JAK Inhibitors

Last Review Performed on June 24th, 2020

Janus Kinase Inhibitors (JAK inhibitor) are small molecules, in pill form only, that inhibit JAK/STAT signaling pathways of multiple cytokines. Each JAK inhibitor has a unique specificity/promiscuity profile for the cytokines it would inhibit, though in general there is a lot of overlap. Most JAK inhibitors demonstrated dose dependent side effects of variable degrees of myelosuppression, increased risk of viral recurrence (particularly Herpes zoster virus reactivation (shingles) and Hepatitis B), and increased risk for thrombosis. Risk of thrombosis and infection is likely dose and duration dependent, however myelosuppression can occur within a week.

Due to scant evidence of efficacy and somewhat concerning safety profile, JAK inhibitors are not recommended for use in COVID-19 outside of a formal clinical trial.

Currently baricitinib has been added to the adaptive wing of NIAID sponsored adaptive therapy trial for COVID-19 for which University of Minnesota is a site.

Due to scant evidence of efficacy and somewhat concerning safety profile, JAK inhibitors are not recommended for use in COVID-19 outside of a formal clinical trial.

Currently baricitinib has been added to the adaptive wing of NIAID sponsored adaptive therapy trial for COVID-19 for which University of Minnesota is a site.

JAK inhibitors includes: Ruxolitinib, Baricitinib, Tofacitinib, Upacitinib, Fedratinib

Peer-reviewed Studies

Cantini et al 2020 “Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact” Journal of Infection. https://doi.org/10.1016/j.jinf.2020.04.017
- OBSERVATIONAL, CASE SERIES, HISTORICAL COHORT MATCHED
- Case n = 12; cohort n = 12
- inclusion = moderate COVID19, 18yo+, already on HCQ or antiviral
- exclusion= history of thrombophlebitis, latent TB, pregnancy, lactation
- cohort = previous patients treated with HCQ or antiviral
- Treatment = 4 mg per day for 2 weeks
- Results = improvement in clinical (fever, oxygenation, ICU transfer, etc) and laboratory markers at 1 week (CRP, etc). Improvements sustained at 2 weeks, many discharged home. No adverse events noted in treatment group.
- Caveats = treatment group started with higher CRP, better blood pressure. One patient discontinued baricitinib early due to LFT elevation though authors attribute that to antiviral. Distribution of antiviral/HCQ use is not reported. No long term followup reported. Use of antibiotics not reported.
Gaspari et al 2020 “Side effects of ruxolitinib in patients with SARS-CoV-2 infection: Two case reports” Int J Antimicrob Agents. https://doi.org/10.1016/j.ijantimicag.2020.106023
- CASE REPORT
- Case n = 2
- Treatment = up to 20 mg a day
- Results = adverse events concerning for purpuric lesions, vasculitis like diffuse rash, thrombocytopenia, anemia
- Caveats = both patients on multiple therapies including antivirals, +/- dexamethasone, tocilizumab, plaquenil.
Cao et al 2020 “Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial” J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.05.019
- PROSPECTIVE RCT, multicenter, single-blind, phase II trial
- 1:1 assignment of 41 patients
- inclusion = COVID19+, 18yo+, <75yo, severe cases
- exclusion= concomitant malignant tumors, severe uncontrolled cardiovascular +/- metabolic disease, mental/severe psychiatric disorder, need for invasive vent at time of recruitment, patients who could not followup, pregnant or lactating women, other active infections.
- Treatment = 5 mg twice per day for ?10 days (not specified!) + SOC versus placebo + SOC. Corticosteroid and antiviral use was balanced between two groups.
- Endpoints = 1° is time to clinical improvement. 2° includes improvement rate, recovery of lymphopenia, time to invasive ventilation, duration of hospitalization for survivors, time to death, time to viral clearance, serious adverse events at 28 days, viral clearance, anti-SARS-CoV2 IgG and IgM antibodies, overall mortality
- Results = 1° endpoint no statistical or numeric difference, in regards to secondary endpoints most were not significantly or numerically different except for 28 day mortality (14% in control, 0% in ruxolitinib group) and recovery of lymphopenia (median 5 days in ruxolitinib versus 8 days in control). Importantly, no difference in days to discharge, viral clearance, adverse events. Several cytokines/chemokines were reduced in ruxolitinib group.
- Caveats = well designed study hindered by small sample size due to limited recruitment towards end of pandemic.
- Overall = neutral study.
A4. Rosée et al 2020 “The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation” Leukemia. https://doi.org/10.1038/s41375-020-0891-0
- OBSERVATIONAL, RETROSPECtiVE CASE SERIES
- Case n = 14
- inclusion = COVID19+, clinical inflammation score >10
- exclusion= none
- Treatment = 7.5 mg BID uptitrated to 15 mg BID
- Results = improvement in clinical inflammation score, regardless of steroid use, in 12/14 within 7 days of ruxolitinib induction. 11/14 with sustained improvement. No red flags.
- Caveats = laboratory based outcome, not clinically, no matched comparative cohort to indicate if any significant change in clinical outcomes.
- Overall = unclear

