COVID-19 Therapeutics Research Reaches New Highs

This year began with additional rhetoric surrounding COVID-19’s pandemic status. With the rise of a milder strain, called Omicron, some countries like Spain reconsidered their approach to COVID-19. This shift in focus has put the spotlight back on effective treatments for the disease.

The state of COVID-19 therapeutics in 2022

As of early this year, hundreds of drug development programs are in progress and being monitored by the U.S. Federal Drug Administration (FDA). Of these, many are monoclonal antibodies targeting the virus itself or acting as immunomodulators—a group of drugs that are directed at immune system effectors to regulate or refine the immune response. More than 40 types of combination or cocktail-based therapies are also being studied.

In addition, countless clinical trials evaluating COVID-19 treatments are ongoing; of these, more than 470 clinical trials have been reviewed by the FDA to date. These reviews have led to the authorization of 14 treatments for emergency use, but only one drug has been approved for routine use in treating hospitalized patients suffering from COVID-19—this drug is called remdesivir, a Gilead-manufactured antiviral.

Antivirals fail to deliver in potency and efficacy

Remdesivir was approved early in the pandemic despite major discontent in the scientific community, which had been keeping a close eye on studies and clinical trial results for remdesivir. This nucleoside analog inhibits coronaviruses’ RNA-dependent RNA polymerase, which orchestrates viral replication. Remdesivir was approved with the promise to substantially reduce hospitalizations and hospital stays. However, despite multiple studies, including results from the World Health Organization (WHO)’s Solidarity Trial, that pointed out its low efficacy, remdesivir remains in use in many countries, including Canada and the US, where its use has been expanded. Similarly, clinical trials on recently FDA emergency use authorized Merck’s molnupiravir, another nucleoside analog that promotes error propensity of the RNA polymerase of many viruses, including coronaviruses, have reported lower efficacy compared to initial preclinical data.

Other antivirals still hold promise, though some may have to overcome a common hurdle in drug development: human metabolism. Pfizer’s combination therapy, Paxlovid, includes an antiviral (nirmatrelvir) that inhibits one of SARS-CoV-2’s proteases to interrupt its replication cycle and stop the virus from spreading. Paxlovid has been shown to reduce the risk of hospitalization by 89 percent and was also recently authorized for emergency use by the FDA.

However, this protease inhibitor is quickly broken down by liver enzymes, which is why Paxlovid also includes ritonavir, a liver enzyme inhibitor. That means that individuals who take other medications that rely on the liver for processing to their active forms are unable to take Paxlovid for COVID-19. This includes people who are immunocompromised and people with certain comorbidities—the very people who rely on alternative treatments such as this one.

Hossain and colleagues recently reviewed many of the antivirals being considered for COVID-19 treatment, including the aforementioned remdesivir and ritonavir, and concluded that antivirals are far from being an all-encompassing solution to this disease. Some like remdesivir have low efficacy, others like Paxlovid have limited use in the population at risk of severe disease, or cannot be administered at the efficacious dose for danger of toxicity, and lastly, the side effects of some outweigh their benefits.

Monoclonal antibodies remain the best approach to prevent and treat viral infection

In contrast to antivirals, monoclonal antibodies have proven much more efficacious. Other than the three mentioned antivirals, the remaining 11 authorized therapies for emergency use are monoclonal antibodies, and many more are currently being investigated in ongoing clinical trials. Most recently, in early December 2021, two additional neutralizing antibodies were given emergency use authorization (EUA) by the FDA.

These are the only antibodies to date that are meant for preventive use. In a randomized, double-bind and placebo-controlled clinical trial of 5,000 people, those who received the neutralizing antibodies were 77 percent less likely to contract COVID-19 compared to the placebo group, and this effect lasted half a year.

"In contrast to antivirals, monoclonal antibodies have proven much more efficacious."

These antibodies were discovered by the Crowe lab at Vanderbilt University Medical Center and represent a great proof of concept for the development of monoclonal antibodies in the treatment and prevention of future pandemics. The Crowe lab and other collaborators at the U.S. Centers for Disease Control (CDC) have been tasked with an initiative called AHEAD 100.

The project involves the discovery of monoclonal antibodies to treat 100 of the most likely pathogens to cause future epidemics or pandemics. The Crowe lab has already discovered robust monoclonal antibody therapeutics for Ebola, the flu, and another 30 emergent pathogens; Crowe and the CDC’s initiative will aim to establish a global monoclonal antibody bank ready to be deployed at a moment’s notice to protect those in need.

