Developing or finding the right, existing candidate for the treatment of coronavirus became one of the priorities during the COVID-19 pandemic. Effective treatment is not only needed for the current outbreak of the virus but also in case of any future outbreaks if seasonality is observed in the rates of infections, like with influenza (‘flu’) virus. Poorer countries with weak healthcare infrastructure (number of doctors and respirators, for example) will solely rely on cheap drug treatment donated from other countries. The purpose of this post is to list drugs which are or were considered as the treatment of coronavirus (Covid-19) infection.
Under normal circumstances, clinical trials that assess the suitability of drugs take a number of years, including a lengthy application process. Few drugs have received a priority, with clinical trials already happening worldwide to evaluate safety and efficacy in the treatment of coronavirus (covid-19). Well designed clinical trials are needed to provide the best information on the safety and efficacy of potential Covid-19 treatment. As we will learn from this post, the information available on the possible treatment of Covid-19 comes so far mainly from lab-based experiments and/or small clinical trials, which do not provide reliable information.
EMA on Covid-19 treatment and vaccine
On 31/03/2020, European Medicines Agency (EMA) announced that no drug ‘has yet demonstrated efficacy in treating COVID-19. EMA supports rapid development, approval of safe and effective coronavirus drug treatment.
EMA listed the following drugs which are currently being investigated at potential candidates in the treatment of coronavirus infections (EMA, 2020):
- remdesivir (initially developed to treat Ebola infections)
- lopinavir/ritonavir (drug currently licensed as an anti-HIV medicine)
- chloroquine and hydroxychloroquine (currently licensed as treatments against malaria and certain autoimmune diseases, for example, rheumatoid arthritis)
- systemic interferons, in particular, interferon-beta (currently licensed to treat conditions such as multiple sclerosis)
- monoclonal antibodies with activity against components of the immune system
EMA: comments on vaccine production against COVID-19
Additionally, in its press release, EMA talks about the development of a vaccine against COVID-19. Currently, two vaccines are taking part in phase I of clinical trials. During phase I of clinical trials vaccines are given to healthy volunteers to assess safety in humans.
How long will it take to develop a vaccine against COVID-19?
EMA noted that it might take another 12 months before a vaccine against COVID-19 is ready for license approval and widespread use in Europe, which means a number of vaccines which is enough to meet forecasted demand for all European countries (ibid). Bringing a vaccine against coronavirus in 20201 will be a challenging task.
Covid-19 drug treatment: 30 leads?
Research teams from Shanghai Institute of Materia Medica and Shanghai Tech University believe there are 30 potential coronavirus treatment drug candidates. After doing some tests (drug screening in silicon and an enzyme activity test), the following drugs were listed by both teams as potential coronavirus treatment: indinavir, saquinavir, lopinavir, carfilzomib, ritonavir, remdesivir, atazanavir, darunavir, tipranavir, fosamprenavir, enzaplatovir, presatovir, abacavir, bortezomib, elvitegravir, maribavir, raltegravir, montelukast, deoxyrhapontin, polydatin, chalcone, disulfiram, carmofur, shikonin, ebselen, tideglusib, PX12, TDZD-8, cyclosporin A, and cinanserin.
(Covid-19) Coronavirus drug treatment leads
Antiviral drugs are at the centre of attention for the treatment of Covid-19. Antiviral drugs used in the treatment of HIV are a perfect example of what science can achieve with rational drug design, which resulted near to normal life expectancy for HIV patients.
Remdesivir as COVID-19 treatment candidate
Remdesivir was developed by Gilead, an American biotechnology company, which specialises in the development of antiviral drugs.
Recently, it was announced that clinical trials involving remdesivir will take palace to assist this drug as a candidate in the treatment of coronavirus. Remdesivir was initially developed as a drug to treat the infection with the Ebola virus. Remdesivir was found to have broad-spectrum activity against other viruses (Dong et al, 2020).
