The science, progress and high stakes of COVID-19 drug developments

Updated 29th June with information on the latest developments on steroid treatment for COVID-19

The world needs it. Lives depend on it. Researchers are urgently working on it. But what's needed to find the right drug to manage or cure COVID-19? Such a success would reduce deaths and serious illness and allow the population to develop immunity with fewer human and economic consequences.

Thanks to antiviral research over recent decades, HIV has become a manageable condition. However, despite outbreaks of SARS and MERS, no antiviral drug development was taken forward to combat novel coronaviruses. Given the typically long timescale of new drug development, and the pressing need to control the pandemic, urgent research is now underway to see if existing drugs can be repositioned against COVID-19. Considerable time and resources are being channelled into repositioning research; and there have already been positive anecdotal findings of drug redeployment. However, even with accelerated approvals, it will take years rather than months to complete the large-scale clinical trials needed to properly judge the safety and efficacy of re-purposed drugs.

This report provides a summary of various approaches and their current potential.

Introduction

Unless COVID-19 is allowed to run its course, with a high burden of excess mortality and morbidity to build natural immunity, the only way to fully end the need for social distancing is medical intervention. Vaccines confer immunity on the individual, inhibiting the virus' propagation, and thus the spread of the disease. Significant resources are currently being dedicated to vaccine development. However, as covered in our vaccine report, there is no guarantee of swift success1.

In the absence of rapid vaccine development and distribution, antiviral drugs can limit the virus from reproducing. This eventually causes the immune system to destroy the virus and reduce its symptoms. While anti-inflammatory drugs can take care of the symptoms, they don't stop the virus.  That's job is left to our immune system. In some infectious diseases caused by viruses, notably the Human Immunodeficiency Virus (HIV) antivirals can effectively manage the condition, reducing excess mortality.

Currently, there are no approved drug therapies for novel coronaviruses, despite outbreaks of Severe Acute Respiratory Syndrome (SARS, 2002-4) and Middle East Respiratory Syndrome (MERS, 2012)3. Many things have discouraged private sector development of such drugs, including uncertain return on investment, high failure rates, short treatment courses and mutability of viruses. You'll find more on this at the end of the article.

Given development times that typically last many years, our pressing need for a COVID-19 antiviral won't be solved with a treatment developed from scratch.  Repositioning existing drugs is a faster, more efficient way to respond. Existing drugs have already been tested for their safety within the parameters of their targeted disease. Indeed, desperate medical staff have already informally experimented with existing pharmaceuticals. While understandable in very trying circumstances, this is far from best medical practice, and could lead to unchecked side-effects. The World Health Organisation (WHO) is concerned by reports of individuals self-medicating with chloroquine and causing themselves serious harm2.

Clinical trial phases in drug development

New drugs go through several clinical trial phases that test the substance for both safety and efficacy. Drug trials typically take six to seven years to complete.

Before going to clinical trial, the discovery and preclinical phase research can take between three to six years. Generally, researchers will test a potential new treatment in a laboratory and on animals before moving on to the first stage of clinical testing in humans (preclinical phase).

Of the four phases, phase three trials last the longest as they compare a drug's effect against the current gold standard treatment in thousands of patients. The approval phase by the relevant government agency can take another few months to two years.

Table 1: Pre/Clinical trial phases including primary goal of trial, average number of participants, success rates and duration of trials. Adapted from Wikipedia.

Efforts to fast track drug trials

Already in the last four months, there's been a significant amount of time and investment dedicated to repurposing existing drugs. According to clinicaltrials.gov, there are a total of 1,621 trials running as of 21 May 2020. Almost half of these are testing pharmacological therapy to treat COVID-19 in adult patients, including 197 placebo-controlled trials. The risk with this huge and sudden level of activity is that multiple small, non-controlled and non-randomised trials won't generate the strong evidence needed to determine the relative effectiveness of potential treatments.

Number of COVID-19 clinical trials per phase as of 21 May 2020.

Source: www.clinicaltrials.gov.

As an attempt to better channel resources, improve coordination and share potential outcomes, the WHO and partners recently launched Solidarity Trial, an international clinical trial to help find an effective treatment for COVID-19. The Solidarity Trial will look into four treatment options to assess their effectiveness against COVID-19. By enrolling patients in multiple countries, the Solidarity Trial aims to rapidly discover whether any of the drugs slow disease progression or improve survival. While randomised clinical trials normally take years to design and conduct, the Solidarity Trial will reduce the time by 80%, according to the WHO. This would suggest the completion of trials for an effective antiviral by around 2022. The four drugs (or combinations) considered in the first wave are: Remdesivir; Lopinavir/Ritonavir; Lopinavir/Ritonavir with Interferon beta-1a; and Chloroquine/Hydroxychloroquine (see below).

