From the Journals

Tofacitinib shows mortality benefit in patients with COVID-19 pneumonia


 

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

The Janus kinase inhibitor tofacitinib reduces the risk of both death and respiratory failure in hospitalized adults with COVID-19 pneumonia, a new Brazilian study has found.

“Whether the use of JAK inhibitors is superior or additive to other specific immunomodulatory therapies in patients hospitalized with COVID-19 remains to be determined,” Patrícia O. Guimarães, MD, PhD, of the Hospital Israelita Albert Einstein in São Paulo, and coauthors wrote. The study was published in the New England Journal of Medicine.

The results of previous trials that tested JAK inhibitors as therapies for COVID-19 have been mixed. The second iteration of the Adaptive COVID-19 Treatment Trial (ACTT-2) found that a combination treatment of baricitinib and the Food and Drug Administration–authorized remdesivir was superior to remdesivir alone, but ACTT-4 – which compared baricitinib plus remdesivir with dexamethasone plus remdesivir – was stopped for futility in April 2021.

To assess the efficacy and safety of tofacitinib as a potential treatment for COVID-19, the researchers launched a randomized, double-blind trial made up of 289 patients from 15 sites in Brazil. The Study of Tofacitinib in Hospitalized Patients with COVID-19 Pneumonia (STOP-COVID) split its participants into two groups: one (n = 144) received 10 mg of oral tofacitinib twice daily and the other (n = 145) received placebo. Treatment was to be administered for up to 14 days or until hospital discharge. The participants’ mean age was 56 years, and 34.9% were women.

Over 89% of participants received glucocorticoids during hospitalization, a significant increase, compared with ACTT-2’s 12%. Through 28 days, death or respiratory failure occurred in 18.1% of the tofacitinib group and in 29.0% of the placebo group (risk ratio, 0.63; 95% confidence interval, 0.41-0.97; P = .04). Death from any cause occurred in 2.8% of the tofacitinib group and 5.5% of the placebo group (hazard ratio, 0.49; 95% CI, 0.15-1.63). The median number of days that treatment was administered was 5 in the tofacitinib group and 6 in the placebo group, and the median duration of hospital and ICU stays were similar across groups.

On the eight-level National Institute of Allergy and Infectious Diseases ordinal scale of disease severity, the proportional odds of having a worse score with tofacitinib, compared with placebo, was 0.6 (95% CI, 0.36-1.00) at day 14 and 0.54 (95% CI, 0.27-1.06) at day 28. Adverse events occurred in 26.1% of the tofacitinib group and 22.5% of the placebo group, with serious adverse events occurring in 20 patients (14.1%) on tofacitinib and 17 patients (12%) on placebo. Patients on tofacitinib suffered from events like deep vein thrombosis, acute myocardial infarction, ventricular tachycardia, and myocarditis, each of which affected one person, while one placebo patient each suffered from hemorrhagic stroke and cardiogenic shock. The incidence of serious infection was 3.5% in the tofacitinib group and 4.2% in the placebo group.

Timing may be everything

“There is a lot of interest in repurposing a variety of disease-modifying antirheumatic drugs for the treatment of COVID-19, which includes JAK inhibitors,” Zachary S. Wallace, MD, of the rheumatology unit at Massachusetts General Hospital, Boston, said in an interview. “The ACTT-2 data was compelling; it did suggest perhaps a benefit associated with baricitinib for COVID. This study certainly is more compelling.”

Dr. Zachary Wallace Rheumatology Unit at Massachusetts General Hospital in Boston

Dr. Zachary Wallace

“For many people, there is this hyperinflammatory response in COVID-19 that seems to drive a lot of the morbidity and mortality that we see,” he added. “I think we all hypothesize that some of our treatments may be beneficial there. The challenge that we face is figuring out when the best time is to administer these medicines, and whether they need to be administered as part of a cocktail of therapy.”

Along those lines, Dr. Wallace cited a recent study he coauthored in which rheumatoid arthritis patients who were on JAK inhibitors at baseline had worse COVID-19 severity. But he emphasized that, despite their differing findings, the two studies are not irreconcilable.

“What this might speak to is, the timing of your exposure may be really important,” he said. “At the time of your initial infection, you may need certain aspects of your immune system that a JAK inhibitor may interfere with. But when you initiate a JAK inhibitor, once that phase is complete and you’re in this hyperinflammatory phase, you may have more benefit to target and treat the intense inflammation that we observe in patients who have COVID.”

He also offered up another variable potentially in play: different JAK inhibitors having different targets among the JAK receptors. “It may be that targeting specific JAKs is more beneficial when it comes to treating the hyperinflammatory response of COVID-19.”

The trial was sponsored by Pfizer. Several authors acknowledged potential conflicts of interest, including receiving grants and personal fees from Pfizer and various other pharmaceutical companies.

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