Coronavirus: Therapeutic strategies under consideration

Apr 9th, 2020 by Guillaume Leboucher, PhD

science lab

France is gradually realizing the implications of the major health crisis represented by the SARS-CoV-2 pandemic, and it might take months to fully understand the economic and social impact of this virus. Many players in the pharmaceutical industry are now getting in motion using different means and approaches to solve the crisis, from a therapeutics perspective.

In this article, I am listing the options currently available to Research Institutes, biotech companies and the Pharmaceutical industry.

The common sense would be to imagine that when a new disease emerges, a new drug must be found, and this is currently expected from non-scientists. However, this solution is probably not the most efficient way out of the crisis, and we must look at the different options available to the scientific community.

Finding a new drug for COVID-19

To start a new drug project, researchers generally begin by identifying a therapeutic target that is involved in the development of the pathology. In the case of SARS-CoV-2, the target may, for example, be a function essential to viral replication, whether it comes from the virus itself or from a host function that the virus uses to its advantage.

For example, an initial study shows that one of the virus' proteins, the S protein, interacts with two proteins in human cells (ACE2 and TMPRSS2): those two proteins become potential targets for drug development.

In France, three fundamental research projects have been launched as part of the REACTing plan to gain a good understanding of the virus replication mechanisms and to create a model of the virus that will be useful for future projects.
Depending on the results of these research projects, molecules may be tested for their effects on the virus replication cycle. These molecules are selected from molecule libraries or by using molecules already known to act on the target or a similar target.

La simulation in silico

In silico simulation, which uses artificial intelligence algorithms to generate multiple proposals in a short period of time, can limit the number of molecules to be tested in vitro and optimize the cost of this step.

Once the best candidates have been identified, the objective is to transfer them as quickly as possible to preclinical and clinical testing.

Preclinical and clinical phases

Preclinical and clinical tests are numerous and costly. On average, a pharmaceutical company will have to spend around €1 billion over at least 8 years to make the drug available to patients. Research institutes and the pharma industry are well equipped, but these delays are not compatible with the urgency of the situation.

There is a good chance that many projects will emerge in this direction for this health crisis, particularly thanks to European initiatives and the joint project of the Bill & Melinda Gates Foundation and the Welcome Foundation.

However, what will be the future of these projects when the crisis is over? It is indeed quite possible that such a drug marketed after the peak of the pandemic will no longer be relevant.

Developing a vaccine against the virus responsible for COVID-19

The alternative considered by many countries, including the United States and the Pharma industry, is the development of a vaccine to protect against the virus responsible for COVID-19. The first clinical trial for a vaccine has begun, under a project led by the NIH (National Institutes of Health) and biotech company Moderna Inc.
Indeed, in some countries, politicians urged the scientific community to develop vaccines, if possible, within weeks. The mainstream understanding at the beginning of the pandemic was that it would come up really quickly with a vaccine, like every year a new flu vaccine is developed in just a few months.

Why do scientists aim for 18 months to prepare a first vaccine against the coronavirus? Conversely, why does the classical development of a vaccine take between 10 and 15 years as for drugs, which is at least 8 years longer than that for coronavirus?

Why developing a vaccine would be faster?

First, the development of the flu vaccine has already been done, the one that arrives in the pharmacy every year is a kind of seasonal update of the virus. In some countries, it is not necessary to test the toxicity of this new version, which drastically shortens the time to market.

Secondly, the development of a coronavirus vaccine can be done by taking over ongoing projects. Scientists from Research Institutes and the pharma industry must then find the projects that would be most relevant, and for which testing has already taken place. This facilitates the clinical phases of toxicity of the candidate vaccine.
This is particularly the case in the development of a vaccine for the infectious bronchial virus by researchers at the Migal Galilee Research Institute. This virus has a high genetic similarity with SARS-CoV-2, and the Research Institute has announced that the vaccine could be ready within a few weeks!
For its part, Sanofi has announced that it is testing the repositioning of a SARS vaccine project for SARS-CoV-2.

Finally, the project of the US biotech company Moderna is a candidate developed as part of a treatment against Ebola. It represents the 10th vaccine developed by Moderna against infectious diseases to enter clinical trials. The study will include a total of 45 adults, followed for 12 months.

The project underway by the NIH and Moderna is based on an innovative and relatively recent method for the development of a new vaccine: injecting messenger RNA (mRNA), a molecule derived from DNA, into patients so that immunogenic peptides are expressed and considered as foreign bodies by the immune system. The advantage is that the large-scale production of mRNA is fast compared to traditionally injected peptides or polysaccharides. The disadvantage is that the method is highly experimental, and only a crisis such as todays could see the FDA approve such projects so quickly (as is the case with Roche's SARS-CoV-2 diagnostic test).