While the WHO is looking to streamline clinical trials, the US Food and Drug Administration (FDA) has also re-examined its approval process, fast tracking several drugs. The FDA Coronavirus Treatment Acceleration Program is designed to bring new therapies to COVID-19 patients as quickly as possible while supporting research to determine whether those therapies are safe and effective. The agency has reported it is reviewing study protocols within 24 hours in many cases and reviewing expanded access requests within three hours.

Figure 1: Key drug targets of COVID-19 throughout its path infecting human cells

A virus consists of a shell enclosing its genetic material. In an infection, the virus smuggles its genome into host cells and hijacks the cells’ metabolism in order to replicate itself. To do this, the coronavirus uses a binding 'key' spike protein (S-protein) on its shell to dock to an ACE 'lock' receptor on the cell’s surface. This triggers the uptake of the viral genome into the cell. If the viral key to the human cell can be blocked, the virus is rendered harmless.

Summary of drugs and treatments being considered

The following different treatment approaches are tested for Covid-19:

1. Immuno-modulators: Drugs that target respiratory symptoms, especially the inflammation that occurs in severe cases.

2. Viral growth inhibitors: Drugs that based on different action mechanisms prevent the virus from propagating.

  • Antiviral entry inhibitors: Drugs that seek to prevent the virus from entering the target cell, either by disabling the 'key' or the 'lock' mechanisms in the virus and the cell.
  • RNA-synthesis inhibitors: Drugs that inhibit the means by which the virus can take over the target cell and propagate itself.

3. Blood plasma transfusions: An old technique that takes blood plasma from recovered COVID-19 patients to inject antibodies into a patient with severe COVID-19.

4. Genetically-engineered antibody therapy: Based on a similar concept to blood plasma transfusions, but with artificially engineered antibodies. 

An overview of COVID-19 drugs and treatments in the research pipeline.

1. Immuno-modulators

A subgroup of patients with severe COVID-19 might have demonstrated a serious immune response known as cytokine storm syndrome. Current suggestions are to screen all patients with severe COVID-19 for the syndrome, even though it's usually rare.

Corticosteroids and monoclonal antibodies

To treat hyper-inflammation, immune-modulator drugs such as corticosteroids or monoclonal antibodies can be used. These were originally developed to treat conditions such as rheumatoid arthritis. They may limit lung inflammation but also inhibit immune responses and pathogen clearance, according to observational studies on SARS /MERS patients.

Due to the lack of reliable evidence from large-scale randomized clinical trials, there has been uncertainty with regards to the effectiveness of corticosteroids in COVID-19 patients3. However, preliminary findings from a recent study purport that a low dosage  of dexamethasone reduces 28-day mortality in patients with COVID-19 who are receiving respiratory support4. The results suggest that 1death would be prevented by treatment of around 8 patients requiring invasive mechanical ventilation. On a cautionary note, there was no benefit (and the possibility of harm) among patients who did not require oxygen.

Currently treatment protocols show that placing the most severely affected patients on to a ventilator gives the most likely successful outcome; treatment that could make this option more successful would be welcomed. Following the results of this initial study, clinical guidelines in the UK recommends dexamethasone for patients on mechanical ventilators, with other countries adopting similar approaches. As a drug, dexamethasone is frequently prescribed, well-tolerated and cheap to manufacture.

The early signs for dexamethasone as an efficacious form of treatment in the severely sick are promising, and its low cost and widespread availability enables worldwide usage.

The two monoclonal antibodies, Tocilizumab and Sarilumab, are approved for the treatment of rheumatoid arthritis. Tocilizumab has a promising safety profile and according to a non-controlled, retrospective study of 21 patients with severe COVID-19 led to drop of fever, improved peripheral oxygen saturation and improvement of lung lesions5. Positive patient outcome observed in this study needs to be confirmed by a randomised controlled trial with more patients. A trial for hospitalised patients with severe COVID-19 is ongoing.

Interferons

Interferons are approved for treatment of hepatitis B and C viruses and could be used to stimulate innate antiviral responses in patients infected with SARS-CoV-2. Trials involving Interferons have been initiated.

2. Viral growth inhibitors

Antiviral entry inhibitors

Chloroquine and hydroxychloroquine

Probably the most talked about drug class in the media, is also the most controversial. Chloroquine, a widely used and cheap anti-malarial and autoimmune disease drug, has been reported as a potential broad-spectrum antiviral drug6. This drug has been known to block virus infection by decreasing acidity in the cell required for virus/cell fusion and has been shown in laboratory tests to interfere with cell receptors on the SARS virus7. Besides its antiviral activity, chloroquine has an immune-enhancing activity, which likely increases its antiviral effect in cells8.

