NIH Pushes Ahead With First COVID-19 Combo: Remdesivir Plus Lilly’s Olumiant
Adaptive Trial Skips Monotherapy Arm, Uses Factorial Design
Executive Summary
Eli Lilly’s drug is one of many anti-inflammatory medicines in late-stage trials against coronavirus but will be the first to be combined with Gilead’s recently approved remdesivir.
The US National Institutes of Health (NIH) is to build on its ground-breaking ACTT trial of Gilead Sciences Inc.’s remdesivir in COVID-19 patients by adding Eli Lilly & Co.’s rheumatoid arthritis drug Olumiant (baricitinib) into the mix for patients with more severe disease.
The initial ACTT data formed the basis of the US Food and Drug Administration’s emergency use approval of remdesivir on 2 May. (Also see "After Remdesivir's Emergency Use Authorization, US Gov't Must Now Decide How To Distribute Limited Supply" - Pink Sheet, 1 May, 2020.)
It showed remdesivir could speed up the recovery of people hospitalized with COVID-19, and reduce hospital stays by 31% compared with placebo, but did not significantly improve survival.
Now the NIH's National Institute of Allergy and Infectious Diseases (NIAID) and its international partners are pressing ahead with the next stage of the trial, named ACTT2. The hope is that the combination of the anti-inflammatory effects of Lilly’s JAK 2 inhibitor drug with the antiviral action of remdesivir will help save lives of critically ill patients, who often suffer from life-endangering inflammation in the lungs – acute respiratory distress (ARDS) – and other organs such as kidneys.
NIAID's director Anthony Fauci
“We now have solid data showing that remdesivir diminishes to a modest degree the time to recovery for people hospitalized with COVID-19,” said NIAID Director Anthony Fauci. “ACTT2 will examine if adding an anti-inflammatory agent to the remdesivir regimen can provide additional benefit for patients, including improving mortality outcomes.”
Lilly’s JAK 2 inhibitor is just one of many already-approved anti-inflammatory drugs being studied in patients with severe COVID-19, which often results in potentially fatal conditions such as ARDS.
Other drugs in late-stage studies include Roche’s Actemra (tocilizumab), Regeneron and Sanofi’s Kevzara (sarilumab), both IL-6 inhibitors, and Novartis’s Jakafi (ruxolitinib), another JAK inhibitor.
These are all being studied in robust placebo-controlled Phase III trials, with mortality reduction endpoints. However baricitinib could emerge with an edge if it proves to complement the effects of remdesivir in what is the first combination trial against the disease.
Working to the same lightning speed as the first study, those results could be ready within just a few months.
A Rousing Second ACTT?
The placebo-controlled, double-blind ACTT2 trial is now enrolling hospitalized adults with COVID-19 in the US, with Europe and Asia to follow shortly, and is expected to include more than 1,000 participants.
Its adaptive trial design is aimed at getting answers to the coronavirus pandemic as quickly as possible, but retains placebo control and double blind components to make its data robust.
At the same time, the trial does contain a gamble, as it does not feature a monotherapy arm looking at baracitinib alone – so if the combination produces ambiguous safety or efficacy results, identifying the cause might be difficult. The study uses a ‘factorial design’ instead, which should help researchers look at how multiple factors within one study affect a dependent variable, both independently and together.
The international consortium of researchers believe this innovative trial design can help it get results rapidly for critically ill patients, who are currently have little more than oxygen and ventilators to help them recover from the virus.
Patients who have mild symptoms will not be included in the trial, which will focus on those who have lung involvement, including a need for supplemental oxygen, abnormal chest X-rays, or require mechanical ventilation.
Lilly R&D leader Daniel Skovronsky
Speaking at Lilly’s recent Q1 results call, the company’s chief scientific officer Daniel Skovronsky said: “We believe baricitinib could have potential to dampen the cytokine storm that occurs when hospitalized COVID-19 patients are fighting to combat the inflammation in their lungs, which often leads to requiring a ventilator.
“While we are cautiously optimistic about the potential of baricitinib to help treat patients with COVID-19, it's important to also note the approved rheumatoid arthritis indication includes warnings about the risk for developing serious infection.”
The potential of the combination was identified through a novel route – research carried out with AI-based drug discovery conducted by Benevolent AI. It published its research which modeled out effects both on viral entry and on inflammatory response, and concluded that baritinib was the most likely of all the JAK 2 inhibitors to succeed.
Skovronsky added: “I think if we see success there [in severe COVID-19] that could give us confidence to go earlier in the disease course. But given sort of the mixed mechanism of action here, right now, we're looking at those hospitalized patients.”
Faster Roll-Out Than Remdesivir?
While Gilead has invested greatly in manufacturing ‘at risk’ before remdesivir gained EUA from the FDA in early May, there remain many supply chain and administration issues to work out for the previously unapproved therapy.
Lilly says the story will be quite different for baricitinib, which gained its first approval as Oluminant in May 2018.
“It's a small molecule that can be produced at large capacity, and it's already approved in geographies around the world for rheumatoid arthritis,” said Skovronsky.
“So depending on the quality of the data and the benefit/risk that we see in COVID-19 patients, you could expect that could potentially move very, very quickly if it's successful,” he concluded.
Compelling results from the trial would also bring challenges for Lilly, as it has for Gilead, however. These would be on questions of access and price, where Lilly would be expected to provide the therapy at a low cost for patients around the world.
Lilly’s Other COVID-19 Hopefuls
The company also has a monoclonal antibody which targets angiopoietin 2, or Ang2, in pneumonia patients hospitalized with COVID-19 now entering a Phase II trial, as well as its collaboration with AbCellera on developing neutralizing antibody therapies.
(Also see "Antibody Drugs Could Be Next COVID-19 Milestone" - Scrip, 4 May, 2020.)It is these the company says could be its most significant COVID-19 candidates, as they could potentially be used for people already infected with the virus but also as a prophylaxis against infection, standing in for vaccines currently under development.