Investigators shift from anti-virals to drugs that target the immune system.
The search continues to find effective treatments for covid, which has now killed almost 3.9 million people worldwide, and drugs developed for rheumatic diseases are leading the charge.
The World Health Organisation’s Solidarity trial, the second largest clinical trial in the world after the UK’s RECOVERY trial, has a renewed focus on targeting immune responses after the first four antiviral agents it tested failed to save lives or shorten hospital stays.
The move signals a broader shift in clinical trials towards testing existing drugs that target the immune system – which may help reign in the aggressive inflammatory responses that accompany severe forms of covid.
“It’s a very smart strategy,” said Professor Philip Robinson, a rheumatologist at the University of Queensland who co-founded the COVID-19 Global Rheumatology Alliance. “Generally, it’s the hyper-inflammatory response that kills the patient, not the virus.”
Infliximab, a TNF inhibitor which may dampen covid immune responses, is one of the three drugs in line for the second phase of Solidarity, according to reports from Nature News. Infliximab was chosen for its promising results in smaller trials and widespread availability, investigators said.
But there are several other immunomodulatory drugs showing promise as covid treatments, with new data emerging in recent months.
A June preprint study published in medRxiv ahead of peer review points to prioritising namilumab, a drug candidate in late-stage trials for rheumatoid arthritis, more so than infliximab.
Only namilumab, not infliximab, demonstrated “proof-of-concept evidence” for reducing inflammation (C-reactive protein levels) in a group of 146 patients hospitalised with cvoid, the CATALYST trial investigators found.
Namilumab blocks an immunoregulatory cytokine called GM-CSF, whereas infliximab is a TNF inhibitor.
However, Professor Robinson said: “I don’t think we should dismiss infliximab because of an early proof-of-concept trial with a proxy endpoint in very sick patients.”
“There is data suggesting some of these agents are only effective in some subgroups, so it’s a matter of working out where they fit,” based on safety, efficacy, disease stage and severity, he said.
Namilumab is slated for another international, adaptive trial called REMAP-CAP which, like Solidarity, also plans to test the cancer drug imatinib in severe cases of covid.
Also on the agenda are IL-6 inhibitors such as tocilizumab, after promising results in over 800 critically-ill covid patients.
As the REMAP-CAP trial investigators reported in the New England Journal of Medicine in April, tocilizumab improved outcomes and reduced deaths in covid patients on organ support in intensive care, as did sarilumab, another cytokine-targeting drug.
Although smaller trials of tocilizumab have reported conflicting results, it looks like a solid contender – and has been added to the US National Institute of Health’s COVID-19 Treatment Guidelines – with data from the RECOVERY trial of 4416 hospitalised patients, published in The Lancet in May, showing it improved survival.
Another emerging prospect is mavrilimumab, a monoclonal antibody in development for rheumatoid arthritis, with new data from 116 patients presented at the EULAR 2021 Virtual Congress in June.
The preliminary results from an ongoing randomised placebo-controlled phase 2/3 trial suggest that patients hospitalised with severe covid had a reduced risk of death and mechanical ventilation on mavrilimumab compared to a placebo.
“That looks certainly encouraging but it’s a matter of seeing the full dataset,” Professor Robinson said. “Trials aren’t just about efficacy, they’re also about safety.”
As for existing drugs, tofacitinib, a JAK inhibitor used to treat rheumatoid arthritis, may have some survival benefit, according to results from the STOP-COVID trial published in the New England Journal of Medicine in June.
Among 289 hospitalised adults, those treated with tofacitinib for covid had a lower risk of death or respiratory failure than the placebo group, regardless of their age, sex or duration of symptoms.
“Obviously, we need more data to be more confident about it,” Professor Robinson said. “But it looks like two of the three available JAK inhibitors [tofacitinib and baricitinib, in combination with remdesivir] actually improve outcomes on covid.”
Other observational data from the Global Rheumatology Alliance has, however, flagged concerns about using JAK inhibitors, as well as rituximab, to treat covid.
Published in Annals of the Rheumatic Diseases, the study – which did not discriminate among JAK inhibitors – found that rheumatoid arthritis patients treated with a JAK inhibitor at the onset of covid were twice likely to be hospitalised or die than those on TNF inhibitors.
But that result may be due to other factors not captured in the analysis, such as prednisone use or high disease activity, Professor Robinson said.
While the critically-ill need urgent attention, finding therapies for treating early-stage cases of covid is also an ongoing priority, to reduce the strain on hospitals.
“Our holy grail,” said Professor Robinson, “is to find combination therapies against both the virus and hyperinflammatory response, that prevent people becoming more unwell and also can treat the virus.”
