BEIJING – While repurposing drugs may be a quick solution to an epidemic like COVID-19 that has a limited research window, it’s just luck as to whether an already available drug candidate exists for newly emergent diseases. Experts say it’s more realistic to develop better drugs instead of attempting to repurpose old ones.
Gilead Sciences Inc.’s remdesivir seemed like a miracle, when the drug candidate designed for Ebola showed promise in curing the COVID-19 coronavirus. But Tomas Cihlar, vice president of virology at Gilead, stressed it is “the expansion of indication” based on the existing profile of the drug candidate, and it is unlikely that other hypertension or diabetes drugs will be efficacious inhibitors for COVID-19 in any meaningful way.
On Wuxi Apptec’s online forum on Wednesday, Cihlar said the expansion of indication is possible when the drug candidate aims at related or similar targets and has broad-spectrum features. Remdesivir, for example, features broad-spectrum activity against viruses that have very similar RNA polymerase machinery and target.
“There are examples of other molecules like favipiravir, galidesivir and nucleoside analogues that have been established to have potentially both a broad-spectrum and antiviral activity,” he said, suggesting an approach that needs pursuing, especially currently.
In order to be able to develop better small-molecule drugs for a disease like COVID-19, Cihlar suggested three criteria: administration, infrequent dosing and a high resistance barrier.
He also proposed additional features that may allow for effective administration of the drug in the larger population, not only for treatment but also for post-exposure prophylaxis.
“Ultimately, we would like to have a drug that can be given orally and intranasally, potentially through inhalation,” Cihlar said.
He also noted that it would be ideal to build the feature of long-acting action into the drug’s profile, and a high resistance barrier would allow basic administration of the drug without the potential risk of conferring resistance to the virus.
Another biotech scientist, David Ho, director of Aaron Diamond AIDS Research Center and medicine professor of Vagelos College of Physicians and Surgeons at Columbia University, is also cautious about the idea of drug repurposing, saying one has to be “awfully lucky” to achieve a solution via that method.
While HIV and HCV protease inhibitors could show promise in the COVID-19 fight, Ho said those agents were tested against SARS some years ago mostly in anecdotal form, so the results are not conclusive.
A case in point is lopinavir, a HIV protease inhibitor that Ho said many believe to have activity against COVID-19 “almost out of desperation.” He said the recent clinical trials in China comparing lopinavir to placebo to Arbidol (umifenovir) show essentially no observed discernible difference.
“We really need to aim for much better drugs and now is the time,” he said. “Better drugs that work not just against the current virus but hopefully across all the coronaviruses.”
At Columbia, Ho has assembled teams to search for protease inhibitors and polymerase inhibitors. They have a big pool of protease inhibitors, polymerase inhibitors or their analogues to work from, and Ho said he believes those compounds are likely to yield results.
“They may not be potent activity, but they will point a way for optimizing those small molecules into much better drugs,” he said. “That's the kind of undertaking that we embark on in an academic institution.”
Looking for antibodies
Attention has also been focused on antibodies. Vir Biotechnology Inc. CEO George Scangos said a solution in addressing current and future outbreaks is to develop broadly neutralizing antibodies.
Vir will work with Chinese CRO Wuxi Biologics to develop and produce human monoclonal antibodies for clinical development that Vir has found are able to bind to SARS-CoV-2, the virus that causes COVID-19. Those antibodies were isolated from people who recovered from SARS. Vir is carrying out work to determine if those antibodies can be effective as treatment and/or prophylaxis against SARS-CoV-2.
“Right now, we are looking very hard for antibodies that will neutralize COVID-19,” said Scangos. “In the longer term, we would like to identify coronavirus antibodies that will neutralize SARS, MERS, COVID-19 and hopefully the next coronavirus outbreak.”
To do that, he said one must look for antibodies that will neutralize two strains of coronavirus that are on the opposite end of the coronavirus evolutionary tree, so they are very divergent types of viruses.
“You look for these antibodies and once you find them, you can map the epitopes, you can understand where they bind, you can then assess that region of the virus, how similar it is across the known strains of the coronavirus,” he said.
“You can assess the function of that region whether or not it is likely the virus can mutate that and still be viable.”
While it is hard to find cross-reactive neutralizing antibodies, Scangos reminded forum attendees that there has been success with flu and respiratory syncytial virus, and there are antibodies that recognize virtually all strains.
While agreeing on a common goal to develop better drugs that can treat present and future diseases, the experts also worried whether antibodies and vaccines might enhance infection.
Scangos cited dengue and Zika vaccines, saying they could protect against one virus section, but with the unforeseen effect of enhancing infection in other sections.
“The challenge of coronavirus vaccines is going to be to make sure that if the vaccine does provide protection against COVID-19, it doesn’t actually enhance infection with the next coronavirus,” he explained. “That is going to be difficult, but not insurmountable.”