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Treatment with the investigational monoclonal antibody mavrilimumab significantly improved outcomes among patients with severe COVID-19 also given standard of care treatment, an international phase II randomized trial found.

Among patients who were not on mechanical ventilation at the time of study enrollment, but had severe COVID-19 with hyperinflammation, those given one of two doses of mavrilimumab had a 65% lower risk of mechanical ventilation or death by day 29, reported Lara Pupim, MD, of Kiniksa Pharmaceuticals in Lexington, Massachusetts.

Compared with patients given placebo, those on mavrilimumab also had a 61% reduction in risk of death at day 29, she reported during a late-breaking session of the European League Against Rheumatism virtual meeting.

Mavrilimumab targets the cytokine granulocyte macrophage-colony stimulating factor (GM-CSF), which is vital to lung homeostasis and in the regulation of inflammation and immunity. GM-CSF has been implicated in the excessive, aberrant immune cell infiltration and activation in the lungs in COVID-19, and may contribute to respiratory failure and death in these patients. Blocking it limits the cytokine's signaling and downregulates the inflammatory process.

Previous experience with mavrilimumab has included two phase II trials, one in rheumatoid arthritis that included 550 patients and the second in 70 patients with giant cell arteritis, with the primary endpoint having been met in both.

There also have been two small studies evaluating this agent for COVID-19. In one that included 13 patients and 26 controls, all mavrilimumab-treated patients had clinical improvement by day 28 compared with 65% of controls (P=0.030). The second was a small blinded, of 40 patients from three centers in the U.S., which demonstrated trends toward clinical improvement, lower mortality, and shorter duration of mechanical ventilation.

The current study included 116 patients who were randomized to a single intravenous infusion of placebo or mavrilimumab, 6 mg/kg or 10 mg/kg, with the primary endpoint being the proportion of patients alive and not on mechanical ventilation at day 29. All participants were receiving supplementary oxygen.

The prespecified evidentiary standard was a two-sided P-value of 0.2 without adjustment for multiplicity, she said.

Patients were recruited from centers in the U.S., Brazil, Chile, Peru, and South Africa. They ranged in age from 29 to 86 (mean 57), and 29% were ages ≥65. A total of 43% were women, 43% were nonwhite, and 49% were obese. Corticosteroids were given to 96% of patients and almost one-third received remdesivir (Veklury).

No differences in outcome were seen for the two dose groups, so the results were pooled in this analysis.

At day 29, the proportion of patients alive and free of mechanical ventilation was 12.3 percentage points higher in the mavrilimumab group (86.7% vs 74.4%), with a P-value of 0.1224, which met the prespecified evidentiary standard of 0.2. "A quarter of placebo patients progressed to mechanical ventilation or death," she noted.

Day 29 mortality was 12.5 percentage points lower in the mavrilimumab group (8% vs 20.5%), for a hazard ratio of 0.39, P=0.0726. A total of 21% of patients receiving placebo died by day 29.

Nonsignificant differences were observed on two secondary endpoints: Median time to a 2-point improvement on the ordinal scale of the National Institute of Allergy and Infectious Diseases (7 days vs 11 days), and median time to room-air only (7 days vs 9 days).

The treatment was well tolerated, with no drug-related serious adverse events seen among mavrilimumab-treated patients. Secondary infections, which are known complications of COVID-19, occurred in four patients in each mavrilimumab group and in nine patients in the placebo group.

One patient residing in an endemic area for tuberculosis developed active TB 10 days after receiving 10 mg/kg. The patient had previously been given high-dose corticosteroids, a known risk factor for reactivation of TB. Thus, the potential additive contribution of mavrilimumab, if any, is uncertain, Pupim said.

Thrombotic events, another recognized complication of COVID-19, occurred in the placebo arm only, with five cases.

"In a global, diverse population of patients with severe COVID-19 pneumonia and hyperinflammation receiving supplemental oxygen therapy, corticosteroids, and remdesivir, a single infusion of mavrilimumab reduced progression to mechanical ventilation and improved survival," she said.

"Of potential importance is that this treatment strategy is mechanistically independent of the specific virus or viral variant," she noted.

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