Remdesivir stops viral RNA transcription, which is needed for the virus to replicate – make a copy of itself (Agostini et al, 2018).
Patients who wish to use remdesivir can only access it through clinical trials; however, emergency treatment requests are also considered. Gilead is currently working on an emergency access program to give the treatment access to a broader population and not on the individual compassionate basis in an emergency, which is presently the case.
Gilead has started two (phase 3) clinical trials to assess efficacy and safety in adult patients infected with Covid-19. Around 1000 patients will take part in clinical trials, mainly from countries highly affected by Covid-19, including the UK.
The first study aims to evaluate the safety and efficacy of two different treatment durations: a 5 and 10-day course of remdesivir alongside standard care in patients with severely affected by Covid-19. The second study will examine the safety and efficacy of treatment (same duration and dosing) in patients with moderate Covid-19 symptoms alongside standard care in comparison to standard care alone (Gilead, 2020).
Two clinical trials are also taking place in China since February 2020 with the expected time to conclude the trial at the end of April 2020.
Remdesivir was given to the first US patient who was diagnosed with Covid-19 based on compassionate use. Remdesivir was given to the patient on day 7 of hospitalisation. On day 8 (12 days of illness), the patient’s condition improved (Holshue, 2020).
Why is Remdesivir is a Covid-19 drug treatment candidate?
In animal studies, remdesivir reduced the number of viral particles present in mice lungs infected with SARS/MERS-COV (another type of coronavirus). Remdesivir has also shown to stop the infection of SARS-Cov-2 (a virus that causes Covid019) at low concentrations in kidney cells derived from monkeys (Wang et al, 2020). This study showed that remdesivir works against the virus after it entered the cell. The initial research suggests that remdesivir can stop the viral infection in human cell lines in the lab experiment (ibid).
Darunavir as Covid-19 treatment candidate
Darunavir (brand name: Prezista) is a drug which currently licensed for the treatment of HIV (the human immunodeficiency virus) infection in combination with other antiretroviral drugs. Scientists in China reported in February that darunavir is effective in blocking SARS-COV-2 virus replication in vitro (test performed in the lab in a cultured dish, in other words, not in humans).
In the UK, darunavir carries a high price tag. A box of 30, 800mg tablets (a monthly supply when used in the treatment of HIV) costs around £300.
UK producer of darunavir, Janssen made a statement around the use of protease inhibitors such as darunavir in the treatment of COVID-19 infection. The use of protease inhibitors s treatment of Covid-19 is based on limited and unpublished virologic and clinical data.
In its statement, Janssen also stressed about the importance of the use of darunavir in combination with other antiviral agents (‘boosting drugs’). Higher rates of adverse side effects and a lower concentration of drug in the body were observed when darunavir was used without a boosting agent, which makes the treatment less effective.
Lastly, Janssen announced that several drugs, including darunavir, are in the process of being evaluated as candidates against SARS-COV-2 infection.
Lopinavir/ritonavir is another drug licensed in the UK as a combination treatment (with another drug) in the treatment of HIV infection.
A small randomised trial took place intending to assess the effectiveness of lopinavir/ritonavir in hospitalised patients with laboratory-confirmed severe Covid-19. 199 patients took part in the trial, 99 of which were given lopinavir/ritonavir drug, and 100 received standard care.
Key results from this clinical trial (Cao et al, 2020):
- No difference was observed between both groups of patients in terms of time need to see a clinical improvement (improvement in symptoms)
- Mortality (number of deaths) was similar between a group that took lopinavir/ritonavir drug and group which received standard care at 28 days
- Both patient groups had the same amount of virus present when measured at different time points
Overall it was concluded that no benefit was found when lopinavir/ritonavir was used in the treatment of patients with severe Covid-19 as compared to standard care. Further trials are needed to confirm if treatment with lopinavir/ritonavir is beneficial in Covid-19 patients.
