Not only the Chinese Hubei’s province: while we are writing and after Italy being the first European country, almost all the EU and many other countries have been totally locked down to try avoid the spreading of the new SARS-CoV-2 coronavirus. No pharmaceutical treatment is currently available to fight the infection, which can cause a severe interstitial pneumonia representing the main cause of death for the disease. An outlook on SARS-CoV-2 virus’ characteristics and available therapeutical options can be found on the dedicated webpage of the Johns Hopkins Institute.
According to the European centre for disease prevention and control (ECDC), as of 26th March more than 467,700 cases have been reported worldwide and 204,900 in the EU/EEA, most of them in Italy (74,386), France (1,784), Spain (47,610) and Germany (36,508). There have been 69,000 case in the US up to now. Reported deaths are currently more than 20,900, mainly in Italy (7,505), Spain (3,434), China (3,293) and Iran (2,077).
The reaction of the pharmaceutical industry to activate the search for treatments and vaccines against the virus has been immediate, after the first round of the epidemic in China. “This outbreak is a test of solidarity – political, financial and scientific. We need to come together to fight a common enemy that does not respect borders, ensure that we have the resources necessary to bring this outbreak to an end and bring our best science to the forefront to find shared answers to shared problems. Research is an integral part of the outbreak response,” said WHO Director-General Tedros Adhanom Ghebreyesus during the meeting organised by the WHO in February.
We resume the main research activities, with a focus on Europe.
A special IMI2 Call
The Special Call 21 of the Innovative Medicines initiative (IMI2) was launched on March 3rd and it will close at the end of the month. The call is entirely devoted to find new therapeutic and diagnostics interventions for the SARS-CoV-2 virus, with the exclusion of vaccines. The total available budget is € 45 million, plus the contributions made by single pharmaceutical companies’ members of EFPIA.
The scope of the Call is very broad, as it is not limited to the SARS-CoV-2 but it extends to the general coronavirus family, in order to face the current emergency and prepare for possible future outbreaks. Four different goals have been set for research, staring from the development of new antiviral compounds and other therapeutics useful to fight the current epidemics. Pharmaceutical companies can look in their already existing pipelines for relevant “clinical ready”-assets. Approved therapies or compounds in development can be repurposed to treat the coronavirus infection on the basis of a preliminary rationale of the compound’s potential efficacy.
The second action involves the development of new potential assets to be used also for future outbreaks, including preventive strategies and combination approaches. This line of research includes the investigation of potential resistance and the optimisation of promising treatments used in rapid response (e.g. reformulation).
New diagnostics specifically targeted to the identification of the virus should allow for the rapid evaluation of candidates based on existing technologies. These tests will also prove useful during clinical studies to be run under the two above mentioned actions, in order to stratify patients and assess treatment efficiency (for example, using surrogate endpoint such as viral clearance).
The development of diagnostic tools based on completely new technologies is the focus of the fourth line of action. A particular attention is due to the differentiation of the coronavirus and other types of similar pathogens, for example through point-of-care (POC) testing or centralised testing.
EFPIA’s actions to contribute to the global effort
EFPIA has supported the launch of the special IMI2 Call through a dedicated webinar for its members. The Federation has also remarked the fast track collaborative research on the new coronavirus, calling its member companies to identify any suitable assets in their libraries that could turn useful. Financial support and in-kind donations to organisations on the ground, and a strict collaboration with European, Chinese, and global health authorities has been also confirmed. Many of the associated companies contributed to fight the epidemic providing a variety of crucial supplies including advanced surgical equipment, antibiotics, disinfection equipment, batch virus testing devices, vitamins, protective clothing, goggles, masks, gloves and more.
EMA and the European Commission are ready
The European Medicines Agency (EMA) opened a dedicated page on its website to inform on different aspects of the current Covid-19 health emergency. The Agency has activated its plan for managing emerging health threats and is actively monitoring potential medicinal product and vaccines within companies’ pipelines, and also through an exchange of information with the European Commission, the Health Safety Committee, WHO and the ECDC. EMA is also participating to the International Coalition of Regulatory Authorities (ICMRA), where to discuss at the global level regulatory issues pertaining Covid-19.
EMA also announced in February the activation of supporting actions for companies involved in the search for new therapeutics and vaccines against the virus. A fast-track route to scientific advice has been specifically activated; EMA asks the company to contact the Agency for early discussion of strategies aimed to evidence-generation. The procedure can be activated by emailing the address email@example.com. The PRIME scheme, accelerated assessment and conditional marketing authorisation procedures are all possible ways to reach rapid regulatory approval.
