As vaccines have rolled out in the US and around the world, the focus on fighting COVID-19 has centered almost exclusively on vaccine effectiveness, mass vaccination goals, and herd immunity. Epidemiologists have emphasized that continued use of non-pharmaceutical interventions (NPIs) like masking and limiting indoor gatherings will be necessary to slow or stop the virus.
Vaccines and NPIs have already proven they can greatly reduce infection rates, but there are many reasons why mass vaccination may not be enough to fully stop it. Among those are vaccine hesitancy and new variants such as the South African variant B.1.135 that shows signs of resistance. Successful therapeutics and antivirals could be the missing bridge between a constantly receding and resurging worldwide endemic virus, and true eradication of the virus globally.
Some of therapies have already been identified and approved for emergency use including dexamethasone, monoclonal antibodies, and the antiviral drug remdesivir. These treatments have blunted the fatality rate of COVID-19, but they are just a small fraction of the arsenal or new and repurposed therapeutics that the biotech industry is currently advancing through clinical trials. Among the treatments being tested are novel drug compounds, repurposed old drugs, high-tech biologics like antibodies, and new applications of CRISPR gene editing and messenger RNA. At least 70 COVID-19 candidates are in human clinical trials, according to Regulatory Focus. Here are a few examples:
Eli Lilly’s rheumatoid arthritis drug, Olumiant, received emergency use authorization in the US for COVID-19 in November 2020, and the company recently reported Phase 3 results showing a significant decrease in death in hospitalized patients with COVID-19. The European Medicines Agency has promised to quickly review the drug for approval.
Pfizer just kicked off a Phase 1 study of its oral antiviral candidate PF-07321332, which it says has shown potent activity against the virus in vitro. The drug is a protease inhibitor that prevents the virus from entering the cell. The drug is currently being tested on healthy adults to ensure the safety and tolerability of the drug. Researchers are also testing another protease inhibitor, PF07304814, in people hospitalized with COVID-19.
The NIH is carrying out three late-stage clinical trials of the blood thinners apixaban and heparin for treatment of COVID-19.
A little way behind these later stage therapies, the preclinical pipeline of therapeutics features groundbreaking new technology comparable to the mRNA platform used for the Pfizer-BioNTech and Moderna COVID-19 vaccines. In May 2020, Alnylam Pharmaceuticals partnered with Vir Biotechnology to develop a COVID-19 antiviral based on RNA interference (RNAi), in which short RNAs silence gene expression by attacking messenger RNA. Basically, it’s a custom “off” switch for any gene you could think of. And Alnylam is thinking of a few. For example, the company has RNAi drugs that switch off expression of transthyretin (TTR) in TTR-mediated amyloidosis, and 5-aminolevulinic acid synthase, a key enzyme in hepatic porphyria.
From the world of gene editing, Excision Therapeutics is working on a CRISPR-based therapeutic for COVID-19. CRISPR is a relatively new breakthrough in biotech, barely a decade old. But the work has already garnered its inventors, Jennifer Doudna and Emmanuelle Charpentier, a Nobel Prize in chemistry. CRISPR is like a tiny pair of molecular scissors that can cleave DNA at specific places. Excision’s platform programs those scissors to chop up large sections of viral DNA, with lethal results for the virus. Its most advanced drug candidate is an HIV antiviral, the company also is researching applications for treating the herpes simplex virus and hepatitis B virus, among others.
Vaccine development programs for COVID-19 benefited from a boost provided by almost-there technology that had been in the works already for other coronaviruses. That’s also true for therapeutics, most of which have benefited from very recent technology advances in areas like bioinformatics, artificial intelligence, gene editing, genomics, and proteomics.
As with vaccines, drug repurposing was viewed from an early stage of the pandemic as an important way to gain an advantage over the SARS-CoV-2 virus, with the hope that some already-approved drugs that might also have activity against COVID-19 infections. Some promising early repurposing candidates, like hydroxychloroquine, a malaria drug, didn’t pan out when they were put through high quality clinical trials. However, two repurposed drugs have turned out to be successful—dexamethasone and remdesivir.
Drug repurposing studies have taken a few different forms. One early effort, spearheaded by the U.S. Department of Energy’s Biological Environmental Research office, uses supercomputers to model how drug compounds might fit with viral proteins. At Oak Ridge National Laboratory, the Molecular Biophysics group took the lead in a spontaneous global collaboration to search for cures for COVID-19 that started coming together around February of 2020. The effort brought together disparate disciplines—biophysicists, computer scientists, crystallographers, structural modelers, geneticists, and more—leveraging the power of ORNL’s Summit Supercomputer, the world’s fastest. Summit, unveiled in June 2018, is capable of 200,000 trillion calculations per second (200 petaflops) and has more than 10 petabyes of memory. Within a month, the project had already produced 77 small molecule compounds as candidates for COVID-19 therapeutics.
