Candidate: Olumiant® (baricitinib)
Type: Janus kinase (JAK) inhibitor indicated for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.
2021 Status: More Positive COV-BARRIER Data—Eli Lilly and Olumiant on August 3 announced additional data from an additional cohort of 101 adult participants in the Phase III COV-BARRIER trial (NCT04421027), showing that COVID-19 patients on mechanical ventilation or extracorporeal membrane oxygenation (ECMO) who received baricitinib plus standard of care were 46 percent less likely to die by Day 28 compared to patients who received placebo plus standard of care. The cumulative proportion of patients who died by Day 28 was 39.2% (20 of 51) in the baricitinib arm versus 58% in the placebo arm (29 of 50). A similar mortality benefit was seen by Day 60, with a cumulative proportion of death of 45.1% (23 of 51) for baricitinib compared to 62% for placebo (31 of 50). The findings were consistent with the reduction in mortality observed in the overall COV-BARRIER patient population, the companies said.
By Day 28, the frequency of adverse events, serious adverse events and serious infections were similar in the baricitinib group (88%, 50% and 44%, respectively) compared to placebo (95.9%, 71.4% and 53.1%, respectively), Lilly and Incyte said.
EUA EXPANDED—The FDA on July 28 expanded its Emergency Use Authorization (EUA) for Olumiant® (baricitinib) as a COVID-19 treatment by allowing the drug’s use with or without Gilead Sciences’ Veklury® (remdesivir); the agency previously required Olumiant to be used in combination with Veklury. The EUA now provides for the use of baricitinib for treatment of COVID-19 in hospitalized adults and pediatric patients two years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
The FDA based its decision on data from the Phase III COV-BARRIER trial (NCT04421027) showing Olumiant met a pre-specified key secondary endpoint when used in addition to standard of care by meaningfully reducing the risk of death by 39% percent by Day 28 when compared to standard of care alone (62/764 [8.1%] for baricitinib, 101/761 [13.3%] placebo).
Phase III Trial Fails—Eli Lilly and Incyte acknowledged April 8 that Olumiant® (baricitinib) missed the primary endpoint of the Phase III COV-BARRIER trial by not meeting statistical significance on the study’s primary endpoint, a difference in the proportion of participants progressing to the first occurrence of non-invasive ventilation including high flow oxygen or invasive mechanical ventilation including extracorporeal membrane oxygenation (ECMO) or death by Day 28. Baricitinib-treated patients were only 2.7% less likely than those receiving standard of care to progress to ventilation (non-invasive or mechanical) or death, the companies said.
In COV-BARRIER, treatment with baricitinib in addition to standard-of-care (SoC) resulted in a significant reduction in death from any cause by 38%. In SoC, 79% of participants received corticosteroids, 19% received Gilead Sciences’ Veklury® (remdesivir), and some received both. Lower mortality was seen for all baseline severity subgroups of Olumiantb-treated patients and was most pronounced for patients receiving non-invasive mechanical ventilation at baseline (17.5% for Olumiant plus SoC; 29.4% for SoC).
Lilly said it intends to publish detailed results in a peer-reviewed journal “in the coming months,” and share data from COV-BARRIER with regulators to evaluate next steps for Olumiant as a treatment for hospitalized COVID-19 patients.
2020 Status: EUA GRANTED IN COMBINATION WITH REMDESIVIR—The FDA on November 19 issued an Emergency Use Authorization (EUA) for the distribution and emergency use of Olumiant® (baricitinib) in combination with Gilead Sciences’ Veklury® (remdesivir) in hospitalized adult and pediatric patients two years of age or older with suspected or laboratory confirmed COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
The EUA was based on data from the Adaptive COVID-19 Treatment Trial (ACTT-2), showing that patients treated with baricitinib in combination with remdesivir had a significant reduction in median time to recovery from 8 to 7 days (12.5% improvement) compared to remdesivir. Patients treated with baricitinib in combination with remdesivir were more likely to have a better clinical status at Day 15 compared to patients treated with remdesivir. And proportion of patients who progressed to non-invasive or invasive ventilation, or died by Day 29 was lower in baricitinib in combination with remdesivir (23%) compared to remdesivir (28%)
An international research team coordinated by investigators from Sweden’s Karolinska Institutet on November 13 published a study in Science Advances supporting the continuation of clinical trials by reporting that Olumiant (baricitinib) can block viral entry and reduce mortality in patients with moderate to severe COVID-19. The researchers showed a 71% mortality reduction in 83 patients with moderate-to-severe SARS-CoV-2 who were treated in Italy and Spain, with few drug-induced adverse events, including a large elderly cohort (median age: 81 years). A further 48 cases with mild-moderate pneumonia recovered uneventfully following treatment at two hospitals in Italy.
