key: cord-326169-delehk6x
authors: CJ Jorgensen, Sarah; LY Tse, Christopher; Burry, Lisa; Dresser, Linda D
title: Baricitinib: A review of pharmacology, safety and emerging clinical experience in COVID‐19
date: 2020-06-15
journal: Pharmacotherapy
DOI: 10.1002/phar.2438
sha: 
doc_id: 326169
cord_uid: delehk6x

A hyperinflammatory response to SARS‐CoV‐2 infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with COVID‐19. Agents that inhibit components of the pro‐inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the pro‐inflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus‐associated kinase (JAK)‐inhibitor that interrupts the signaling of multiple cytokines implicated in COVID‐19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin‐converting‐enzyme‐2 up regulation. However, baricitinib’s immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients’ immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events which is concerning given the proclivity towards a hyper‐coagulable state in COVID‐19 patients. In this article we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety and current progress in COVID‐19 clinical trials.

152 The JAK family is comprised of 4 cytoplasmic protein tyrosine kinases: JAK1, JAK 2, JAK3 and 153 tyrosine kinase 2 (TYK2). 21 244 Approximately 75% is excreted in the urine (69% unchanged) and 20% in the feces (15% 245 unchanged). 1, 3 The half-life is 6 to 9 hours in healthy volunteers but increases to 12 hours in RA 246 patients and 19 hours in subjects with severe renal impairment or ESRD. 1, 3 Baricitinib is effectively

This article is protected by copyright. All rights reserved 247 dialyzed with a mean clearance by hemodialysis of 6 L/h. 3 The impact of continuous renal 248 replacement therapy and extracorporeal membrane oxygenation on baricitinib PK have not been 249 described at this time. In population PK analyses, body weight did not have a clinically meaningful 250 impact on baricitinib clearance, however obese RA patients have been reported to have lower 251 response rates. 3 275 Although a small fraction (6%) of baricitinib is metabolized by CYP3A4, co-administration with 276 ketoconazole (a strong CYP3A4 inhibitor) or rifampin (a strong CYP3A4 inducer) did not have a 277 clinically meaningful impact on baricitinib PK. 1, 3

This article is protected by copyright. All rights reserved 279 As noted in the PK section, baricitinib is a substrate of several drug transporters (P-glycoprotein, 280 BCRP, MATE2-K, OAT3). 1, 3 Co-administration with cyclosporine (P-glycoprotein inhibitor) did not 281 result in clinically relevant changes to baricitinib PK however, co-administration with probenecid (a 282 strong OAT3 inhibitor) lead to decreased renal clearance and a ~2-fold increase in AUC. 1 296 Treatment Trial (ACTT-2). 27-29 ACTT-2 is an adaptive, randomized, double-blind, active-controlled 297 multinational study. 27, 29 Hospitalized patients with laboratory confirmed SARS-CoV-2 infection and 298 one of the following are eligible for enrolment: infiltrates on chest imaging, an oxygen saturation ≤ 299 94% on room air, need for supplemental oxygen or need for mechanical ventilation. 29 The primary 300 endpoint is time to recovery within 28 days after randomization using a 3-point ordinal scale. 29 In the 301 first iteration of the study (ACTT-1), patients were randomized to the antiviral drug, remdesivir, or 302 placebo. 33 Preliminary results were recently published after enrolling over 1000 patients: the median 303 time to recovery was significantly shorter in the remdesivir group (11 days vs. 15 days, hazard ratio 304 1.32; 95% confidence interval 1.12 -1.55). 33 Moving forward in ACTT-2, all patients will receive 305 remdesivir and additionally be randomized to baricitinib 4 mg daily or placebo for up to 14 days. 27 

This article is protected by copyright. All rights reserved 340 program has been used to characterize baricitinib's safety profile. 2, 23 One caveat to these analyses is 341 that patients in the placebo or baricitinib 2 mg/day arms of many studies were allowed to crossover 342 to the 4 mg/day group after week 16 which complicates interpretation and raises the possibility that 343 some risks in the 4 mg/day group may be overestimated. Furthermore, as discussed below, although 344 many adverse effects appeared to be dose related, far fewer patients were exposed to 2 mg/day so 345 there is more uncertainty in relative risk estimates. In ongoing COVID-19 studies, the duration of 346 baricitinib therapy is typically 7 to 14 days. Safety data by contrast is derived from patients who 347 received baricitinib for months and many adverse effects manifested after prolonged exposures. 394 Increased CPK is correlated has been with mortality in COVID-19 4 and rhabdomyolysis has been 395 reported as a late complication. 17 The interaction between possible baricitinib-associated CPK 396 elevations and those secondary to COVID-19 requires further study.

