While others were stocking up on toilet paper, they set up a trial in record time
Part of their reward for their hard work was that The Lancet published the result even though it was negative – but the researchers are still on the case and are now experimenting with new doses and indications.
In March last year, while many other Danes were stocking up on toilet paper, Mads Kjølby, Ole S. Søgaard and their team set up an international trial in just three weeks and one day – and what’s more, they did it with a drug that was not approved in either the USA or the EU, but only in Japan and South Korea, and with almost all the information about it written in Japanese or Korean.
Assistant Professor Mads Kjølby MD, PhD is a DDA alumnus who works at the Centre for Clinical Pharmacology, Department of Biomedicine, Aarhus University, and also at DANDRITE. Right now he works in Dundee, supported by among others also Steno Diabetes Center Aarhus. Ole S. Søgaard is a professor in the Department of Infectious Diseases, also at Aarhus University.
The trial: day by day
On Day 1, Mads Kjølby read an article by Stefan Pöhlmann in Cell, which gave him the idea of testing whether the Japanese anti-pancreatitis drug concerned, camostat mesylate, might be effective against Coronavirus. Previous mouse experiments in 2015 had indeed shown that, ‘dosed at concentrations similar to the clinically achievable concentration in humans’, it could reduce mortality following SARS-CoV-1 infection from 100% to 30-35%. As the mechanism of virus infection in lung cells requires ACE2 and TMPRSS2 in the case of both SARS-CoV-1 and SARS-CoV2 (COVID-19), there was a theoretical basis for hypothesising that the drug would also work against COVID-19. Mads then contacted Ole S. Søgaard, who agreed with the idea.
On Saturday (Day 2), the medication was ordered from Japan via the Hospital Pharmacy Service in Aarhus. In the remaining three weeks, they drew up the study protocol, obtained approval from the scientific ethics committee and the Danish Medicines Agency, and on a practical level they set up the whole network of hospitals so that 50% of the Danish population was covered. They also managed to get the camostat mesylate delivered – while the world was locked down because of COVID-19, that is - and they had all available material on the drug translated. ‘Fortunately, we had colleagues in DANDRITE at Aarhus University who stepped in and helped with translating the relevant Japanese and Korean articles. Several other colleagues at Aarhus University also helped with writing a synopsis of the sub-topics that needed to be clarified so that the study could be launched’, says Mads Kjølby.
As meeting at the university was impossible, the collaboration, which included about 40 people, took place virtually via Slack, a kind of professional bulletin board in the Teams/Facebook mould. No one was paid for their help, although they put in a substantial effort to make it possible.
They also managed to obtain funding: as the first applicants, they were awarded 5 million Danish kroner by the Lundbeck Foundation from its special Corona-related fund, while Central Denmark Region and the State Emergency Fund for COVID Medication paid for the drug.
‘The drug was almost the least of it’, says Mads Kjølby, ‘because camostat is cheap. We treated 137 people for the price of treating four with remdesivir’.
The big savings are helping him and his team to continue the work even though the first study was unable to show sufficient effect in humans.
‘But we did find out that there are no side effects and that camostat has no negative impact on patients. But we still don’t know at what point patients should be treated or at what dose. In the animal trial, the mice were treated before they were exposed to infection. So, from those trials, we have to assume that the sooner treatment is initiated, the better the effect. But the ongoing worldwide trials will have to help prove or disprove that’, he says.
New trials with higher doses and different indications
One thing the scientists are now investigating more closely is whether the result will be different if the dose is changed or if camostat is administered earlier. ‘Will it affect deaths, the severity of the disease or its late complications?’ In the trial that has now finished, there were 205 patients altogether – 68 received the placebo – and they all had the very low maximum dose of 600 mg that is approved in Korea and Japan. In the trials that are going on now in a number of countries, the researchers are using three or four times the dose – in one Japanese trial, the dose has been quadrupled. ‘We are taking part in some of the trials ourselves and carrying out sub-components of the trials, but we have no results yet’, says Mads Kjølby.
My family hardly saw me – and when they did, I was on the phone
He makes no secret of the fact that it has been difficult. ‘My family actually didn’t see me for weeks, and when they did, I was mainly on the phone’, he says. On the other end of the line were researchers from more or less everywhere in the world, discussing research results – and there were journalists. He was interviewed for a great many media outlets, including China’s billion-viewer Xinhua News, Denmark’s DR and TV2, and various newspapers and radio stations.
Involving genetic information in the treatment of type 2 diabetes
Mads Kjølby is currently working in Scotland, as part of his specialisation in clinical pharmacology, on a new research project dealing with the implementation of precision medicine, including the involvement of genetic information in the treatment of type 2 diabetes. This work is going on at the University of Dundee. The project is being carried out in collaboration with Professor Ewan Pearson, who is a pioneer in precision medicine and pharmacogenetics.
‘The project includes a “recruitment-by-genotype” trial in which we are investigating whether we can use “metabolomics” to study a particular the function of a particular liver enzyme’, he says.
The enzyme is important in the effect and side-effect profile of relatively commonly used drugs, including diabetes drugs. If we know the function of the enzyme (which is determined partly by the genotype, but also by the inhibiting effect of other medications on the enzyme), it may be possible to use this information to 1) select medication for the individual, and 2) determine the dosage. Read more in the article “Inddragelse af genetisk viden i behandling af type 2 diabetes".
The background to the team’s interest in camostat mesilate is an article in Cell of 5 March 2020: a German scientist, Stefan Pöhlmann, had found that camostat mesylate, which inhibits proteases in the pancreas and has been used in Japan and Korea since the 1980s, could inhibit viruses’ access to cells. ‘We know that 70% of all viruses entering a cell use this mechanism, and we know it works in animals, so we banked on that’, says Mads Kjølby.
The team’s theory is that camostat can counteract the virus by inhibiting an enzyme that everyone has in their body. With this enzyme out of action, the theory is that Coronavirus will be unable to work its way into the healthy lung cells, making it impossible for it to replicate and attack more healthy cells.
Experiments on mice have previously shown that, dosed at concentrations similar to the clinically achievable concentration in humans, the drug can reduce mortality following SARS-CoV infection from 100% to 30-35%.
Read the article about the study in EClinicalMedicine (The Lancet):
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00129-2/fulltext (original article - the trial)
And the background information in the following two publications:
Read about DANDRITE here:
Read about Ewan Pearson here:
The current clinical trial in Scotland: ISRCTN88417663
Mads Fuglsang Kjølby
Assoc. Professor, MD, PhD
University of Dundee and Ninewells Hospital, Scotland, UK
Clinical Research Fellow
Phone: +44 07434 658430
Aarhus University Hospital
Phone: +45 2328 0601
Danish Research Institute of Translational Neuroscience
Nordic EMBL Partnership for Molecular Medicine
Department of Biomedicine
Mobile: +45 6086 6653