Further, the researchers showed that while interferons significantly increased the expression of the ACE2 receptor, an entry point for SARS-CoV-2 into human cells, barcitinib reversed ACE2 gene expression changes triggered by interferons and reduced SARS-CoV-2 infectivity, by combining 3D mini organs of human liver cells, RNA sequencing and super-resolution microscopy. However, the interferons did not have the same effect on the ACE2 receptor in lung organoids, suggesting that these signaling proteins affect pulmonary and liver organs differently.
Eli Lilly on October 8 shared additional data from the Phase III Adaptive COVID-19 Treatment Trial 2 (ACTT-2; NCT04401579), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), showing that Olumiant in combination with Gilead Sciences’ Veklury® (remdesivir) reduced time to recovery and improved clinical outcomes for patients with COVID-19 infection compared with remdesivir alone.
Lilly revealed that patients treated with Olumiant plus remdesivir improved their median time to recovery from 8 to 7 days compared to remdesivir. The study also met a pre-specified secondary endpoint, as the odds of improvement in clinical status at Day 15 were 30% greater in patients being treated with baricitinib plus remdesivir compared with remdesivir alone. The company announced those positive findings in September without disclosing the underlying data.
The greatest benefits were seen in patients requiring supplemental oxygen (ordinal scale grade 5 or OS5) and those who required high-flow oxygen/non-invasive ventilation (OS6) at baseline. A 35% decrease in death was seen through Day 29 in patients treated with Olumiant plus Veklury compared to Veklury in the overall population (5.1% vs. 7.8%, respectively), Lilly reported. In patients receiving oxygen, mortality at Day 29 was 60% lower and 43% lower for the OS5 and OS6 subgroups respectively.
The additional data was presented at a special International Society for Influenza and other Respiratory Virus Diseases Antiviral Group (isirv-AVG) Virtual Conference on ‘Therapeutics for COVID-19.’ Lilly added that it was continuing talks with the FDA concerning the potential for Emergency Use Authorization (EUA) of Olumiant.
In June, the first patient had been enrolled in a Phase III randomized, double-blind, placebo–controlled study to evaluate the efficacy and safety of Olumiant. Lilly expects to enroll 400 patients and said data from the trial was expected “in the next few months.” The Phase III trial will be conducted in the U.S., Europe and Latin America and includes patients hospitalized with SARS-CoV-2 infection who have at least one elevated marker of inflammation but do not require invasive mechanical ventilation at study entry.
Lilly reasons that Olumiant may reduce the cytokine storm associated with the complications of SARS-coV-2 through JAK1 and JAK2 inhibition. Olumiant may also have a role in inhibiting the host cell proteins that assist in viral reproduction, reducing the ability of infected cells to make more virus. The company said a manuscript detailing Olumiant’s mechanism of action of baricitinib in COVID-19 has been accepted for publication by EMBO Molecular Medicine.
In May, the NIH said its National Institute of Allergy and Infectious Diseases (NIAID) was sponsoring a clinical trial launched to assess the efficacy and safety of the combination of a 4-mg daily dose of Olumiant plus Gilead Sciences’ remdesivir, compared to remdesivir alone, in COVID-19 patients. More than 1,000 patients are expected to be enrolled in the study, the second iteration of NIAID’s Adaptive COVID-19 Treatment Trial (ACTT-2), which began in February with astudy of remdesivir alone that closed enrollment in April after recruiting 1,063 participants in 47 U.S. and 21 international sites.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: