Baricitinib EUA shakes up COVID-19 therapy: What ID physicians, intensivists need to know
On the evening of Nov. 19, the FDA issued an emergency use authorization for the rheumatoid arthritis drug baricitinib in combination with remdesivir for patients hospitalized with suspected or confirmed COVID-19.
Although this news was no doubt exciting for many who are eager for more available treatments against COVID-19, the decision came as a shock to some within the rheumatology field, who are still waiting for additional, and stronger, data on the safety and efficacy of janus kinase inhibitors in COVID-19.
“Since the start of the pandemic, we as rheumatologists have been interested in the JAK inhibitor class as a prospect for treatment of COVID-19, but I was surprised that baricitinib was approved based upon so little data — at least what we have seen of it so far — as the more granular data is not yet available to us,” Cassandra Calabrese, DO, of the department of rheumatologic and immunologic disease at the Cleveland Clinic, told Healio Rheumatology. “We have concerns surrounding safety of this drug class in critically ill patients.”
Calabrese specializes in infections in the context of immunosuppressive treatment for rheumatic diseases, as well as rheumatic manifestations of infectious diseases and human immunodeficiency virus, with a particular interest in infection prevention. In August, she alongside Leonard H. Calabrese, DO, and Tiphaine Lenfant, MD, both colleagues at the Cleveland Clinic, published a review in the Cleveland Clinic Journal of Medicine on cytokine storm release syndrome, immunotherapy with COVID-19, and the role of JAK inhibition.
In their review, the authors concluded that the history of JAK inhibitors in non-COVID settings suggests potential safety issues. This knowledge, they wrote, will “hopefully allow effective risk-mitigation,” with several trials of JAK inhibitors currently under way that should provide meaningful data on the drug class’ potential effects in COVID-19.
Calabrese recently spoke with Healio Rheumatology regarding the use of baricitinib (Olumiant, Eli Lilly & Co.) for the treatment of COVID-19. Here, she details what infectious disease physicians and intensivists need to know about this and other JAK inhibitors when considering their armamentarium in the battle against COVID-19.
Q. What is this class of drugs all about?
Calabrese: JAK inhibitors are a class of oral medications — targeted synthetic [disease-modifying antirheumatic drugs (DMARDs)] — that inhibit a key signal-transduction pathway, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. This pathway mediates biologic activity for a large number of inflammatory cytokines and mediators, many of which are known to be elevated in COVID-19.
This is part of the rationale for using JAK inhibitors in COVID-19. There are currently JAK inhibitors approved for treatment of rheumatoid arthritis and the class of drugs is growing rapidly for treatment of a wide variety of immune-based diseases.
Q. What do you think of the data on baricitinib/remdesivir combination therapy in COVID-19 so far?
Calabrese: So far, I am underwhelmed and have lots of questions. We will proceed with caution until more data are available to us. The biggest elephant in the room is how to approach this EUA when dexamethasone has already demonstrated efficacy in patients with severe COVID-19, as we do not feel they can be used together safely.
Q. How does baricitinib compare with dexamethasone?
Calabrese: As drugs, baricitinib and dexamethasone are not exactly comparable, as baricitinib is a targeted synthetic drug that is designed to be taken long term with a favorable safety profile, while dexamethasone is a systemic glucocorticoid that dampens the immune response in a broad manner and is not intended for long term use, as it is accompanied by serious side effects that are additive over time, including serious infection, osteoporosis and diabetes, to name a few.
For treatment of COVID-19, we cannot compare the two drugs in terms of absolute risk reduction — we have not seen enough of that data for baricitinib. The RECOVERY trial data for dexamethasone are far more robust, reducing death by one-third in patients receiving invasive mechanical ventilation, with a number needed to treat of 8.
Q. Can dexamethasone and baricitinib be combined safely?
Calabrese: This concept makes us very uncomfortable from a safety standpoint. The risk for serious infection with any of our biologics or targeted therapies is significantly increased by concomitant steroid use. The data that led to EUA for baricitinib was from a time before dexamethasone was widely used for treatment of severe COVID-19. Until we see data on how patients fare when these drugs are administered together, I would recommend against their combination.
I am eager to hear how our intensivists and infectious disease physicians will craft decisions between baricitinib, for which we have very little data in the setting of COVID, and dexamethasone, a drug whose efficacy data we are all familiar with for treatment of severe COVID-19. We feel strongly that there is no rationale to combine these and that this would lead to great risk of harm.
Q. What is the adverse event/safety profile of baricitinib?
Calabrese: We have robust data from the past decade on the safety of JAK inhibitors and based on this there are formidable concerns that include infectious and cardiovascular issues. Aside from an increased risk for serious infections comparable to other biologics, it is well known that JAK inhibitors are associated with a significantly increased risk for herpes zoster compared with all other biologics and DMARDs. However, the relevance of this toxicity to COVID-19 is not apparent.
Aside from infectious complications, another major area of concern with JAK inhibition is the potential for an increased risk for venous thromboembolism, as the class is known to increase VTE risk in patients with RA, and immunothrombosis is known to play a role in patients with severe COVID-19.
Finally, there is a concern for off-target effects on integrated antiviral immunity through inhibition of interferon signaling. Other known side effects include anemia, lymphopenia and elevated liver enzymes. It should be noted that only baricitinib 2 mg daily dose is approved in the United States for the treatment of RA, so we are also talking about a higher dose.
Q. Following this EUA, are you concerned at all about baricitinib shortages, like what was seen with hydroxychloroquine?
Calabrese: This is possible, but I am not overly concerned at present. To clarify, I suppose it is too soon to say if I am worried about a drug shortage, as I do not know how baricitinib is going to be used given the widespread use of dexamethasone, but it is a possibility.
For more information:
Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Desk A50, Cleveland, OH 44195.