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Inhibiting granulocyte/macrophage–colony stimulating factor (GM-CSF) with mavrilimumab prevented some patients with severe COVID-19 pneumonia and hyperinflammation from needing mechanical ventilation and reduced their risk of dying versus placebo in a phase 2 study.
There was no difference in outcomes between the two doses of mavrilimumab used in the trial (6 mg/kg or 10 mg/kg) and combined data showed a higher percentage of patients achieving the primary endpoint of being alive and free of mechanical ventilation at 29 days, at 87%, versus placebo, at 74%.
The P value was 0.12, “which achieved the prespecified evidentiary standard of 0.2, generic viagra soft online ca now ” according to Lara Pupim, MD, vice president of clinical research and development at Kiniksa Pharmaceuticals in Lexington, Mass.
Importantly, there was a 61% reduction in the risk of dying if patients had received mavrilimumab rather than placebo, she reported at the annual European Congress of Rheumatology. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07).
Hendrik Schulze-Koops, MD, called it a “surprising study” and that “the outcome is very spectacular” in his short appraisal of the study during the Clinical Highlights session on the final day of the congress.
Mavrilimumab was “a compound that we would not have thought that would have such an impact on the outcome of COVID-19 infected patients,” Schulze-Koops of Ludwig Maximilian University of Munich added.
In this small study, “there was a consistent suggestion of a biological effect across key endpoints,” Richard Conway, MBChB, PhD, a consultant rheumatologist at St. James’s Hospital in Dublin, pointed out in an interview.
“Similar to tocilizumab, the benefits with mavrilimumab appear to be in addition to those seen with glucocorticoids, as 96% of patients received dexamethasone,” Conway observed. Furthermore, nearly one-third received antiviral or remdesivir treatment.
“This study was likely underpowered to assess a clinically meaningful benefit,” he said, adding that “there is insufficient evidence at present to begin using mavrilimumab as an alternative to currently available agents.” That said, “these results are promising for future studies.”
Rationale for GM-CSF Inhibition With Mavrilimumab in COVID-19 Pneumonia
“The cytokine GM-CSF is vital to both lung homeostasis and regulation of inflammation in autoimmunity,” Pupim explained.
She added that “GM-CSF is implicated in the mechanism of aberrant immune cell infiltration and activation in the lungs, and it may contribute to respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.”
The efficacy and safety of blocking GM-CSF with mavrilimumab have been shown previously in phase 2 studies in other diseases, Pupim noted. This includes patients with rheumatoid arthritis and those with giant cell arteritis.
“It was hypothesized that GM-CSF receptor–alpha blockade may reduce infiltration of pathogenic cells into the lung and may suppress inflammation in COVID-19 pneumonia in hyperinflammation,” she explained.
Study Details and Other Outcome Results
The study presented by Pupim was a phase 2/3 double-blind, placebo-controlled trial predominantly conducted in Brazil, the United States, and South Africa, with some participation in Peru and Chile.
Patients were eligible for inclusion if they had had a positive COVID-19 test within 14 days of randomization and had been hospitalized but not ventilated. Evidence of bilateral pneumonia on chest x-ray or CT scan and clinical laboratory evidence indicative of hyperinflammation were also prerequisites for study enrollment.
The ongoing study comprised two cohorts, Pupim explained: patients who have not been ventilated and those who have recently been ventilated. Pupim presented the data on the nonventilated cohort, noting that there was a total of 116 patients aged a mean of 57 years.
Patients were randomized to one of three treatment arms: two groups received a single intravenous infusion of mavrilimumab, either 6 mg/kg or 10 mg/kg, and the third group got a placebo.
“Using a time-to-event approach, looking at mechanical ventilation-free survival, mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death,” Pupim said (P = .0175).
“Separation in the Kaplan-Meier curves was evident very early after study drug administration,” she added.
There were trends toward a faster benefit with mavrilimumab than placebo in two other key secondary endpoints: the median time to achieving a two-point clinical improvement (7 vs. 11 days) and the median time to room air (7 vs. 9 days).
Timing of Mavrilimumab Administration and Safety
Study coauthor and chief clinical development officer at Kiniksa, Arian Pano, MD, answered questions on the presentation. When asked about the timing of giving mavrilimumab, he said: “Based on these data it is before they go to ventilation, as soon as you have symptoms of hyperinflammation and a need for oxygen.”
Mavrilimumab is given as a single infusion “and has been well tolerated; virtually no interruptions occurred in this study.”
No serious adverse events related to mavrilimumab were seen, and adverse events, including secondary infections, which are known complications of COVID-19, occurred less frequently in mavrilimumab recipients, compared with placebo.
Pupim reported that there was a case of tuberculosis in one patient treated with mavrilimumab (10 mg/kg). That case had occurred in an “endemic area for tuberculosis,” and the patient had been screened before entry but only via a sputum sample.
“Prior to these events, the patient received high-dose corticosteroids, a known risk factor for reactivation of TB, and thus the potential additive contribution of mavrilimumab, if any, is uncertain.” Pupim said.
“Thrombotic events, another known complication of COVID-19, occurred in the placebo arm only,” she added.
Pano commented that the study has now “seamlessly continued to phase 3. So, basically, we did not stop the study. At the end of phase 2, we just locked the database and collected the data.” Both the 6 mg/kg and 10 mg/kg are being studied, but it’s “very likely [that] 6 mg/kg could be the dose that we may bring forward to the clinic in terms of registration, but that’s at this point in time. We will need to wait for the phase 3 data,” he observed. Those findings will hopefully be available later this year.
Kiniksa funded the study. Pupim, Pano, and multiple study coinvestigators are employees of the company.
Schulze-Koops was not involved in the study and had no specific disclosures. Conway had no financial disclosures to make in relation to his comments.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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