Slotting anti-inflammatories into COVID-19 treatment

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While repurposed agents for COVID-19 have largely focused on suppressing SARS-CoV-2, there is a strong case to be made for evaluating anti-inflammatory agents in patients with severe disease.

As more emerges about the disease, it’s becoming clear that the early stage requires a different treatment strategy from the later stage, when respiratory function deteriorates.

Mortality in COVID-19 is associated with acute respiratory distress syndrome (ARDS), which results from damage to lung alveoli that triggers a cycle of mounting tissue damage, inflammation and reduced lung capacity. A retrospective analysis of 191 COVID-19 patients, published March 11 in The Lancet, showed that ARDS typically manifests about 8-15 days after symptom onset, and several studies have suggested that COVID-19 patients who develop severe ARDS do not see a survival benefit from antivirals.

This underscores the rationale for creating or repurposing drugs that suppress the immune response later in the disease.

Examples are anti-inflammatory therapies Actemra tocilizumab from Roche (SIX:ROG; OTCQX:RHHBY), Kevzara sarilumab from Regeneron Pharmaceuticals Inc. (NASDAQ:REGN) and partner Sanofi (Euronext:SAN; NASDAQ:SNY), and remestemcel-L from Mesoblast Ltd. (ASX:MSB; NASDAQ:MESO), which are either in ongoing or planned trials to treat COVID-19.

Actemra and Kevzara are both mAbs against interleukin-6 (IL-6) approved for rheumatoid arthritis. Actemra is also approved to treat cytokine release syndrome (CRS) induced by CAR T cell therapy.

This underscores the rationale for creating or repurposing drugs that suppress the immune response later in the disease.

The Lancet study supports IL-6 as a tractable target. Serum IL-6 levels were higher at time of hospital admission in patients who died than in those who survived (11 pg/mL vs. 6.3 pg/mL, p<0.0001), and high IL-6 levels were associated with in-hospital death (univariable odds ratio=1.12, p=0.008).

Roche's Genentech Inc. unit said Thursday it had begun a global Phase III trial of Actemra in hospitalized patients who had developed pneumonia related to COVID-19. By early next month, Genentech aims to begin enrolling up to 340 patients, with primary and secondary endpoints evaluating clinical status, mortality, mechanical ventilation and intensive care unit (ICU) variables. Patients will receive standard of care plus Actemra or placebo. HHS' Biomedical Advanced Research and Development Authority (BARDA) is backing the trial.

On March 3, China’s National Health Commission and National Administration of Traditional Chinese Medicine updated COVID-19 treatment guidelines to include Actemra to treat patients with high IL-6 levels and extensive lung disease or severe disease.

Regeneron and Sanofi announced March 16 the initiation of a double-blind, adaptive Phase II/III trial of Kevzara to treat severe COVID-19. Regeneron spokesperson Sarah Cornhill told BioCentury the Phase II portion of the trial, which will assess fever and need for supplemental oxygen, will determine transition into the Phase III portion, which will evaluate longer term outcomes including mortality and need for mechanical ventilation. The partners said they would begin enrollment immediately but have not disclosed when data are due. “We hope to share results as soon as possible" said Cornhill.

Mesoblast is taking a regenerative approach via its allogeneic mesenchymal stem cell (MSC) therapy. On March 10, it announced its intention to evaluate whether remestemcel-L could benefit COVID-19 patients with ARDS. The company said that in a chronic obstructive pulmonary disease (COPD) study, the cell therapy improved pulmonary function and reduced levels of inflammatory markers that are also elevated in COVID-19 patients.

Antiviral benefit unclear

While anti-inflammatory agents are likely best suited for patients with severe or critical COVID-19, emerging clinical data suggest that antivirals may be most beneficial early in the disease, and in milder cases.

A medRxiv preprint posted March 12 showed that among three U.S. COVID-19 patients treated with remdesivir from Gilead Sciences Inc. (NASDAQ:GILD), there was no clear link between remdesivir administration and clinical benefit. The patients had received remdesivir at time of clinical disease worsening until respiratory symptoms improved -- on days 11-15, 7-10 and 11-20 after symptom onset; but whether remdesivir led to lower viral levels, via detection of SARS-CoV-2 RNA, was inconclusive.

At least five clinical trials are evaluating remdesivir for COVID-19.

While it's still too early to draw definitive conclusions about remdesivir's efficacy against SARS-CoV-2, data from a Phase III trial in Ebola patients suggest that remdesevir improved survival benefit when administered soon after disease onset. The Ebola data were reported in the New England Journal of Medicine in December 2019.

Other antivirals under evaluation for the infection include lopinavir/ritonavir and HCV drug Ganovo danoprevir from Ascletis Pharma Inc. (HKEX:1672).

Data from an open-label study published March 18 in the New England Journal of Medicine showed the lopinavir/ritonavir combination provided no benefit later in disease progression.

Hospitalized COVID-19 patients were treated with lopinavir/ritonavir plus standard-of-care or SOC alone starting 11-17 or 10-16 days, respectively, after symptom onset. Antiviral therapy didn't lead to statistically significant reductions in the 28-date mortality rate, time to clinical improvement, throat swab viral loads or the percentage of patients with detectable SARS-CoV-2 RNA. The study was performed in Jin Yin-Tan Hospital, in Wuhan, China.

Ganovo has produced positive results, although the trial excluded patients with severe disease. Ascletis announced on March 10 that 11/11 hospitalized COVID-19 patients who received Ganovo in combination with ritonavir in a Phase IV trial were discharged after satisfying discharge criteria under “Diagnosis and Treatment Program for Novel Coronavirus Infection (Trial Version 6)." Ascletis’ study was performed at the Ninth Hospital of Nanchang, in Jiangxi, China.

This would not be the first time the clinical benefit of an antiviral was tied to early administration. A post-marketing study of Tamiflu oseltamivir had shown higher survival rates with earlier administration after flu symptom onset, and Tamiflu's label indicates administration within two days of symptom onset and for prophylactic use.

Editor's note: This story was updated on March 20.

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