Chloroquine is relatively well tolerated to prevent and treat malaria9. Both chloroquine and hydroxychloroquine are affordable, widely available internationally and have been used in humans for decades. Their potential applicability for COVID-19 was noted early in the pandemic and many mainly non-controlled trials have been initiated all over the world. A medical research team from Shanghai recommend clinical trials with hydroxychloroquine to be performed for treatment, including an assessment of the preventive effects of the substance on infection as well as malignant progression10.

The first clinical results from China reveal that treatment of over 100 patients with chloroquine phosphate resulted in significant improvements of pneumonia and lung imaging, with reductions in the duration of COVID-19 disease. No adverse events were reported11. A similar study in France with 36 patients reported that patients in the treatment group were significantly more likely to test negative for the virus on day six than patients in the control group. Interestingly, a further six patients who also received an antibiotic (azithromycin) in addition to hydroxychloroquine all tested negative on day six – potentially demonstrating a synergistic effect of the combination treatment12. This treatment is currently standard in many US states, often with the addition of a zinc supplement. 

Despite the described in vivo activity and a lot of anecdotal reports on chloroquine/ hydroxychloroquine treatment outcomes, no high-quality evidence exists for the efficacy of chloroquine/ hydroxychloroquine treatment of SARS or MERS in humans13.

Chloroquine and hydroxychloroquine, despite being relatively well tolerated in their original use as anti-malarial drugs, cause rare and serious adverse effects, such as heart rhythm issues (QTc prolongation). A COVID-19 study in Brazil with 600 mg twice daily of chloroquine for 10 days was associated with more toxic effects and lethality, particularly affecting QTc interval prolongation14. Other dangerous side-effects have included an increase in blood sugar (hypoglycaemia), neuropsychiatric effects and eye damage (retinopathy)15. Side effects impacting heart rhythm are especially concerning in elderly patients with underlying heart disease who are at highest risk for COVID-19.

The need of larger randomised -controlled studies of chloroquine and hydroxychloroquine seemed obvious to assure safe and effective treatment protocols for COVID-19 patients. The WHO has taken this up in one of its Solidarity Trial arms.  Based on newest findings from the observational study of nearly 100,000 people that linked the antimalarial drug to an elevated risk of death and abnormal heart rhythm when used in hospitalized coronavirus patients, the World Health Organization (WHO) has paused testing of hydroxychloroquine as a treatment for COVID-19 until safety risks can be analysed16.

Camostat

Besides binding to ACE-2 receptors, COVID-19 uses a cellular enzyme to fuse with the targeted cell's membrane. Substances that inhibit this enzyme (transmembrane-protease serine 2) prevent the virus from entering the cell17. In Japan, Camostat is approved for the treatment of chronic pancreatitis; and has demonstrated potential for repurposing to COVID-19.

Umifenovir

Umifenovir is a broad-spectrum repurposed antiviral substance inhibiting the membrane-fusion of virus and host cell by targeting the S-protein /ACE-2 interaction18. Approved in Russia and China for treatment and prophylaxis of influenza, in-vitro data suggests effectiveness against SARS19. While ongoing randomised clinical trials are evaluating the agent in China, so far only limited clinical experience with Umifenovir for COVID-19 is available. Results of a non-randomised study in 67 COVID-19 patients showed lower mortality rates and higher discharge rates for patients who received Umifenovir compared to patients who didn't. However, the observational data cannot establish the efficacy of the drug20. In a smaller retrospective cohort study of mild to severe COVID-19 cases, the treatment with Umifenovir plus Lopinavir resulted in nasopharyngeal clearance in 75% compared to Lopinavir monotherapy, showing a nasopharyngeal clearance in only 35% of patients. The chest CT scans improved for 69% of patients in the combination group after seven days, compared with 29% for the monotherapy group. The effect seems impressive but has not been further explained by the authors21.

ACE-inhibitors

ACE-inhibitors are normally prescribed to treat high blood pressure and heart failure.  They play a double role in COVID-19 by blocking receptors COVID-19 uses to dock to host cells. Coronaviruses use their S-protein for adhering to cellular ACE-receptors (see graphic above). Scientist have discovered that COVID-19 uses these same ACE (2) (angiotensin-converting-enzyme) receptors for entering the host cell22. This fact raises the question as to whether ACE-inhibitors are potential COVID-19 treatment options or whether they could worsen the disease by indirectly increasing the number of ACE receptors in the cell membrane. Conflicting in vitro data exists to demonstrate whether ACE-inhibitors have a detrimental or protective effect. Pending further research, clinical societies and practice guidelines are recommending continuing therapy for patients already taking these agents23,24. These recommendations are supported by a cohort study of 18,472 patients that found no association between ACE-inhibitors use and COVID-19 test positivity25.