Major peer-reviewed studies providing context for therapy

Gavegnanno et al. 2019. “Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro.” Journal of Neuroinflammation. https://doi.org/10.1186/s12974-019-1565-6
- PRECLINICAL, NOT SARS1 or 2 RELATED
Sanchez et al. 2018. “JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.” J Clin Invest. https://doi.org/10.1172/JCI98814
- CLINICAL, CASE SERIES, NOT SARS1 or 2 RELATED
Ahmed et al. 2019. “Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial.” Lancet Hematology. https://doi.org/10.1016/S2352-3026(19)30156-5
- CLINICAL, CASE SERIES, NOT SARS1 or 2 RELATED but includes EBV associated HLH

Notable Clinical Trials

University of Minnesota: Baricitinib arm is considered in Stage II of NIAID Adaptive COVID-19 Treatment Trial (ACTT) (Remdesivir trial) NCT04280705 https://clinicaltrials.gov/ct2/show/NCT04280705?cond=covid-19&cntry=US&state=US%3AMN&city=Minneapolis&draw=2&rank=8
Baricitinib trials: https://clinicaltrials.gov/ct2/results?term=baricitinib&cond=COVID
Ruxolitinib trials: https://clinicaltrials.gov/ct2/results?cond=COVID&term=ruxolitinib&cntry=&state=&city=&dist=&Search=Search
Upacitinib trials: https://clinicaltrials.gov/ct2/results?cond=COVID&term=tofacitinib&cntry=&state=&city=&dist=&Search=Search
Fedratinib trials: https://clinicaltrials.gov/ct2/results?cond=COVID&term=Fedratinib&cntry=&state=&city=&dist=&Search=Search

JAK inhibitors: background, potential pathways related to COVID-19, current state of clinical data

Inhibitors of JAK/STAT pathways that are signaling mechanism for many cytokines. (see Figure 1). They are small molecule inhibitors, pill form only, theoretically easier to increase mass production compared to biologics. There are several in development, more in pre-clinical/animal trials, and some that already have approvals for multiple indications. I have listed all the ones that already have FDA approval and are used more frequently in table 1. When reviewing JAK specificity IC50s, keep in mind that relative binding for one drug is more important than best IC50 across multiple drugs as actual signal inhibition also depends on dose of drug used—larger within drug JAK specificity simply widens the therapeutic window. JAK inhibitors do have varying level of promiscuity for different JAKs and this is further complicated by each individual JAK being involved in more than one cytokine pathway. In general, most JAK inhibitors demonstrated dose dependent side effects of variable degrees of myelosuppression, increase risk of viral recurrence (particularly Herpes zoster virus reactivation (shingles) and Hepatitis B), and increased risk for thrombosis. Risk of thrombosis and infection is likely dose and duration dependent, however myelosuppression can occur within a week.

Figure 1. Basic JAK/STAT pathway (taken from website)

JAK inhibitors: theories of utility for COVID19

Baricitinib specific antiviral activity is hypothesized by artificial intelligence algorithms to arise from inhibition of the numb-associated kinase (NAK) AAK1 which is an important regulator of clathrin-mediated endocytosis. Inhibition of AAK1 would likely reduce the ability of viruses to infect lung cells, and is being proposed as a pharmacological mechanism that warrants further investigation as a treatment for SARS-CoV-2 infection (COVID-19). (Stebbing et al 2020 “COVID19: combining antiviral and anti-inflammatory treatments. Lancet. Feb 27, 2020 https://doi.org/10.1016/S1473-3099(20)30132-8)

In addition, the powerful anti-inflammatory activity of JAK inhibitors in general is proposed to be effective against the pathological effects of raised cytokine levels (e.g. interferon γ, IL-6, etc) in patients with hyper-inflammation syndrome such as cytokine release syndrome, HLH, secondary HLH aka MAS. (Favalli et al. Autoimmune Rev. March 20, 2020. https://doi.org/10.1016/j.autrev.2020.102523) This has been demonstrated in case series publications for ruxolitinib in secondary HLH (Ahmed et al. 2019. “Ruxolitinib in adult patients with secondary hemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial” Sept 16, 2019. Lancet Hematology. https://doi.org/10.1016/S2352-3026(19)30156-5 )

Figure 2 shows the schema of how Baricitinib is proposed to both limit viral cell entry (via inhibition of endocytosis) and also inhibit cytokine storm (Richardson et al. Baricitinib as potential treatment for 2019-nCOV acute respiratory disease. Lancet, Feb 4, 2020 DOI:https://doi.org/10.1016/S0140-6736(20)30304-4)

In regards to Baricitinib, it has been shown in modified murine models to reverse cognitive deficits and curtail inflammatory markers in HIV-associated neurocognitive disorders (HAND). (Gavegnano et al. Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro. September 2019. Journal of Neuroinflammation. doi: 10.1186/s12974-019-1565-6). A small study of 18 patients, comprising of 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies received Baricitinib treatment in an expanded access program. Clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies. One CANDLE patient discontinued treatment because of BK viremia and azotemia (Sanchez et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest 2018; 128. doi: 10.1172/JCI98814)

JAK inhibitor use for COVID-19

Safety and Efficacy of Baricitinib for COVID-1
Sponsor: University of Colorado, Denver

Study Description: This study plans to learn more about the effects of a medicine called baricitinib on the progression of COVID-19 (coronavirus disease of 2019), the medical condition caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Baricitinib is FDA-approved for the treatment of rheumatoid arthritis, an autoimmune condition. This study intends to define the impact of baricitinib on the severity and progression of COVID-19. This drug might lower the hyperinflammation caused by the virus, which would prevent damage to the lungs and possibly other organs.

The study will recruit patients who have been diagnosed with COVID-19.The goal is to recruit 80 patients.This is an adaptive Phase 2/3 clinical trial, with a focus on the assessment of safety in the first 20 participants (Phase 2), followed by a much broader assessment of efficacy, while continuing to monitor safety, in an additional 60 participants (Phase 3, total participants across Phase 2/3 n=80). Both phases are single arm, open label, and occur at a single site at the University of Colorado Hospital (UCH). Data from participants in this study will be compared with data from other COVID-19 patients not receiving baricitinib. Study participants will receive 2 mg/day of baricitinib for 14 days and will be followed for up to 29 days.

