Kinase Inhibitors: Bruton’s Tyrosine Kinase Inhibitors and Janus Kinase Inhibitors
Last Updated: July 17, 2020
The COVID-19 Treatment Guidelines Panel recommends against the use of Bruton’s tyrosine kinase (BTK) inhibitors, such as acalabrutinib, ibrutinib, and zanubrutinib; and Janus kinase (JAK) inhibitors, such as baricitinib, ruxolitinib, and tofacitinib; for the treatment of COVID-19, except in a clinical trial (AIII).
BTK inhibitors and JAK inhibitors have broad immunosuppressive effects. Ongoing clinical trials should help clarify their role in the treatment of COVID-19.
BTK inhibitors are licensed by the Food and Drug Administration (FDA) for the treatment of B-cell malignancies.1 BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion.2
JAK inhibitors are potent immunosuppressive agents that are FDA approved for the treatment of rheumatoid arthritis, psoriatic arthritis, polycythemia vera, myelofibrosis, ulcerative colitis, and graft-versus-host disease. JAK inhibitors interfere with phosphorylation of signal transducer and activator of transcription (STAT) proteins3,4 that are involved in vital cellular functions, including signaling, growth, and survival. Phosphorylation of STAT proteins involved in these pathways can increase or decrease their function, and aberrant activation of these proteins has been associated with autoimmune disorders and cancers.5 JAKs transmit cytokine signaling by pairing with another JAK (e.g., JAK1/JAK2, JAK1/JAK3); however, whether inhibition of specific JAKs is relevant to therapeutic effectiveness is unknown.
Rationale for Use in Patients With COVID-19
The kinase inhibitors are proposed as treatments for COVID-19 because they can prevent phosphorylation of key proteins involved in the signal transduction that leads to immune activation and inflammation (e.g., the cellular response to proinflammatory cytokines such as interleukin [IL]-6).6 This immunosuppression could potentially reduce the inflammation and associated immunopathologies that have been observed in patients with COVID-19. Additionally, JAK inhibitors, particularly baricitinib, have theoretical direct antiviral activity through interference with viral endocytosis, potentially preventing entry into and infection of susceptible cells.7
Most of the data on adverse effects of BTK and JAK inhibitors refer to chronic use of the agents. Adverse effects include infections (typically respiratory and urinary tract infections) and the reactivation of herpes viruses. Additional toxicities include myelosuppression and transaminase elevations. Hemorrhage and cardiac arrhythmia have occurred in patients who received BTK inhibitors. Thrombotic events and gastrointestinal perforation have occurred in patients who received JAK inhibitors.
Considerations in Pregnancy
- BTK inhibitors: There is a paucity of data on human pregnancy and BTK inhibitor use. In animal studies, in doses exceeding the therapeutic human dose, acalabrutinib and ibrutinib were associated with interference with embryofetal development.8,9 Based on these data, BTK inhibitors may be associated with fetal malformations when use occurs during organogenesis. The impact of use later in pregnancy is unknown. Risks of use should be balanced against potential benefits.
- JAK inhibitors: There is a paucity of data on the use of JAK inhibitors in pregnancy. Fetal risk cannot be ruled out. Pregnancy registries provide some outcome data on tofacitinib used during pregnancy for other conditions (e.g., ulcerative colitis, rheumatoid arthritis, psoriasis). Among the 33 cases reported, pregnancy outcomes were similar to those among the general pregnant population.10-12 Risks of use should be balanced against potential benefits.
Bruton's Tyrosine Kinase Inhibitors
Acalabrutinib is a second-generation, oral BTK inhibitor that is FDA approved to treat B-cell malignancies (i.e., chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma). It has a better toxicity profile than first-generation BTK inhibitors (e.g., ibrutinib) due to less off-target activity for other kinases.13 Acalabrutinib is proposed for use in patients with COVID-19 because it can modulate signaling that promotes inflammation.
Clinical Data for COVID-19
Data regarding acalabrutinib are limited to a retrospective case series of 19 patients with severe COVID-19.14 However, data interpretation to discern any clinical benefit is limited by the study’s small sample size and lack of a control group.
Please check ClinicalTrials.gov for the latest information on studies of acalabrutinib and COVID-19.
