. Nine trials are ongoing without testing whether at the
current recommended dose and route of administration, it has the expected PK/PD and safety profile.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