Routine adoption of monoclonal antibodies for the treatment of COVID-19 and other diseases will take time

However, unlike antivirals that can be taken orally, monoclonal antibody immunotherapy is typically delivered intravenously. Monoclonal antibodies are also more expensive to develop than antivirals, which represents a major hurdle in their adoption. However, these two obstacles may soon be solved. The Crowe lab has teamed up with Moderna to trial mRNA-based delivery of a neutralizing monoclonal antibody, this time against another viral threat—the Chikungunya virus, a mosquito-born pathogen that leads to inflammation in the joints.

Results of the Phase 1 trial published December of last year in Nature Medicine were promising: no adverse effects were noted, and the mRNA-expressed antibodies drawn from participants maintained neutralizing activity. This study represents a great marriage of mRNA and immunotherapy technologies, and most importantly, an elegant proof of concept for how to rapidly deploy future monoclonal antibodies to a large population while minimizing cost.

Even if monoclonal antibodies remain at the forefront of therapies used against COVID-19, it is important to remember that there is no single drug discovered to date that can obliterate SARS-CoV-2 or sufficiently manage COVID-19 symptoms. The need for additional treatments has been highlighted with the rise of Omicron and other variants, whose mutation load in the Spike (S) and ORF3a proteins could increase resistance to many of the previously mentioned treatments, including vaccines.

Most of the monoclonal antibodies given EUA are neutralizing antibodies targeting the S protein, often sharing overlapping epitopes. Most of the discovered neutralizing antibodies thus far also share the same target because the other SARS-CoV-2 surface proteins have not been shown to raise a strong humoral immune response. Even so, only two of the monoclonal antibodies given EUA by the FDA have documented viral resistance. The monoclonal antibody bamlanivimab’s standalone EUA was revoked last April due to the resurgence of COVID-19 cases, triggered by the rise of resistant viral strains to bamlanivimab.

Similar to antivirals, a cocktail approach has been found to be more suitable to prevent such mishaps. For this reason, the FDA has allowed EUA for bamlanivimab in combination with other monoclonal antibodies that target overlapping and non-overlapping regions of the S protein in specific US jurisdictions, territories, and states with low incidence of bamlanivimab-resistant SARS-CoV-2 strains.

Other therapies are still needed due to complications surrounding COVID-19

Neither antivirals nor monoclonal antibodies can wholly mitigate the complexity of COVID-19. Part of the problem with this disease is that the activation of the immune system in response to the virus can result in devastating outcomes for patients. Whereas in the initial stages of the disease, antivirals and monoclonal antibodies may prove effective, their efficacy wanes in more severe stages of the disease.

Curtailing the immune system often becomes a necessary measure in many COVID-19 cases resulting in hospitalization. Other treatments stem from repurposed therapies for other diseases such as corticosteroids, anti-cytokines, anti-complement, and many more immunomodulators. And yet, switching off the immune system may prove detrimental in patients with concurrent infections. For this reason, interferon therapy, which modulates the immune response while inhibiting viral replication has often been used, though its impact was found to be insignificant by the WHO.

"The lack of an all-encompassing treatment for COVID-19 continues to fuel research."

Thus, the lack of an all-encompassing treatment for COVID-19 continues to fuel research. The Randall and Rosner labs from the University of Chicago set off to meet that challenge. Their work, funded by the National Institutes of Health, has now been filed as a provisional patent and after first being released as a bioRxiv preprint early last year, has been recently published by Science. In their COVID-19 study, Nguyen and colleagues put cannabidiol (CBD)’s previously studied antiviral properties to the test.

Nguyen et al. found that CBD was capable of inhibiting SARS-CoV-2 replication, recruiting interferon, and dampening a chemokine response in vitro, while decreasing the risk of contracting COVID-19 by one order in magnitude in human patients. In the clinical study portion of this paper, the authors reported that patients consuming CBD had a statistically significant lower incidence of contracting COVID-19 compared to patients that did not consume CBD or had different types of cannabinoids.

Despite these optimistic results and a relatively large clinical sample size (over 93,000 patients), the authors pointed out that more research is needed. Interestingly, CBD, under the brand name Epidiolex, is already prescribed for epilepsy in the US where it is approved by the FDA. As such, Epidiolex could be repurposed to treat COVID-19 and/or used in combination therapies (Nguyen et al. also tested CBD treatment in combination with a neutralizing antibody). CBD may also prove beneficial to people suffering from the long-term effects of COVID-19 involving inflammation. At the very least, it would be the most relaxing way to end this pandemic.