In March 2020, as much of the US plunged into lockdown, Ada Sedova, an R&D Associate with the group, described the project as “kind of a moonshot.” She says their type of model simulates protein shapes more the way they would behave in real life, as opposed to a rigid crystal form. “Now, of course, it’s still really inaccurate in a way, because there’s a lot of cellular details and other things that are ignored. If we really wanted to a complete physical simulation to get every physical detail, we would never be able to do that even with the Summit supercomputer, because there’s quantum mechanics involved, there’s billions of possible atoms involved, and there’s a whole bunch of things we don’t even really know from the cell biology perspective.” But even so, she says, using the methods available can produce viable drug candidates that can then be tested in the laboratory.
Another drug repurposing study, using different technology, comes from the laboratory of Neville Sanjana at the New York Genome Center. Sanjana and his colleagues used CRISPR editing technology to probe gene pathways in the lungs that are required for infection by SARS-CoV-2. As described above, CRISPR is already being used to cut and rewrite DNA for therapeutic purposes, but in Sanjana’s lab, those scissors are probing for attack points to block the virus that causes COVID-19. This work highlighted the cholesterol biosynthesis pathway as potentially relevant. Specifically, the researchers theorized that a drug that increases intracellular cholesterol could block the virus. The study turned up amlodipine, a drug already approved by the FDA, as a powerful inhibitor of the virus.
“It’s been FDA-approved for 30 years or more, and it’s a calcium channel blocker that increases intracellular cholesterol. We took cells that were pretreated with amlodapine and we challenged them with the virus and we saw a huge inhibitor effect. Orders of magnitude less virus after exposure,” says Sanjana. Separately, some validation of that theory seems to come from a study in Cell Discovery published in Dec. 2020 looking at hospitalized patients with COVID-19 and hypertension. Those who were treated with amlodipine had a dramatically lower fatality rate compared to similar patients who were not on the drug. The case fatality rate for patients not receiving amlodipine was 19.5%, whereas in the group receiving amlodipine, there were zero fatalities.
In addition to expanding the search for therapeutics into new territories, technological advances have significantly compressed the timeline from early discovery to clinic. Once a process that can take years, a collaboration centered on the laboratory of Nevan Krogan at UCSF was able to push a candidate into Phase 3 studies in about nine months starting from zero, according to Robert Deans, Chief Scientific Officer of Synthego. A sprawling 200-author paper published in Science details an effort that combines an encyclopedia of the latest technologies, including CRISPR, RNAi, genomics, next-generation proteomics, and intensive computational analysis. The outcome of the study was the identification of a class of drugs, typical antipsychotics, as having strong potential activity against SARS-CoV-2, with support for that theory from a review of real world medical records showing patients on those drugs had better COVID-19 outcomes. Deans says a candidate produced by this study is now in Phase 3 trials.
Remdesivir is the only antiviral drug authorized for use against COVID-19. However, its effectiveness is relatively modest. In hospitalized patients with COVID-19, those receiving remdesivir recovered in 10 days on average, compared to 15 days for the placebo group. However, remdesivir’s effectiveness gets a boost of up to 10-fold when combined with certain hepatitis C drugs in human cell culture—simeprevir, grazoprevir, paritaprevir, and vaniprevir. That’s according to a new study in Cell Reports. The authors note a synergistic relationship between remdesivir and the hep C drugs that could lead to a powerful antiviral cocktail for treating COVID-19 if born out in human trials.
The work was inspired by a study that predicted the hepatitis C drugs would have anti-SARS-CoV-2 activity using a supercomputer to model their binding to a viral protein that is highly similar to a protein in the hepatitis C virus. Because these drugs are already approved and on the market for hepatitis C, the drug cocktail could be expedited through human testing fairly quickly, compared to new investigational drug compounds.
Still, a list of promising candidates isn’t much good without clinical trial followup, and many ambitious drug repurposing programs have languished while governments have focused resources on vaccine development. Speaking with 60 Minutes in March, NIH Director Francis Collins described, “scattershot efforts to try and find effective treatments. It wasn’t as coordinated as it needed to be. … I wish we had had a stronger push for agents that you can take by mouth before you get in the hospital to prevent disease. It took a while after the hydroxychloroquine debacle to get that back on track.”
That stumble is being belatedly rectified now under the NIH’s newly announced ACTIV-6 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) initiative. The trial will evaluate up to seven as-yet unnamed existing drugs in hospitalized patients with moderate to severe COVID-19. The drugs will be chosen from the CORONA (COVID19 Registry of Off-label and New Agents) database maintained by the University of Pennsylvania in Philadelphia.
It’s important to keep in mind that drugs in clinical trials are far from a sure thing, and preclinical candidates even farther. However, the intensity of focus on vaccines has obscured the role that curative treatments could play in ending the pandemic. With truly effective antivirals and other treatments, herd immunity through vaccination could even become an irrelevant goal.