How biotechs are racing to develop COVID-19 treatments
This article is the second in a three-part series covering the response of biotech companies to the COVID-19 crisis. The first article in this series is: How biotechs are racing to develop COVID-19 tests.
The novel coronavirus has had sweeping effects on the world at large since its emergence last winter, and it will no doubt continue to affect and change the world we live in. As we do our part to shelter-in-place and practice social distancing, there are leagues of scientists and researchers working around the clock on therapeutics to treat patients infected with SARS-CoV 2.
Background on Coronavirus
SARS and MERS
In 2002, the SARS virus emerged in China and spread internationally. The virus was contained by July 2003 thanks to the measures put in place like isolation and screening travelers. Then in 2012, the MERS virus emerged in Saudi Arabia and spread across several continents. Though the total number of cases since its emergence is relatively low (2,499), there continue to be reported incidents of MERS as recently as December 2019.
Both SARS and MERS belong to the family of viruses known commonly as coronavirus, a name with which the world is becoming increasingly familiar. Coronaviruses are enveloped, positive-strand RNA viruses. This family of viruses is known to mutate at a high rate, and are noted by their “Spike” proteins that cover their surface and are used to bind to target cell receptors.
The Novel Coronavirus SARS-CoV 2
In December 2019, another novel coronavirus emerged and has since become the center of global attention. Genetically similar to the original SARS virus, this novel coronavirus has been named SARS-CoV 2, or Severe Acute Respiratory Syndrome Coronavirus 2,” and the illness it causes, “COVID-19.”
This new coronavirus is genetically similar to SARS and MERS [which] gives us a head start to find treatments.
In the end, the SARS and MERS epidemics were self-limiting. There have been no new cases of SARS since 2004, and though research continued in the halls of academia, most work on SARS and MERS in biotech was shelved. The new novel coronavirus, however, is much more contagious and has spread more widely at over 330,000 cases in the US alone and over 1.2 million cases worldwide at the time of this writing. With a heightened sense of urgency, previous cutting-edge research into SARS, MERS, and other viruses, is being taken down off the shelf, dusted off, and put into action. The fact that this new coronavirus is genetically similar to SARS and MERS gives us a head start to find treatments.
In a world where there are new headlines everyday about shortages of ventilators and overcrowded ICUs, the importance of ameliorating the worst symptoms cannot be understated. At home, you may take tylenol and robitussin. But in the hospital, better solutions are needed.
Several categories of therapeutics are being assessed for efficacy in treating COVID-19 symptoms. Within each of these categories, several biotech and pharmaceutical companies, many of which are collaborating with governmental bodies, are working to find safe and effective treatments.
COVID-19 therapeutics in development
Short for Interleukin-6, IL-6 is a cytokine that stimulates a number of defenses when the host encounters an infectious agent. Infections such as SARS-CoV 2 can lead to the overproduction of IL-6, which is thought to cause one of the most lethal symptoms of COVID-19: lung inflammation. An initial, non-peer reviewed single arm study of the IL-6 drug Tocilizumab showed preliminary results that could indicate effectiveness of anti-IL-6 drugs in treating respiratory sickness in COVID-19 patients. A number of anti-IL 6 drugs consist of an antibody that is directed against IL-6 or IL-6 receptors. The following list includes anti-IL-6 medicines that have been previously used to fight disease and are already approved for clinical trials. Others, not included here, are also in the pipeline.
Kevzara is a monoclonal antibody that blocks the IL-6 receptor. Regeneron and Sanofi announced on March 16 that they would be launching a Phase 2/3 trial of Kevzara in patients suffering from COVID-19 in New York. As of March 30, another trial was initiated in Italy, Spain, Germany, France, Canada, and Russia, and the first patient outside of the US was treated. Double-blind trials are being conducted at multiple centers and are actively enrolling patients. The companies are working closely with the FDA and the Biomedical Advanced Research and Development Authority (BARDA).
Actemra, or Tocilizoumab, is an IL-6 receptor antagonist that inhibits IL-6 from binding to its target. Though it was originally approved to treat rheumatoid arthritis in 2010, Chinese officials added Actemra to the treatment guidelines for COVID-19 cases. Actemra is made by Genentech, a member of the Roche Group, who announced a Phase 3 clinical trial on March 23 dubbed COVACTA that will test the efficacy of intravenous Actemra in COVID-19 cases that present with pneumonia. The company is also donating 10,000 vials of Actemra to the US Strategic National Stockpile for future potential use.
