Challenges to ongoing efforts to provide effective aid for hospitalized patients with COVID-19 continued April 8, with two new trial failures reported. A phase III trial testing the Olumiant (baricitinib) vs. placebo, both on top of standard of care (SOC), missed its primary endpoint of progression to non-invasive ventilation, invasive mechanical ventilation or death, said drugmakers Eli Lilly and Co. and Incyte Corp. A phase II trial testing Beigene Ltd.'s Brukinsa (zanubrutinib) vs. placebo in patients hospitalized with respiratory symptoms of COVID-19 also fell short, missing its co-primary efficacy endpoints of respiratory failure-free survival or reduction in days on oxygen.
Baricitinib, an oral JAK inhibitor, was discovered by Incyte and licensed to Lilly. Zanubrutinib, an oral BTK inhibitor, was developed and launched by Beigene. Though all three companies have engaged in other clinical programs aiming to help COVID-19 patients, the new results served as a reminder of the inevitable challenges that will meet many of the 690 therapies currently under testing or provisionally approved for emergency use worldwide.
Lilly's COV-BARRIER trial tested baricitinib in addition to SOC treatments including corticosteroids, remdesivir and sometimes both. Baricitinib-treated patients were 2.7% less likely than those receiving SOC to progress to ventilation (non-invasive or mechanical) or death, but the difference was not statistically significant (odds ratio [OR]: 0.85; 95% CI 0.67, 1.08; p=0.1800).
Investigators also observed a numerical reduction in mortality for all baseline severity subgroups of baricitinib-treated patients that was most pronounced for patients receiving non-invasive mechanical ventilation at baseline (17.5% vs. 29.4% for baricitinib plus SOC vs. SOC alone; hazard ratio [HR]: 0.52; 95% CI: 0.33, 0.80; nominal p=0.0065).
"While the trend observed for the primary endpoint was not significant, the demonstration of a potential effect on mortality is a clinically important finding," said Vincent Marconi, a professor of medicine and global health at Emory University School of Medicine and Emory's Rollins School of Public Health, as well as a co-principal investigator for the COV-BARRIER study.
It wasn't immediately clear what impact the phase III trial outcome would have on baricitinib's November 2020 FDA emergency use authorization (EUA) in COVID-19, covering its use in combination with remdesivir for certain hospitalized patients. However, Lilly's team seemed to remain confident in the broader picture of clinical evidence supporting the drug's use in COVID-19, noting that the EUA is based on data from the U.S. National Institute of Allergy and Infectious Diseases (NIAID)’s Adaptive COVID-19 Treatment Trial, or ACTT-2.
That study was a randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of a treatment regimen of a 4-mg dose of baricitinib in combination with remdesivir vs. remdesivir.
As Lilly's team shares data from COV-BARRIER with regulatory authorities in the U.S., European Union and other geographies, "we expect the totality of data on baricitinib to continue to support the EUA," Anabela Cardoso, global brand development lead for Lilly Immunology, told BioWorld.
No matter the outcome, there was no suggestion baricitinib's future could be imperiled. Even with a recent setback in which the FDA extended the amount of time it will take to review the drug's supplemental NDA in moderate to severe atopic dermatitis, it logged $638.9 million in global 2020 sales.
Lilly's shares (NYSE:LLY) gained 29 cents to close at $182.61 on April 8. Incyte's shares (NASDAQ:INCY) fell 55 cents to $80.83.
Beigene's zanubrutinib also fell short in patients hospitalized with respiratory symptoms of COVID-19, the company disclosed April 9, even as it marked a more positive milestone in Canada – the drug's Canadian launch for the treatment of adult patients with Waldenström’s macroglobulinemia.
Beigene's U.S.-based phase II trial enrolled 67 patients with COVID-19 disease who either required supplemental oxygen or mechanical ventilation in an effort to illuminate whether the BTK inhibitor could increase respiratory failure-free survival rate at day 28 in participants hospitalized for COVID-19 and pulmonary distress. In the end, it missed both that efficacy endpoint and the co-primary endpoint of reduction in days on oxygen as compared to placebo. There were no new or additional safety signals for zanubrutinib identified in the trial.
"While the outcome of this phase II trial is disappointing, I am heartened by the speed at which we mobilized to launch a clinical trial to explore if zanubrutinib might be able to help in the global fight against COVID-19,” said Jane Huang, Beigene's chief medical officer for hematology.
Beigene's U.S.-listed shares (NASDAQ:BGNE) fell 2.2% on April 8 to $314.62.