Study Design
Study Type: Interventional (Clinical Trial)
Estimated Enrollment: 80 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single arm, open label, single site study. Data from participants in this study with data from other COVID-19 patients not receiving baricitinib.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Baricitinib for COVID-19
Estimated Study Start Date: April 2020
Estimated Study Completion Date: October 2020
Baricitinib in Symptomatic Patients Infected by COVID-19: an Open-label, Pilot Study. (BARI-COVID)
Baricitinib Combined With Antiviral Therapy in Symptomatic Patients Infected by COVID-19: an Open-label, Pilot Study

Sponsor: Hospital of Prato, Italy

Study Description: There is no specific antiviral treatment recommended for COVID-19, and no vaccine is currently available. Baricitinib, an anti-Janus kinase inhibitor (anti-JAK) acting against JAK1 and JAK2. The drug was found capable to reduce or interrupt the passage of the virus into target cells, and to inhibit the JAK1- and JAK2-mediated cytokine release. The drug was licensed for the treatment of rheumatoid arthritis at the daily dose of 4 mg/orally, with excellent results in terms of clinical response and a good safety profile. Since baricitinib does not interact with antivirals due to its prevalent renal elimination, it may be used in combination. The evidence on the advantageous action of baricitinib on viral entry and cytokine outbreak constituted the rationale to perform a trial on patients with mild to moderate COVID-19 infection receiving baricitinib combined with antiviral therapy.

Study design
Interventional, open-label, 2-week, prospective trial of a cohort of patients with mild to moderate COVID-19 infection.
Objectives. Primary. To assess the efficacy of baricitinib combined with antiviral therapy in patients with COVID-19-related mild and moderate disease in terms of reduction of the percentage of subjects requiring ICU admission.
Secondary objectives. To describe the clinical findings in a cohort of symptomatic COVID-19-infected subjects; to investigate the role of CRP, IL-6, and TNFα levels as predictor of progression to ARDS; to assess the type and incidence of adverse events (AEs).
Study Type: Interventional (Clinical Trial)
Estimated Enrollment: 60 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Patients. All consecutive patients with mild to moderate COVID-19 infection, older than 18, Patients should present fever, cough and myalgia and weakness and radiological findings of pneumonia.
Controls. All consecutive patients with mild to moderate COVID-19 infection, older than 18, admitted during the previous 2 weeks, who were treated with antiviral and/or hydroxychloroquine.
Masking: None (Open Label)
Primary Purpose: Treatment
Estimated Study Start Date: March 16, 2020
Estimated Study Completion Date: April 30, 2020
Treatment of Moderate to Severe Coronavirus Disease (COVID-19) in Hospitalized Patients

Sponsor: Lisa Barrett, Nova Scotia Health Authority, Canada. Collaborators: Dalhousie University, Nova Scotia, Canada

Study Description: Investigational medications adjunct to clinical standard of care treatment will be assessed to evaluate safety and effectiveness as an anti-COVID-19 treatment. All hospitalized persons with moderate to severe COVID-19 disease that meet eligibility criteria will be offered participation.

One of the experimental drugs proposed is: Drug: Baricitinib (janus kinase inhibitor) 2 mg po daily for 10 days

Study Design
Interventional (Clinical Trial)
Estimated Enrollment:1000 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose:Treatment
Estimated Study Start Date: April 2020
Estimated Study Completion Date: July 2021

Considerations proposed for study associated use:

If patients meet HLH criteria, first line therapy is IL-1 inhibition and high dose steroids. However, JAK1/2 inhibitors, as demonstrated by ruxolitinib and baricitinib case series are efficacious in these cases as well
note that absorption in critical patient may be an issue as these medications are ONLY orally available
anticipate some laboratory response within 1 week, consider discontinuation if not response
anticipate some side effects within 1 week (specifically, myelosuppression)
in patients with high risk for thrombosis at baseline, consider anticoagulation if adding on JAK inhibitor
monitor closely for secondary infections. Patients may not be able to mount a fever. Consider every other day montoring blood cultures
Careful review of current medication to screen for cytochrome incompatibility!! Consider dose reduction.
Special populations:
- JAK inhibitors are not safe in pregnancy, lactation
- JAK inhibitors have been used in pediatric HLH
- Immune suppressed patients would need their immune suppression held while receiving JAK inhibitors

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