Sylvant, a chimeric monoclonal antibody, is an IL-6 receptor that functions by binding to IL-6 directly, which ultimately decreases the amount of IL-6 that can bind to target receptors. Sylvant, or siltuximab, is typically used to treat Castleman’s disease, and it is now part of a study run by EUSA Pharma at the Papa Gionvanni XXIII hospital in Bergamo, Italy to treat severe cases of COVID-19. The study is called SISCO, short for Siltuximab In Serious COVID-19, and aims to alleviate symptoms to reduce need for ventilation and the amount of time in an ICU.
List of potential drugs to treat COVID-19 and their current phase in clinical trials
The antiviral drugs being tested to treat COVID-19 include both repurposed drugs and novel drugs. A wide range of antivirals is being tested to treat SARS-CoV 2 infections, ranging from broad-spectrum antivirals to medicines originally intended to target specific viruses like HIV, Malaria, and Ebola. The following is a list of drugs that are currently in trials.
Remdesivir, a drug from Gilead, is a nucleotide analog antiviral medication. It was originally designed as a generic antiviral that showed promising results against SARS and MERS in animals in preclinical testing. Remdesivir was eventually used to target Ebola, but proved less effective than desired. Remdesivir is now being tested in two Phase 3 clinical trials run by Gilead, as well as in two studies run by Chinese health authorities and in a Phase 2 study run by National Institute of Allergy and Infectious Diseases (NIAID). Early results can be expected sometime in April.
To test remdesivir and other antivirals, the World Health Organization (WHO) has launched a global study, SOLIDARITY, that includes drugs, including Redemsivir discussed above, that have shown promise in inhibiting other viruses, like SARS, MERS, HIV, and Malaria. However, there still needs to be more data to determine if these other treatments will prove effective.
Chloroquine / Hydroxychloroquine
Chloroquine has been in the spotlight in political rhetoric as of late for its potential to treat COVID-19. It works by decreasing the acidity in endosomes, a pathway that many viruses use to enter the cell. However, coronaviruses like SARS-CoV 2 use what is called a spike protein to bind to receptors on the cell membrane and ultimately attach itself to the cell. Still, there are several studies of chloroquine in COVID-19 patients underway in China. A study published in France showed promising results, but the study was not randomized, so further research needs to be done. Another important consideration for this medication is that effective doses can lead to serious adverse side effects, such as damage to the heart in rare cases. Hydroxychloroquine is in clinical trials for prophylaxis in mild-severe COVID-19 cases and has been approved by the FDA for emergency use in the US. Several drug manufacturers, including Bayer, Novartis, Teva, and Mylan, have pledged to donate supplies of hydroxychloroquine.
With seemingly the entirety of the medical community focused on COVID-19 and SARS-CoV 2, there will undoubtedly be novel and newly repurposed drugs on the horizon.
Kaletra/Aluvia, also known as lopinavir/ritonavir, is an HIV-1 protease inhibitor initially approved to treat HIV. Kaletra was used to treat 199 patients in Wuhan, China, the epicenter of the outbreak, but there was no statistically significant improvement on patient health. However, researchers attested that more research needed to be done. AbbVie, the maker of Kaletra, is supporting a number of efforts to determine the efficacy of Kaletra against COVID-19. This includes a partnership with the WHO, which is testing Kaletra alone as well as in combination with interferon-beta, which is known to regulate inflammation. There are several clinical trials, with some in Phase 3.
There is a lot of work being done to discover novel therapeutics to treat COVID-19. For example, Regeneron Pharmaceuticals is developing neutralizing monoclonal antibodies using their drug discovery platform VelocImmune® to develop mAbs that can treat as well as prevent COVID-19. Additionally, Eli Lilly has teamed up with AbCellera to develop a drug that is aimed to be in clinical trials in the coming months.
Ultimately, the hope is that through social policies like self-isolation and social distancing, the spread of the virus slows to buy time to find effective treatments. With seemingly the entirety of the medical community focused on COVID-19 and SARS-CoV 2, there will undoubtedly be novel and newly repurposed drugs on the horizon. The life science community is rallying together across the industry, as well as in academia and government agencies, to aid patients in desperate need and fight SARS-CoV 2.