Bridging The Gap

Old drugs for a new virus

Old drugs for a new virus

In a review published in ACS Infectious Diseases last month, Stanford professors Dr. Shirit Einav, also a SPARK scholar, and Dr. Sirle Saul take a comprehensive look at the major drug repurposing approaches being investigated to treat COVID-19.

Dr. Saul is a postdoctoral research fellow, infectious diseases. Dr. Einav is an associate professor of medicine, infectious diseases, and of microbiology and immunology.

Dr. Einav’s lab focuses on understanding the roles of virus-host interactions during infection and pathogenesis, along with translational efforts to apply that knowledge to development of broad-spectrum host-centered antiviral approaches to combat emerging viral infections and ways to predict disease progression.

In one SPARK project, Dr. Einav and team identified two approved anticancer drugs that can be repurposed as broad-spectrum antivirals by targeting the host response to the virus. Her team has shown that the combination of erlotinib and sunitinib inhibited Ebola and dengue infections in mice. The combination has been licensed to a biotech, which plans to begin clinical trials. Dr. Einav’s lab is also developing more selective antiviral inhibitors.

Dr. Einav is currently working on another SPARK project to develop a set of genes to predict severe dengue infection. “Our severe dengue biomarker program is moving forward nicely,” she said. The team has validated a narrow 8-gene set in a large cohort of dengue patients, and has applied for funding to develop an assay.

Dr. Einav praised the SPARK program for its help with her team’s work. “The support SPARK provided during the 2014 Ebola outbreak was above and beyond.” For instance, SPARK co-director Dr. Kevin Grimes joined her when she presented data at USAMRIID and the Gates Foundation, and SPARK helped get the drug donated. She added, “The advice we were getting from multiple SPARK advisors was invaluable.”

The global pandemic that has occurred due to SARS-CoV-2 infection, the virus that causes COVID-19 disease, has created an urgent need for effective countermeasures, Dr. Einav and Dr. Saul wrote in the review. “The development of novel antiviral drugs is expensive and too slow to meet the immediate need.” It takes 8-12 years to develop a new drug, a timeline that won’t work for an outbreak. Repurposing drugs already approved or under clinical investigation for a different disease and already shown to be safe in humans could be a cost- and time-effective therapeutic solution.

The authors review these approaches in detail, including drugs to reduce SARS-CoV-2 replication by targeting either sites in the virus or the human (the host) required for the viral life cycle, or drugs that modulate the host immune response to SARS-CoV-2 infection. The authors also discuss ongoing challenges associated with the off-label use of existing drugs.

Among the drugs that target the virus itself are direct acting antivirals (DAAs) that go after SARS-CoV-2 polymerase or proteases – enzymes that are “intuitive therapeutic targets” because of “their known biological functions and active enzymatic sites.” One example of a polymerase inhibitor is remdesivir, a compound originally developed for Ebola. Clinical trials in COVID-19 patients suggest remdesivir is moderately effective at shortening recovery time and improving symptoms, and it has been granted emergency use approval by FDA.

A completely different approach than targeting the virus itself is to target the host – the human. Viruses need to replicate inside a human cell using the cell’s own machinery. “Repurposing inhibitors that target cellular functions required for SARS-CoV-2 infection is thus an attractive approach that may have the added benefit of a higher genetic barrier to the emergence of resistance,” the authors wrote.

For instance, cellular kinase inhibitors approved as anticancer or anti-inflammatory drugs have potential to be repurposed into antivirals. There are a number of approved anticancer drugs that fall into this category, including dasatinib, imatinib, nilotinib, and gilteritinib, and investigational drugs like ralimetinib and apilimod.

There are some drugs that have potential to treat COVID-19 “for which the mechanism of antiviral action is complex and unclear.” These include the antiparasitic drugs niclosamide, used to treat tapeworm infection, and chloroquine and its derivative hydroxychloroquine, approved for malaria, lupus and rheumatoid arthritis.

Finally, the authors review drugs that modulate inflammation and tissue injury. If SARS-CoV-2 evades viral clearance, it replicates efficiently in tissues expressing ACE2, such as lungs, heart, and intestines, leading to massive tissue destruction, severe inflammation,” and tissue fibrosis.

Approaches with potential to reduce inflammation and/or tissue injury during COVID-19 include interferons and corticosteroids like dexamethasone. Other classes include JAK inhibitors, BTK inhibitors and various monoclonal antibodies like those that target IL-6.

Ulinastatin, a drug approved to treat pancreatitis and sepsis in Asia, is an anti-inflammatory agent that inhibits IL-6 but may provide additional benefits for COVID-19. The urinary serine protease inhibitor has been shown “to activate the renin–angiotensin system (RAS) by upregulating the expression of ACE2 as well as the anti-inflammatory factor angiotensin 1–7 (Ang 1–7),” making ulinastatin an attractive drug for COVID-19, since the disease may be linked to an imbalance in the RAS. SARS-CoV-2 reduces ACE2 expression when entering cells, so ulinastatin “may reverse this imbalance and reduce tissue injury by directly upregulating ACE2.” The authors also suggest an Ang 1-7 peptide could reverse the RAS imbalance and reduce tissue injury.

Some of these drugs, like remdesivir and dexamethasone, have shown promise in clinical trials, some like hydroxychloroquine and IL-6 inhibitors have been tested and haven’t panned out, and others like apilimod and ulinastatin could be winners, but need more testing to determine how effective they could be at combating COVID-19.

The authors address challenges in repurposing drugs. “One challenge is that the antiviral effect observed in vitro often cannot be reproduced in vivo.” Others include the emergence of viral resistance, a challenge for any antiviral strategy. Challenges specific to repurposing approaches include understanding the mode of action of the drug, access to available drug stockpiles, and the need to prioritize among different approaches to study their effectiveness.

Dr. Einav was invited to write the review due to her expertise in antiviral approaches for emerging viral infections and her experience with drug repurposing efforts. She felt it was important to review current repurposed drug approaches to treat COVID-19 as there was a lot of bias in the literature, particularly early on, she said. “There was too much attention to certain agents (e.g. hydroxychloroquine) based on very little data, whereas other, more promising candidates were not getting enough attention.” She added that “there is a flood of papers and it’s tough for many of us to keep track.”

Additionally, “with our experience in repurposing, I felt that we can add important components,” such as challenges her team faced during the Ebola outbreak and those faced now, and important PK/PD parameters that should be considered.