Ibrutinib is a first-generation BTK inhibitor that is FDA approved to treat various B-cell malignancies9 and prevent chronic graft-versus-host disease in stem cell transplant recipients.15 Based on results from a small case series, ibrutinib has been theorized to improve inflammation and protect against ensuing lung injury in patients with COVID-19.16
Clinical Data for COVID-19
Data regarding ibrutinib are limited to an uncontrolled, retrospective case series of six patients with COVID-19 who were receiving ibrutinib for a condition other than COVID-19.16 However, evaluation of the data for any clinical benefit is limited by the series’s small sample size and lack of a control group.
Please check ClinicalTrials.gov for the latest information on studies of ibrutinib and COVID-19.
Zanubrutinib is a second-generation, oral BTK inhibitor that is FDA approved to treat mantle cell lymphoma.17 It has been shown to have fewer toxicities than first-generation BTK inhibitors (e.g., ibrutinib) due to less off-target activity for other kinases.18 Zanubrutinib is proposed to be of use in patients with COVID-19 by modulating signaling that promotes inflammation.
Clinical Data for COVID-19
There is no clinical data on the use of zanubrutinib to treat COVID-19.
Please check ClinicalTrials.gov for the latest information on studies of zanubrutinib and COVID-19.
Janus Kinase Inhibitors
Baricitinib is an oral JAK inhibitor that is selective for JAK1 and JAK2 and FDA approved for the treatment of rheumatoid arthritis.19 Among the JAK inhibitors studied, baricitinib has been postulated to have the greatest theoretical antiviral efficacy in inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from entering and infecting lung cells because of its affinity for adaptor-associated kinase-1 (AAK1), a regulator of viral endocytosis in pulmonary alveolar type 2 (AT2) epithelial cells.20 In addition, baricitinib can modulate downstream inflammatory responses via inhibition of JAK1/JAK2 kinase and has exhibited dose-dependent inhibition of IL-6-induced STAT3 phosphorylation.21
Clinical Data for COVID-19
This study has not been peer-reviewed.
A small, nonrandomized study in patients with moderate COVID-19 pneumonia compared combination therapy with baricitinib and lopinavir/ritonavir to standard of care (SOC) therapy (i.e., combination lopinavir/ritonavir and hydroxychloroquine). Both study groups included 12 patients. Compared to SOC therapy, combination therapy with baricitinib and lopinavir/ritonavir demonstrated a statistically significant shorter time to improvement of clinical and respiratory symptoms and a greater reduction of C-reactive protein levels.22
Please check ClinicalTrials.gov for the latest information on studies of baricitinib and COVID-19.
Ruxolitinib is an oral JAK inhibitor selective for JAK1 and JAK2 and is currently approved for myelofibrosis, polycythemia vera, and acute graft-versus-host disease.23 Like baricitinib, it is theorized to have antiviral properties through inhibition of AAK1, which may prevent viral entry and infection of pulmonary AT2 epithelial cells.7
Clinical Data for COVID-19
A small, prospective, single-blind, randomized controlled Phase 2 trial in patients with COVID-19 in China compared ruxolitinib 5 mg orally twice daily (n = 20) with placebo (administered as vitamin C 100 mg; n = 21), both given in combination with SOC therapy. The median age of the patients was 63 years. There were no significant demographic differences between the two arms. Treatment with ruxolitinib was associated with a nonsignificant reduction in the median time to clinical improvement (12 days for ruxolitinib vs. 15 days for placebo; P = 0.15), defined as a two-point improvement on a seven-category ordinal scale or as hospital discharge. There was no difference between the groups in the median time to discharge (17 days for ruxolitinib vs. 16 days for placebo; P = 0.94). More patients in the ruxolitinib group than in the placebo group had radiographic improvement on computerized tomography scans of the chest at Day 14 (90% for ruxolitinib vs. 61.9% for placebo; P = 0.05) and a shorter time to recovery from initial lymphopenia (5 days for ruxolitinib vs. 8 days for placebo; P = 0.03), when it was present. The use of ruxolitinib was not associated with an increased risk of adverse events or mortality (no deaths in the ruxolitinib group vs. three deaths [14%] in the control group). Despite the theoretical antiviral properties of JAK inhibitors, there was no significant difference in the time to viral clearance among the patients who had detectable viral loads at the time of randomization to ruxolitinib treatment (n = 8) or placebo (n = 9). Limitations of this study include the small sample size, the exclusion of ventilated patients at study entry, and the frequent concomitant use (among 70% of patients) of antivirals and steroids.24
A small, retrospective, single-arm study in Germany reported no safety concerns in 14 patients with severe COVID-19 who received a brief course of ruxolitinib therapy (with a median of 9 days of treatment).25
Please check ClinicalTrials.gov for the latest information on studies of ruxolitinib and COVID-19.