As of 21 May 2020, 68 separate studies have been registered on clinicaltrials.gov including ACE-inhibitors to investigate:

  • ACE-inhibitor treatment dis-/continuation in patients with hypertension
  • The prevention or worsening of the disease
  • The repurposing of ACE-inhibitors to treat COVID-19 (as animal studies have shown that ACE-inhibitors had a beneficial effect on the course of pneumonia26,27).

3. Viral RNA-synthesis inhibitors

Remdesivir (investigational)

This is an experimental agent that has been synthesised and developed as a treatment for Ebola virus infection, but with disappointing clinical trial results. Currently, Remdesivir is a promising potential therapy for COVID-19 due to its broad-spectrum, potent in vitro activity against several novel coronaviruses, including COVID-1928.

According to Gilead a five-day course of the antiviral drug administered intravenously sped recovery in moderately ill patients with pneumonia from Covid-19. While the preliminary results from a double-blind, randomized, placebo-controlled trial give hope, the evidence of Remdesivir improving mortality remains uncertain. In a different study evaluating the drug in patients who were hospitalised with severe Covir-19 the course of illness was shortened as well29. The US Food and Drug Administration has issued an emergency use authorization for Remdesivir for use as a treatment for the sickest hospitalised Covid-19 patients. Until conclusive results of the above and similar trials are reported, the benefit of Remdesivir remains uncertain.

Darunavir (repurposed)

Darunavir is a protease inhibitor used in the treatment of HIV. Studies in China have assessed its efficacy in inhibiting viral replication of COVID-19 in vitro30. There is no human clinical data in COVID-19 with these drugs, but a randomised clinical trial of Darunavir plus Cobicistat in China is underway31.

However, the pharmaceutical company marketing Darunavir, Johnson & Johnson, recently published an informative study on the inefficacy of this drug for treatment of COVID-19 patients conducted at the Shanghai Public Health Clinical Center32.

Lopinavir/Ritonavir (repurposed)

The WHO has identified this antiretroviral used to treat HIV as a possible treatment for COVID-1933. In vitro testing shows effectiveness against other novel coronaviruses. Limited data exists on the effects of this treatment on SARS and COVID-19 infections. Current research with randomised controlled trials aims to assess efficacy and safety of this treatment34. At the moment, inconclusive results have been generated and the presence of side effects underlie the limited role of Lopinavir/Ritonavir in COVID-19 treatment35.

Ribavirin (repurposed)

An antiviral medication that inhibits RNA-dependent RNA polymerase. Current literature suggests unclear efficacy against other novel coronaviruses. In-vitro testing and systemic reviews of treatment against SARS reveal limited effectiveness and inconclusive results. In order to be clinically efficient, Ribavirin requires high dose and combination therapies (with Interferon). However, severe hematologic adverse outcomes suggest limited value for COVID-19 treatment.

Favipiravir (investigational)

An antiviral medication commercialised in Japan for influenza treatment. High dosages of this drug have been considered for the treatment of COVID-19, but current research is still investigating substantial evidence of the drug's efficacy and safety. In China, Favipiravir has recently been included in treatment guidelines for the treatment of COVID-19 for a limited time of five years. The Chinese action is based on preliminary results of two Chinese studies, in which the drug was well tolerated, and patients experienced a more rapid decline in fever and improvement in lung scans. These patients needed a shorter recovery time than control groups, with no obvious serious adverse effects.

4. Viral release inhibition

Oseltamivir

An antiviral medication commercialised in Japan for influenza treatment. High dosages of this drug have been considered for the treatment of COVID-19, but current research is still investigating substantial evidence of the drug's efficacy and safety. In China, Favipiravir has recently been included in treatment guidelines for the treatment of COVID-19 for a limited time of five years. The Chinese action is based on preliminary results of two Chinese studies, in which the drug was well tolerated, and patients experienced a more rapid decline in fever and improvement in lung scans. These patients needed a shorter recovery time than control groups, with no obvious serious adverse effects.

