KOL Views Results: Leading virologist hopeful therapeutics may be ready for likely re-emergence of COVID-19

FirstWord hosted an expert call this week with Gene Olinger – adjunct associate professor of medicine and associate director for maximum containment training at the National Emerging Infectious Disease Lab at Boston University School of Medicine – to discuss the latest development status of various candidates being tested to treat COVID-19.

Summary points from expert feedback:

  • Big question is not whether a drug can be developed for COVID-19 but if it can be found and tested in time before the outbreak subsides
  • A viable strategy will likely involve multiple mechanisms, with an ideal combination inhibiting the virus and tamping down the host response
  • High likelihood the coronavirus re-emerges this fall will give companies a chance to be ready with emergency use authorisations or at least adaptive-design trials
  • Remdesivir's broad-spectrum activity could prove useful but safety will need watching
  • Vaccines are a better long-term strategy for managing COVID-19 than therapeutics

FirstWord: How optimistic are you that one or more therapies for treating COVID-19 will be successfully tested and approved in time to help head off the current outbreak?

“I think the probability is very, very low. The reason I say that is because there are a lot of steps. I was involved with the Ebola outbreak and saw how difficult it was to do even in a controlled environment in Liberia. This is a global pandemic situation so it is even more challenging.”

“It typically costs $1 to $2 billion and takes a decade to develop a drug using a traditional approach, so trying to condense and accelerate that is very difficult to do.”

“One question is what kind of target product profile are we looking for? If the goal is to give it to someone who is healthy and at home, that is different than a patient who is severely compromised and in the intensive care unit.”

“In my experience the decision to test something in a compassionate care setting – either a novel agent or repurposed drug – is an art for physicians who are very selective in what they are willing to try. Safety is paramount and getting answers on efficacy is very challenging. If you go back to every outbreak since HIV there are always drugs that someone claims were successful in one or two patients because they survived, but was that really the drug or was supportive care enough, or were they getting better on their own? You need randomised, controlled clinical trials to determine that.”

FirstWord: Is the bigger question whether a drug can be identified to treat COVID-19 or, alternatively, identified if one can be identified in time to be tested while the outbreak is still ongoing?

“Whether it can be found in time is the big question. I am hopeful that we will start to see a decline in the middle to end of May, if not a little earlier. But by that time can they get trials up and running and generate efficacy data? It will probably be tough.”

“Viruses causing respiratory infections tend to die out during the summer and come back in the fall, so I would not be surprised if COVID-19 ends up being a bi-phasic event, meaning it goes into decline in April or May but – and I’d say I am 90% confident about this – it then comes back in the fall, and continues to circulate like that for at least a year or two.”

FirstWord: Is it possible that there are too many asymptomatic people infected with the virus for therapeutics to be useful?

“That is something we will only be able to determine with a retrospective look at serology data. Asymptomatic disease is a common part of the disease spectrum. Perhaps this virus involves a little more shedding which is unique but there were asymptomatic people even with Ebola.”

FirstWord: Is there reason to think one of the modalities being worked on – eg, small molecules, RNA interference or cell therapies – has a higher likelihood of success than others?

“Not really, they all play a part in the mixture. We are seeing a lot of individual small molecules but if you look historically at viral diseases like HIV, HCV and others it is usually multi-drug combinations that are required.”

“There can be a lower amount of drug required with small molecules, which can be an advantage for that class. More important than the modality though is hitting the virus at different stages of its lifecycle, such as a ‘nuc’ analogue plus inhibiting entry or budding.”

“Going back to the target product profile, if the goal is to keep viremia low so people don’t transmit the virus, that is very different from trying to save a patient dying from an acute lung response, which is usually driven by a host response. So inhibiting the virus and reducing the inappropriate host response are different concepts, but the combination of those could be very potent.”

“This gets back to one of the reasons why I am less optimistic about finding something that works soon because you typically need to show efficacy with the individual components before trying out combinations. It either takes time or a really fancy study design to get answers to these questions quickly.”

FirstWord: How optimistic are you about the prospects for Gilead Sciences’ remdesivir when preliminary results from studies in China start becoming available in the near-term?

“I am optimistic from the point of view that it is a broad-spectrum antiviral. What I am concerned about though is that a more promiscuous targeting mechanism means you are more likely to have some host response issues – that’s a safety question.”

“Safety will be paramount when it is time to evaluate remdesivir. Gilead has pretty good data from Phase I in healthy volunteers but things change in infected patients. A lot will depend on how the Chinese studies are designed, and whether they meet the standards that would be needed in the US. That remains to be seen.”

FirstWord: Would you say remdesivir has the highest likelihood of success as other candidates in development?

“I would say there are a number of programmes that are all equal at this point. The ideal compound would show in vitro and animal model data, and then of course safety and efficacy in humans, but no drugs tick all the boxes in part because there is no good animal model for COVID-19.”

FirstWord: What would you suggest the bar for success should be for remdesivir?

“Show efficacy by reducing serious disease in the age group of 50 and up, and of course morbidity and mortality outcomes”

FirstWord: Are you at all optimistic about the use of HIV drugs such as AbbVie's Kaletra (lopinavir/ritonavir)?

“They get a lot of excitement anytime there is an outbreak but they feel more like a Hail Mary since there is no good animal or in vitro data to support their clinical impact.”

FirstWord: Do any other programmes stand out as particularly intriguing either because of initial data or compelling biologic plausibility?

“Chloroquine is something I worked with in an NIH lab and it had some interesting in vitro results against MERS and SARS. Remdesivir may look a little more potent but they could be an interesting combination.”

“It will be tough to pull those studies off because it usually takes six to 12 months just to show data in animals, but I do think combinations offer the best chance of success. The best option would be finding old drugs to repurpose because that would shorten the timeline, but there is always hesitancy because of patent issues, how it would be sold and who owns it.”

“Another candidate is Arbidol (umifenovir), another broad-spectrum antiviral that is approved in some countries outside the US, and there are a few others in the literature like Avigan [favipiravir from Fujifilm], which is approved in Japan for influenza.”

FirstWord: Are you more or less optimistic that a drug will be successfully developed now versus when the outbreak first emerged several months ago?

“The government seems committed to seeing it through this time. The excitement with MERS and SARS rose but then the programmes got put on the shelf. Those experiences did offer some lessons on classes or compounds that appeared broadly effective against coronavirus, including remdesivir.”

“So I think we have a good starting point but to go from here and be ready to make an impact in three months is going to be tough.”

“I am more optimistic about the second wave in the fall. By then we could either have drugs available through emergency use authorisation or be ready with controlled studies using adaptive-designs to test promising candidates.”

FirstWord: At the end of the day are therapeutics likely to take a backseat in importance to vaccines?

“They probably should. Vaccines are more important for long-term public health strategy. They prevent disease and lessen the severity for people who do get infected, which provides more protection through herd immunity and reduces the burden of a disease like this. By the time you are infected it is usually a little too late – but don’t tell that to a 70-year-old mother who needs to care for herself or her husband.”

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