The von der Leyen Commission announced at the beginning of March the creation of a “coronavirus response team”, in charged of the central coordination of all efforts against Covid-19 at the European level. The team is managed by five EU Commissioners: Janez Lenarčič (crisis management), Stella Kyriakides (health aspects), Ylva Johansson (borders), Adina Vălean (mobility) and Paolo Gentiloni (macroeconomical aspects). The Health Commissioners Mrs Kyriakides is responsible for all measures in the health sector, included prevention and procurement interventions put in place in collaboration with EMA and the ECDC. Three different mechanisms are used to coordinate with Member States, under the Cross-border Health Threat Decision: the Early Warning and Response System, the Health Security Committee, and the Health Security Committee’s Communicators’ network.
In the health sector, the Commission is called to provide technical guidance on risk assessments, case definition for diagnosis and aligned reporting of suspected and confirmed cases, infection prevention and control in health care settings, updated information on therapeutics and vaccines. A total funding of € 232 million has been decided, €114 million of which for the support to WHO’s global preparedness and response global plan. Some other €100 million will fund research related to diagnostics, therapeutics and prevention, including €90 million through the IMI Initiative.
Other financial resources made available by the Commission in the healthcare sector include €10 million for research that will improve clinical care of patients infected with the virus and the overall public health response. Several ongoing research projects have also been reoriented, e.g. the e PREPARE project that ensures research preparedness of clinical treatment sites and the use of harmonised research protocols across Europe through a network of 3,000 hospitals and 900 laboratories in 42 countries. The European Virus Archive GLOBAL (EVAg) has already made available more than 1,000 kits that support the diagnosis of the novel coronavirus, to 79 countries worldwide.
Experimental drugs to fight the epidemics
EFPIA reported several examples of pharmaceutical companies providing health authorities with medicines to be used to fight the infection. The lopinavir/ritonavir combination, for example, has been provided by AbbVie, while J&J is collaborating with the US Biomedical Advanced Research and Development Authority (BARDA) to identify the pathophysiological mechanisms of the SARS-CoV-2 virus.
The repurposing of several antivirals already available to treat infections by SARS and MERS viruses has been discussed in a paper published in Nature Reviews Drug Discovery; these viruses are structurally similar to the new coronavirus. Also The Lancet initially published an article on possible therapeutic interventions; all the main medical journals have opened dedicated pages to collect all incoming evidence on the new coronavirus and associated Covid-19 disease (see, for example, The Lancet, the NEJM and the BMJ)
Possible candidates include both already approved (i.e. favipiravir and ribavirin) or experimental drugs (i.e. remdesivir and galidesivir). Favipiravir (Toyama Chemical), for example, is approved to treat influenza and acts as an inhibitor of the virus’ RNA-polymerase, a mechanism potentially useful also against other types of viruses (Ebola, yellow fever, chikungunya, norovirus, enterovirus). The Chinese FDA authorised during the local epidemics Zhejiang Hisun Pharmaceutical company to produce the generic version of the drug, to be used in different clinical trials on Chinese patients.
Another promising molecule is Gilead’s remdesivir, structurally similar to a medicine approved to treat HIV. A phase III clinical study should close at the end of April; the Chinese company BrightGene Bio-Medical Technology announced at the end of February the ability to produce great quantities of the product for Chinese patients.
Many other approaches are under testing, including the use of the antimalarials chloroquine and hydrochloroquine (also plus azotromycin), some inhibitors of viral proteases (e.g disulfiram, lopinavir and ritonavir), and interferon to stimulate the immune response. Tocilizumab, a monoclonal antibody that targets the interleukin 6 receptor, is gaining a great popularity as it seems to show promising results. The debate is also ongoing on how to make these products, once approved, readily available to patients, avoiding issues experimented during other outbreaks such as the HIV (see more on Medicines Law & Policy).
Looking for new vaccines
The research for new preventive vaccines for the SARS-CoV-2 virus is a complementary action coordinated by the Coalition for Epidemic Preparedness Innovations (CEPI), under the auspices of Wellcome, Biomedical Advanced Research and Development Authority (BARDA), the Bill and Melinda Gates Foundation, Global Research Collaboration for Infectious Disease Preparedness (GloPID-R) and H2020 Call SC1-PHE-Coronavirus-2020.
More than thirty vaccines are under study at the gobble level. Moderna Therapeutics has been the first company to announce at the end of February the starting of a human phase I clinical trial to test a candidate vaccine, mRNA-1273. The trial is going to be run in collaboration with US’ National institute of allergy and infectious diseases (NIAID), with the financial support of CEPI. The vaccine is based on the prefusion spike protein of the SARS-CoV-2 virus, which is essential for the infection of the host cells and already used to develop vaccines against the SARS and MERS viruses.
Glaxo made available its platform technology for adjuvant vaccines to support the development of new products to prevent the infection. Sanofi is using the experience gained in the development of the SARS’ vaccine; the company is collaborating with BARDA to use its recombinant technologies – developed to produce the influenza vaccine – for the production of a DNA antigen matching some proteins expressed on the surface of the SARS-CoV-2 virus.