Source : 'The Pink Sheet'
Eli Lilly and Company 's plans to seek an emergency use authorization from the US Food and Drug Administration for Olumiant (baricitinib) for hospitalized COVID-19 patients offers the firm a chance to turn a product whose development was almost derailed by thrombosis into a treatment for a disease that itself appears to cause blood clots.
That doesn't mean that Olumiant's black box is going away because of the NIH coronavirus trial that Lilly is relying on for its EUA submission, but it's a reminder that medicine can sometimes be as much mystery and magic as it is science. If cleared, the JAK 1/2 inhibitor would joined some antidepressants and asthma treatments as products that can in fact cause the very symptoms they aim to treat.
Olumiant’s US label carries box warnings about risks of developing blood clots and serious infections and the FDA approved only a 2mg daily dose for rheumatoid arthritis, even though the drug was tested in COVID trail at a 4mg daily – a dose that is approved for RA in many markets outside the US. (See sidebar.)
Patrik Jonsson, Lilly senior vice president and president of Lilly Bio-Medicines, said in an interview that the risk/benefit assessment for Olumiant probably will be “very different for patients being hospitalized with COVID-19 versus the treatment for rheumatoid arthritis, which is a long-term treatment. Here we're talking about patients that are provided baricitinib for a maximum of up to 14 days.”
“The overall risk/benefit assessment, taking into account the length of the therapy but also the indication itself – hospitalization due to COVID-19, which is a relatively high-risk of mortality – I think that would justify a different risk/benefit discussion compared to rheumatoid arthritis,” he said.
Lilly plans to submit for the EUA based on results from a US National Institute of Allergy and Infectious Disease study of Olumiant in combination with Gilead Sciences, Inc.’s Veklury (remdesivir).
Olumiant, which showed a statistically significant improvement versus remdesivir alone in time to recovery, was developed under a partnership with Incyte Corporation and is approved in more than 70 countries for rheumatoid arthritis; it is under review for approval to treat atopic dermatitis in the US, Europe and Japan.
If an EUA is approved for the treatment of hospitalized COVID-19 patients, Olumiant will be the second branded therapy after Veklury cleared for emergency use in the US.
Hydroxychloroquine, a generic drug available from multiple companies, was cleared for emergency use, but its EUA was withdrawn in June. ("Hydroxychloroquine EUA Is First Rx Victim Of Hahns Move Fast Course Correct Philosophy" "Pink Sheet" ) More recently, convalescent blood plasma from patients previously recovered from COVID-19 was controversially cleared via EUA in August to treat patients in the US. ("Plasma Authorization Raises Fears Of PoliticallyInfluenced COVID19 Vaccine Decisions Compromised" "Pink Sheet" )
Lilly did not release detailed results from the Adaptive COVID-19 Treatment Trial (ACTT-2) but said patients treated with the baricitinib/remdesivir combination had a one-day median reduction in recovery time. Recovery was defined as the patient being well enough for hospital discharge, meaning they no longer required supplemental oxygen or ongoing medical care in the hospital or they were no longer hospitalized at day 29. NIAID, part of the National Institutes of Health, is expected to publish the full results in a peer-reviewed journal.
“We are now comparing the incremental benefit of Olumiant on top of remdesivir simultaneously and we are seeing a significant improvement in best supportive care,” Jonsson said. “It's the second medicine to really show improvement in a global standard, double-blinded setting arranged by NIAID. [In terms of] the overall burden on the health care system, one day can make a huge difference.”
More than 1,000 patients in ACCT-2 were treated starting on 8 May with either baricitinib plus remdesivir or remdesivir alone. The combination arm of the study also met a key secondary endpoint comparing patient outcomes at day 15 based on an ordinal eight-point scale ranging from fully recovered to death.
ACCT-2 is an international adaptive design study that is testing various treatments for COVID-19. Data from this trial supported Gilead’s EUA for Veklury monotherapy. Olumiant was added to the trial to determine whether it could improve outcomes for individuals treated with Gilead’s nucleotide analog.
Lilly also is running its own test of baricitinib – the placebo-controlled Phase III COV-BARRIER clinical trial in that began in June to test the drug versus background therapy alone – and plans to discuss with the NIAID any impacts the ACTT-2 results may have on the ongoing company-sponsored trial. Jonsson noted that any safety or other findings from the ongoing ACTT-2 analysis could inform the conduct or design of current or future studies.
The executive explained that there are three major differences between ACTT-2 and COV-BARRIER. First, Lilly’s Phase III trial is testing Olumiant monotherapy on top of best supportive care versus placebo and best supportive care rather than a baricitinib-based combination therapy versus the other agent alone. Second, ACTT-2 included ventilated patients while ventilated patients are excluded in COV-BARRIER. Third, the primary endpoint in Lilly’s monotherapy study is overall survival rather than time to recovery.
“We hope that we will have results by end of this year from BARRIER,” Jonsson said. “If we hit the key endpoints, we would definitely foresee that we will be in discussions with the FDA also on baricitinib, alone but it's all dependent on the data.”
In addition to discussing the potential for an EUA for baricitinib plus remdesivir in the treatment of hospitalized COVID-19 patients with the US FDA, Lilly plans to have similar discussions with regulators in other countries.
“We expect to start discussions with the FDA very, very soon,” Jonsson said. “If the FDA comes to the same conclusion, since we did hit on both the primary and secondary endpoint with statistical significance, it's hard to say how long of a time it will take [to receive an EUA], but I would say it's probably a matter of weeks rather than months.”
“Those discussions will be based on the data from this double-blinded [ACTT-2] trial, so I think those discussions would be focused on our side on baricitinib in combination with remdesivir in hospitalized patients, because that's where we have the data,” he added.
Lilly also plans to propose that Olumiant be distributed to hospitals for COVID-19 treatment through commercial channels rather than through government middlemen. The US Department of Health and Human Services (HHS) has handled distribution of Gilead’s Veklury with mixed results. ("Senators Seek Answers On Remdesivir Allocation As FEMA Aims For Better Process Next Time" "Pink Sheet" )
“Baricitinib is already commercially available in more than 70 markets around the world, so I think that's probably the smoothest way to ensure access for patients in need if it is approved by the FDA for emergency use,” Jonsson said. “I think one of the big advantages here is we are talking about an oral medication that is already supplied across the globe. And we are very confident that we will be able to meet all of the supply needs for patients currently who are treated for rheumatoid arthritis as well as any needs that might raise in the area of COVID-19.”
In addition to Olumiant, Lilly’s COVID-19 clinical trials include studies of LY-CoV555, the lead antibody from the company’s collaboration with AbCellera Biologics Inc. with initial results expected late in the third quarter or early in the fourth quarter of this year. ("Coronavirus Update Lilly Initiates 2400Patient Nursing Home Trial" "Scrip" ) Candidates from the company’s COVID-19 antibody partnership with Junshi Biosciences Co. Ltd. are running behind the AbCellera candidates. ("Deal Watch Menarini Enters US Oncology Market Via Merger With Stemline" "Scrip" )
By Mandy Jackson