Chloroquine as a candidate for coronavirus treatment
Chloroquine is being investigated as a Covid-19 treatment candidate in the US. The Food and Drug Administration (FDA) announced that it is working with government agencies and academic centres to determine the use of chloroquine in patients with mild-to-moderate COVID-19.
Chloroquine: licensed use
In the US and the UK, chloroquine is already licensed in the treatment of active rheumatoid arthritis and lupus. Chloroquine is also used as a drug for the prevention of malaria.
Chloroquine: rationale behind treatment of Covid-19?
A recent systematic review (review of all research publications) concluded that there is sufficient information about the safety from long-term use of chloroquine in the treatment of different diseases to justify clinical trials involving this drug in patients with COID-19 (Cortegiani et al, 2020). Outside the US, 23 trials involving Covid-19 patients and treatment with chloroquine have started or are pending approval.
A group of Chinese scientists investigated the use of chloroquine against Covid-19 in the lab with the use of Vero E6 cells (cells which come from a kidney of monkeys) infected with SARS-CoV-2. This study reported that chloroquine was very effective in reducing the replication of the virus (ibid). Additionally, it is said that viral replication can be reduced with a standard dose of chloroquine, because of favourable penetration into tissues, such as tissue of the lungs (Wang et al, 2020).
The mechanism of action of chloroquine in blocking viral replication is two-fold. Firstly chloroquine increases pH in the cell (endosomal pH). Secondly, it intervenes with a cellular receptor of SARS-CoV, which in turn negatively impacts virus-receptor binding, which helps to fight the infection (Vincent et al, 2005[MS1] ). SARS-CoV virus, like other viruses, use different receptors to enter the cell to replicate (make a copy of itself).
Donald Trump’s misleading press conference
President Donal Trump has announced in his press conference that FDA approved chloroquine or hydroxychloroquine for treatment of Covid-19, which of course, was misleading information. What he was probably trying to say is that FDA fast-tracked chloroquine to possible clinical trials to assess its effectiveness and safety in a patient with confirmed covid-19.
Hydroxychloroquine for Covid-19 treatment
Hydroxychloroquine is related to chloroquine. In the UK, hydroxychloroquine is licensed in the treatment of rheumatoid arthritis, lupus.
Hydroxychloroquine & COVID-19 clinical trial
A small and short trial involving French patients with confirmed Covid-19 infection evaluated the role of hydroxychloroquine on the viral loads (amount of virus present).
In this study, patients were given 600mg of hydroxychloroquine daily with nasal swabs taken daily to assess the amount of virus present in the body. Some patients may have been given azithromycin (another drug) additionally, depending on their symptoms. The presence or lack of the virus on day 6 was the main testing point for this study.
Only 36 patients took part in this trial. 20 patients showed a significant reduction in the presence of the virus as a measure on day 6. Patients treated with hydroxychloroquine and azithromycin showed better elimination of the virus (Gautret et al, 2020).
This study concluded that treatment with hydroxychloroquine is associated with a significant reduction of the virus in Covid-19 patients. The effect of hydroxychloroquine is reinforced by azithromycin.
Despite the conclusion, one needs to be aware of how limited this this study was:
- The study involved only 36 patients, sample size too small to make any confident conclusions
- The study was non-randomised – this means a physician decides on who gets the treatment, which brings bias to the study. Non-randomises studies would not be accepted as a way of bringing a drug to the market in the UK or Europe.
- This study was an open-label: physician(s) were aware of what treatment is received by patients. Although not necessary open-label studies may bring bias to the trial as well.
European Medicines Agency (EMA) issues a reminder for both chloroquine and hydroxychloroquine about the use of both drugs only in the treatment of licensed conditions. EMA also added that although both drugs are investigated for ‘their potential’ to treat Covid-19, there are no studies to confirm their effectiveness.
One of the advantages of both hydroxychloroquine and chloroquine is the price tag. Both drugs are relatively cheap, as compared, for example, to antiviral drugs.