Tofacitinib is the prototypical JAK inhibitor, predominantly selective for JAK1 and JAK3, with modest activity against JAK2, and, as such, can block signaling from gamma-chain cytokines (e.g., IL-2, IL-4) and gp 130 proteins (e.g., IL-6, IL-11, interferons). It is an oral agent first approved for the treatment of rheumatoid arthritis and has been shown to decrease levels of IL-6 in patients with this disease.26 Tofacitinib is also FDA approved for the treatment of psoriatic arthritis and ulcerative colitis.27
Clinical Data for COVID-19
There is no clinical data on the use of tofacitinib to treat COVID-19.
Please check ClinicalTrials.gov for the latest information on studies of tofacitinib and COVID-19.
- Wang Y, Zhang LL, Champlin RE, Wang ML. Targeting Bruton's tyrosine kinase with ibrutinib in B-cell malignancies. Clin Pharmacol Ther. 2015;97(5):455-468. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25669675.
- Chen SS, Chang BY, Chang S, et al. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. Leukemia. 2016;30(4):833-843. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26582643.
- Babon JJ, Lucet IS, Murphy JM, Nicola NA, Varghese LN. The molecular regulation of Janus kinase (JAK) activation. Biochem J. 2014;462(1):1-13. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25057888.
- Bousoik E, Montazeri Aliabadi H. "Do we know jack"about JAK? A closer look at JAK/STAT signaling pathway. Front Oncol. 2018;8:287. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30109213.
- Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology (Oxford). 2019;58(Suppl 1):i43-i54. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30806709.
- Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32222466.
- Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020;20(4):400-402. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32113509.
- Acalabrutinib (Calquence) [Package Insert]. Food and Drug Administration. November 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf.
- Ibrutinib (Imbruvica) [package insert]. Food and Drug Administration. April 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205552s030,210563s006lblPI.pdf.
- Clowse ME, Feldman SR, Isaacs JD, et al. Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis. Drug Saf. 2016;39(8):755-762. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27282428.
- Mahadevan U, Dubinsky MC, Su C, et al. Outcomes of pregnancies with maternal/paternal exposure in the tofacitinib safety databases for ulcerative colitis. Inflamm Bowel Dis. 2018;24(12):2494-2500. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29982686.
- Wieringa JW, van der Woude CJ. Effect of biologicals and JAK inhibitors during pregnancy on health-related outcomes in children of women with inflammatory bowel disease. Best Pract Res Clin Gastroenterol. 2020;44-45:101665. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32359679.
- Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31043832.
- Roschewski M, Lionakis MS, Sharman JP, et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol. 2020;5(48). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32503877.
- Food and Drug Administration. FDA expands ibrutinib indications to chronic GVHD. 2017. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-ibrutinib-indications-chronic-gvhd. Accessed July 14, 2020.
- Treon SP, Castillo JJ, Skarbnik AP, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients. Blood. 2020;135(21):1912-1915. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32302379.
- Zanubrutinib (Brukinsa) [package insert]. Food and Drug Administration. November 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213217s000lbl.pdf
- Tam C, Grigg AP, Opat S, et al. The BTK inhibitor, BGB-3111, is safe, tolerable, and highly active in patients with relapsed/refractory B-cell malignancies: initial report of a Phase 1 first-in-human trial. Available at: https://ashpublications.org/blood/article/126/23/832/136525/The-BTK-Inhibitor-Bgb-3111-Is-Safe-Tolerable-and.
- Baricitinib (Olumiant) [package insert]. Food and Drug Administration. October 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207924s001lbl.pdf.
- Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30-e31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32032529.
- McInnes IB, Byers NL, Higgs RE, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31375130.
- Cantini F, Niccoli L, Matarrese D, Nicastri E, Stobbione P, Goletti D. Baricitinib therapy in COVID-19: a pilot study on safety and clinical impact. J Infect. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32333918.
- J Ruxolitinib (Jakafi) [package insert]. Food and Drug Administration. January 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202192Orig1s019Rpllbl.pdf.
- Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020;146(1):137–146. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32470486.
- La Rosee F, Bremer HC, Gehrke I, et al. The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia. 2020;34(7):1805-1815. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32518419.
- Migita K, Izumi Y, Jiuchi Y, et al. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol. 2014;175(2):208-214. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24665995.
- Tofacitinib (Xeljanz) [package insert]. Food and Drug Administration. July 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203214s024,208246s010lbl.pdf.