The Pasteur Institute projects

In France, the Institut Pasteur is applying the vaccine strategy already developed to deal with SARS-CoV-1 in 2003. The technique is based on the measles vaccine, which is highly effective and has been used for many years. The principle is to introduce pieces of the SARS-CoV-2 genome into the measles vaccine so that it expresses the immunogenic peptides of the virus. This technique led to the patenting of a vaccine against SARS-CoV-1 in 2004. However, clinical trials of this vaccine were not continued because the epidemic had ended before the vaccine was developed, leaving no more patients for testing. This could be the case for the ongoing outbreak. However, researchers at the Institut Pasteur have started preclinical testing for the SARS-CoV-2 vaccine and estimate that it will take about 20 months before the vaccine is released to the market.

Chances are that one of these projects will take the lead in the coming weeks, however, it seems to be relevant for a new season of the virus, if it hasn't mutated by then. If this were the case, we would find ourselves in a situation potentially similar to that of the flu: development of a seasonal vaccine in a few months.

Repositioning an existing drug or vaccine

Drug repositioning consists in using molecules in development or already marketed for indications different from those for which they have been developed or prescribed today. The major advantage is that toxicity tests have already been performed and do not need to be repeated, if the drug is used in an identical way, and new Phase II trials can begin rapidly once efficacy has been demonstrated by pre-clinical studies.

Overall, the repositioning strategy is much faster and less costly than the de novo and vaccine development options, particularly for molecules that are still in development but not yet on the market.

For this reason, many projects are underway, including the following:

Repositionnement du Remdesivir

An antiviral drug initially developed to treat Ebola virus disease, in several studies in the U.S. and France as part of the Reacting projects.

Repositioning of Kevzara

Kevzara (Sarilumab) by Sanofi and Regeneron. This monoclonal antibody was launched in 2017 for the treatment of rheumatoid arthritis. It targets the interleukin-6 (IL-6) receptor, an immune system protein involved in inflammation. Approximately 400 patients are expected to be enrolled in this trial. Regeneron will lead the U.S. trials and Sanofi will lead the rest of the world trials.

Repositioning of Chloroquine

The repositioning of hydroxychloroquine, which was largely debated, as a treatment for rheumatoid arthritis and, for a time, as an alternative anti-malarial treatment to chloroquine, by several groups, including one in Marseilles which demonstrated its effectiveness on a very small group of patients. A new group at the Pitié Salpêtrière has also just started a clinical trial.

Scientists and politics are looking to these repositioning studies, hoping to find an effective way to treat the disease quickly, and thus curb the spread of the virus.

Several other repositioning projects are underway, including Favipavir, Interferon beta, lopinavir, vitamin C, azithromycin, APN01 and Ciclesonide.

What's going to happen, now and tomorrow?

The health crisis at the beginning of 2020 is forcing governments to take drastic measures and the population to change its daily life.

It will find a way out, following containment, validation of drug and vaccine candidates, and when the number of infected patients is falling.

As a former researcher and now an entrepreneur dedicated to Research, the questions asked echo the missions of the startup I created: the need to accelerate R&D projects.

The questions that political decision-makers need to ask themselves are the following: could this crisis be avoided if Research had more resources? How can projects be financed differently? Dr. Abdelhakim Ahmed-Belkacem, head of the coronavirus laboratory at the Henri Mondor Hospital in Créteil says that "as a general rule, when you start writing a research project to find funding, the first thing you write on the file is the number of deaths in the world. The interest of the pathology varies according to its seriousness: its spread and mortality."

If we look at the French case, the government has increased in 2019 and 2020 the budgets allocated to Research. But is this enough and are the projects funded up to the challenges of our society?

As far as ongoing projects on SARS-CoV-2 are concerned, France is fully in line with other countries that invest in research and hosts the major players in the pharmaceutical industry (several vaccine, drug and diagnostic projects). Interestingly, some projects are led by Sanofi and Institut Pasteur but also by much smaller players: Iktos for a project using artificial intelligence, and Novacyt for the development of a diagnostic kit approved by the EMA (European Medicines Agency). The crisis is only just beginning, but Research is a long term task. The efforts made by the ecosystem are supported by the largest structures: NIH, Pharmaceuticals industries, INSERM in France.

Innovation in Health is driven today by small or medium-sized biotech companies that are likely to be bought out by giants and are struggling to find sufficient funding. The risk is to see projects not related to coronavirus and that could save lives come to a halt because today's crisis will inevitably have a major impact on these companies.

Guillaume Leboucher PhD portait

Guillaume Leboucher, PhD
Co-founder of Labtoo