Ivermectin as a candidate as coronavirus treatment
Ivermectin made it the news as possible Covid-19 treatment after one study published and showed that this drug has antiviral properties against a wide range of viruses (Caly et al, 2020). The reduction of viral infection was seen in the lab-based experiment with animal cells being infected with SARS-CoV-2 and treated with ivermectin. Further investigations were recommended to investigate ivermectin against Covid-19.
Ivermectin is an anti-parasitic drug which is available in the UK. It is licensed for the treatment of scabies, Strongyloides infection (roundworm), and Onchocerciasis.
Monoclonal antibodies as Covid-19 treatment
EUSA Pharma, the producer of siltuximab (monoclonal antibody), investigated effectiveness and safety in a small number of Covid-19 patients with serious respiratory complications before admission to an intensive care unit or patients who already required intensive care.
Monoclonal antibodies are similar to naturally occurring antibodies that are produced by our immune system. As with antibodies, monoclonal antibodies are designed to act on a specific target. Siltuximab inhibits (stops from working) interleukin-6 (IL-6) receptor binding.
During the trial, twenty-one Covid-19 patients were treated with siltuximab. It was reported that during the trial, seven patients experienced an improvement in their condition with a reduced need for oxygen support, and nine patients became stable with no changes to their condition. Three patients experienced worsening of their condition, one patient died, and 1 experienced ‘cerebrovascular event.’
EUSA Pharma reported about emerging evidence for Covid-19 patients to overproduce IL-6, which causes over-stimulation of the patient’s immune system, which attacks their own body. This, in turn, leads to severe lung complications and/or Acute Respiratory Distress Syndrome (ARDS), which is the leading cause of patient’s death in Covid-19. It Is suggested that targeting IL-6 by siltuximab may improve patient outcome (EUSA Pharama, 2020).
Although some positive preliminary data came out of this trial, it is too early to say about the broader benefits of siltuximab of Covid-19 patients with severe respiratory complications. A larger clinical trial is needed to assess the efficacy and safety of siltuximab.
In the UK, situximab is known under the brand name of Sylvant, and it is licensed only for the treatment of multicentric Castleman’s disease (MCD) in patients who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. One vial of situximab 400mg costs £1661 (NHS indicative price). A patient who weighs 70kg would require a treatment with almost two vials.
Interferon-beta (IFN-β) as treatment of Covid-19
Last on the list of potential Covid-19 treatment is interferon-beta. Synairgen, the producer of SNG001, an inhaled interferon beta drug, was granted approval to test it in hospitalised patients with Covid-19. SNG001 is an experimental drug, which has not been tested in patients.
How can IFN-β help with the treatment of coronavirus?
IFN-β and other interferon proteins (IFN) are released by the body’s cells in response to infection with viruses. IFN, in turn, causes the immune system to respond to infection, for example, by activating immune cells such as macrophages or natural killer cells. Viruses such as coronaviruses suppress (stop) production of IFN-beta and therefore reduce the effectiveness of the immune system to fight the infection (Synairgen, 2020).
When tested in the lab, IFN-β (SNG001) has shown to fight the infection caused by viruses, including MERS-CoV, SARS-CoV, and SARS-CoV-2, which causes Covid-19. Additionally, SNG001 improved lung function of asthmatic patients with cold and flu infections, as investigated in two different clinical trials (ibid).
100 Covid-19 patients are taking part in a double-blinded, placebo-controlled clinical trial (SG016) from various NHS trusts.
Although several possible drugs currently marketed can possibly be used in the treatment of Covid-19, there is limited data supporting their use. Antiviral drugs such as remdesivir are probably the best lead for the coronavirus treatment as almost rationally their target a specific stage viral cycle. Fast-tracked, well-designed clinical trials are needed to evaluate safety and efficacy of potential drug candidates with a sense of urgency.
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