5. Blood plasma transfusions (convalescent serum therapy)

Convalescent serum therapy was first used to treat the Spanish flu of 1918. It uses antibodies from the blood of COVID-19 survivors, who, most likely, have developed at least short-term immunity. As early as February, Chinese media was reporting36 the use of convalescent serum therapy in specific hospitals. The first blood plasma was collected from patients at the beginning of February and 544 doses of plasma were used to treat 245 COVID-19 patients. Of those, 91 showed significant signs of improvement. The therapy is likely to be most effective for patients who are at risk from complications of COVID-19 infection. The viral load is known to peak within 10 days37, after which time the danger to life comes not from the COVID-19 infection itself, but from a secondary infection from pneumonia or the body's overreaction. This is known as acute respiratory distress syndrome, which is currently believed to onset within 14 days after infection and has been responsible for a significant percentage of COVID-19 related deaths.

Another smaller study38 from Wuhan showed more promising results. Ten critical care patients with severe COVID-19 symptoms received a single dose of convalescent plasma approximately 16 days after infection. Although the patients remained in serious condition, they all showed improvement in their laboratory tests and clinical observations. No adverse effects were noted, and seven of the patients were free from viral infection after three days.

While these studies are optimistic, they represent a small sample and require further investigation. A system for donation and transfusion would have to be established, likely borrowed from current blood donation systems. It is not known how long this donated immunity would last, what level of protection it offers and who is most eligible to receive a donation. The therapy is not easily scalable; a single blood donation will only be sufficient for 2-3 patients; and the process cannot be replicated quickly. 

5. Genetically modified antibodies

Other researchers are looking for a middle ground. A Swiss company, Molecular Partners, is working on a genetical-engineered antibody treatment. Known as DARPin, these proteins have been shown in other disease clinical trials they are able to attach to dangerous agents, such as proteins or viruses. Once attached, DARPin reduces movement of the target and, in some cases, neutralises its infectivity. This approach has proven successful in clinical trials on eye diseases39. The first laboratory studies on COVID-19 proved successful. Small quantities of three subtypes of DARPin were combined to neutralise the infectivity of the virus, acting as a "sticky web" to slow the spread of the virus. The three types of DARPin focused on "locking" the three main points of infection for COVID-19: ACE2 receptors (on the target cell), the S-protein and an enzyme on the S-protein (preventing it from activating). The three-pronged attack from DARPin has the advantage that if the virus was to become resistant to one of the attacks, the other two could still work.

Using genetical engineered antibodies has an unusual advantage in that higher concentrations of COVID-19 are stopped more effectively by DARPin, as more of the virus is present to be bound together by the antibodies. Animal studies are set to begin in May 2020, with human clinical trials beginning by the end of the year. While this timescale means that it is unlikely that DARPin will be initially used as a front-line treatment, it might have a future use as long-term treatment option when combined with other drugs.

Conclusion: The high stakes of a COVID-19 cure

Whether the answer comes in the form of a drug or vaccines, we are all waiting for successful medical intervention to stop COVID-19 but it's still likely to take years vs. months.

Another scenario of concern would be a virus mutation, possibly into a disease with higher mortality rates and a moving target that would require renewed drug and vaccine development. The good news is that coronaviruses appear more stable for mutation than influenza. We have explored this in more detail in our recent article on vaccinations.

As with vaccine development, COVID-19 treatments are being fast tracked, and backed by significant funds. The advantage with drugs is the ability to repurpose existing treatments; and skip early stages of clinical trials. Even though this is a difficult time, there are some positive developments. Nevertheless, it's going to be time consuming to establish the safety and efficacy of treatments for COVID-19 and many studies will ultimately fail.

Accelerated approvals also carry risks. For example, widespread prescription of drugs with serious and unexpected side effects could only add to the current healthcare burden. Given that severe COVID-19 patients frequently enter a prolonged period in intensive care, a successful medication will also likely be cost positive for health care. Never before has the global medical research community been so focused on the treatment for an acute infection. Even though patients are continuing to recover without pharmaceutical invention, this disease stands the best chance of ever finding a treatment

A call for public and private effort

For all the resources being channelled to antiviral drugs and vaccines in the wake of COVID-19, we would have been much better off with validated antiviral drugs to distribute at the first signs of an outbreak of a novel coronavirus. The development of antiviral drugs – and antibiotics – cannot be left to the private sector alone. The economic returns are too uncertain and too fragile. It is illustrative that at the end of 2019, there were around five times more oncology drugs in the pre/clinical pipeline than infectious disease drugs40. If there is to be something beneficial to emerge from the COVID-19 crisis, it will be that public and private sectors work together to improve and strengthen our knowledge and arsenal of weapons against both viral and bacterial infectious diseases.

Managing editor: Susan Imler

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