Numerous approaches to tackle Covid-19 are in clinical trials or heading there. But how do these potential treatments differ, and what should biopharma make of them all? Vantage asked Dan Chen, someone especially well placed to comment on the new coronavirus.
Mr Chen is upbeat about antivirals, notwithstanding the fact that most have middling efficacy, and he is intrigued by the anti-cytokine approach of Actemra but says better understanding of this mechanism is urgently needed. Of antimalarials, around which President Donald Trump’s comments have prompted a recent surge of interest, he seems less convinced.
Biopharma investors will be familiar with Mr Chen as the former head of cancer immunotherapy at Roche’s Genentech division, and he is now chief medical officer of IGM Biosciences. But outside oncology his views on Covid-19 should also be heeded: his PhD was on molecular virology, with a focus on coronavirus infection.
Taking the top off
Antivirals, like Gilead’s remdesivir, Abbvie’s Kaletra or Taisho’s Avigan, hold the potential for a broad-based first line of attack against an entire class of viral pathogens, though their efficacy is fairly modest.
But complete viral clearance does not need to be every therapeutic’s goal, Mr Chen explains. It might be enough to “take the top off” the viral infection, something that could make “the difference between someone having flu-like symptoms versus needing to be on a respirator”.
As for the various antiviral classes, he says blocking viral proteases has disappointed, but this is likely because drugs like Kaletra (whose lopinavir component is a protease inhibitor) were developed for HIV, not Covid-19.
A keenly awaited catalyst for RNA polymerase inhibition are remdesivir data from a Chinese trial next month, and from Gilead’s own studies in May. Blocking viral entry is a separate consideration, however, and "may need to be utilised earlier than generally blocking viral replication”, says Mr Chen.
Possible entry blockers include antibodies against Spike protein, blockers of Ace2 – it is via this receptor that the Covid-19 virus enters target cells – and TMPRSS2, and calcium channel inhibitors, but all are early in development.
Then there are treatments for malaria and lupus like Plaquenil, which President Trump three days ago suggested should be deployed quickly against Covid-19. This was prompted by a highly equivocal academic trial in France; a randomised Chinese study showed no benefit.
Mr Chen says he is not sure whether to give the existing data any credence, but is “hopeful [of] some modest amount of activity”. With anecdotal reports of lupus patients now being denied Plaquenil because it is being hoarded for coronavirus treatment, there is a pressing need for more evidence.
It’s not cytokine storm
What about cytokine inhibitors? This idea gained traction after Roche’s Actemra, an anti-IL-6 rheumatoid arthritis drug, was added to China’s emergency treatment guidelines. Other MAbs against the IL-6 pathway being rushed into the clinic now include Sanofi/Regeneron’s Kevzara and Eusa Pharma’s Sylvant.
One theory driving this is that coronavirus infection prompts a surge in cytokines akin to that seen in response to Car-T therapy, and this causes patients to become extremely ill.
But Mr Chen is not convinced: “I don’t think we are treating cytokine release syndrome as some have suggested, and I’ve pushed back hard to be more precise in our scientific communications. IL-6 levels [in Covid-19 infection] are multiple orders of magnitude lower than what we see with Car-T.”
This does not mean that IL-6 is not important. But what might be happening in seriously ill Covid-19 patients is that IL-6 – a minor part of the cytokines secreted in an antiviral response – creeps up, driving macrophage dominance and creating an unfavourable environment for T cells.
Mr Chen is concerned that characterisation of this as cytokine release syndrome will see “physicians start to use steroids, which appear not to help clinically, and which slow clearance of the virus”.
He welcomes some access to Actemra – “we don’t have time to wait in patients who are critically ill” – but cautions that there is no understanding yet what the timing of treatment should be. He also says he is unaware of specific reasons why, for instance, Actemra should differ biologically from Kevzara.
Ultimately, the most powerful way to limit the impact of viral infection will be vaccines, but since these are highly specific to the molecular makeup of each virus they take a long time to develop, and are then susceptible to being rendered useless if the virus mutates.
Vaccine development “needs to hurry up!”, says Mr Chen. “Effective therapeutics [are] the foundation of how we’re going to get ourselves not only out from under Covid-19 but to be best prepared for the next potential pandemic.”