398 Increased platelet counts is a unique baricitinib effect and has not been observed with other JAK-399 inhibitors. 2, 36, 43 In fact, small decreases in platelets and occasional thrombocytopenia occur 2 other 400 JAK-inhibitors, tofacitinib and upadacitinib. 36, 43 With baricitinib, platelet counts increase rapidly after 401 initiation and peak around week 2 (mean increase 50 x 10 9 /L). 2, 23 Thereafter they decline and 402 stabilize but remain above placebo and comparators for the duration of therapy. Thrombocytosis Accepted Article 499 treatment strategies aimed at attenuating both pathogen virulence and the pro-inflammatory 500 phenotype seen in the many critically ill patients with COVID-19. 5, 9, 12, 13, 20, 56 As detailed in this 501 review, baricitinib pairs immunosuppressive properties with antiviral activity making it a logical 502 candidate for further evaluation in COVID-19 clinical trials . 9, 12, 13, 20 503 504 It is unlikely that a single treatment strategy will help all patients with COVID-19 or have the same 505 effect in an individual patient as illness evolves over time. For many years, an uncontrolled pro-506 inflammatory response was thought to be the driver of poor outcomes in sepsis. 57, 58 On the basis of 507 this theory and supportive pre-clinical data, multiple immunosuppressive agents were investigated in 508 sepsis but with uniformly disappointing results. 57-62 We now know that anti-inflammatory mediators, 509 which invoke a state of immunoparalysis, also contribute to poor outcomes by impairing the host's 510 ability to clear infection and increasing vulnerability to secondary opportunistic infections. 57 Our 511 understanding of the pathogenesis of and immune response to COVID-19 is rapidly evolving and, 512 like sepsis, relative immunodeficiency also appears to be at play. 9, 37, 39, 50 At this time we do not have 513 a reliable way to gauge whether the over-ruling response is pro or anti-inflammatory and this 514 complicates deployment of immunosuppressive drugs like baricitinib. If given to the wrong patient 515 (i.e. a patient with a predominantly immunosuppressed phenotype) or at the wrong time during the 516 illness, these drugs could cause harm by inhibiting the cytokines required for viral clearance (type-I 517 IFNs) or immune restoration (IL-2, IL-7). 

The process is initiated when the virus binds to the host cell surface receptor 185 (angiotensin-converting enzyme 2 (ACE2) in the case of SARS-CoV-2). 25, 27 Receptor binding leads 186 to activation of 2 host-derived kinases, AP2-associated protein kinase 1 (AAK1) and cyclin G-187 associated kinase (GAK). 25, 28 AAK1 and GAK in turn phosphorylate and activate key host proteins 188 called adaptor protein complexes (APs). 25, 28 Activated APs bind to the cytoplasmic tail of the cell-189 surface receptors and recruit clathrins to assemble into a cage-like structure in preparation for 190 endocytosis. 25, 28 Next, the cell surface receptor with bound virus is invaginated into the cage-like 191 structure which pinches off and traffics the virus and associated APs in early endosomes

GAK (Table 1) and may thereby 197 impede viral cell entry and internal transport. 12, 13 It is uncertain if compounds need to inhibit both 198 AAK1 and GAK to block SARS-CoV-2 viral cell entry although in murine infection models the 199 combination of both sunitinib (an anticancer drug that inhibits AAK1) and erlotinib (an anticancer drug 200 that inhibits GAK) was required to protect mice from lethal Ebola and dengue virus challenges. 19, 28 It 201 should also be pointed out that, SARS-CoV-1 uses several different endocytic pathways for viral 202 entry 25

decrease ACE2 expression and thereby interfere with 210 the ability of SARS-CoV-2 to infect neighboring cells. 30 However, ACE2 is also counter-regulatory to 211 the renin-angiotensin-aldosterone-system (RAAS) and has a protective effect against RAAS-related 212 organ damage, including acute lung injury. 31 One of SARS-CoV-2's key virulence factors is its ability 404 association between platelet increases and thromboembolic events (discussed below) has been 405 established. 2, 23 The etiology is not known although the prevailing theory, based on animal 406 experiments, implicates selective JAK2 inhibition in increased circulating thrombopoietin (TPO, the platelet counts seen with baricitinib. JAK-inhibitors that are less selective for JAK2 may act counts in COVID-19 patients

Besides common side effects and changes in laboratory parameters, baricitinib has been associated 422 with serious adverse effects including infections, thrombosis, malignancy, gastrointestinal 423 perforations, and major cardiovascular events. 2, 23 Adverse effects of particular relevance to COVID-424 19 patients are infection and thrombosis and are expanded upon below

Overall the incidence of serious and opportunistic infections in RA patients treated with JAK-427 inhibitors is comparable to other biological DMARDs, however the risk of viral infections, specifically 428 herpes zoster virus (HZV) reactivation, appears to be higher with JAK-inhibitors

Type I IFNs orchestrate a critical antiviral defense via the JAK/STAT pathway and 434 their inhibition by baricitinib is thought to be responsible for HSV reactivation. 9, 23 Critically ill patients Accepted Article This article is protected by copyright. All rights reserved correlated with higher viral loads and poor outcomes

With regards to thrombosis, there was a numerical imbalance in both arterial and venous 447 thromboembolic events (VTE) not favoring baricitinib treated patients in pooled safety data

In total 39 VTE have been reported with baricitinib in the clinical trials program (34 at 4 mg/day and 5 0.3 / 100 patient year for 4 mg/day and 2 mg/day respectively) versus 1 event with placebo. 2, 34 It 456 should be noted that in population-based observational studies

FDAs failure to approve the manufacturer's first submission in 2017. 2, 34 Baricitinib was approved one 464 year later but only at the lower 2 mg/day dose. 2, 34 Health Canada has similarly only approved the 2 the following patients: 486 age ≥ 75 years, a history of chronic or recurrent infections

mL/min and 60 mL/min, and concomitant use of a strong OAT3-inhibitor. 1 According to current 488 prescribing information, baricitinib should not be initiated and therapy should be interrupted for the 489 following laboratory parameters

< 1 x 10 9 /L and hemoglobin < 8 g/mL. 1, 2, 17 Baricitinib is contraindicated in patients with CrCl < 30

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