JAK Inhibitors In COVID-19 - Uses, Facts, And Limitations

Introduction:

Janus kinase (JAK) is an enzyme under the family of tyrosine kinases (which is present in the fluid of cells). JAK enzymes are responsible for establishing a biochemical reaction in the human body through the JAK-STAT (Janus kinase - signal transducer and activation of transcription) pathway. The JAK-STAT pathway is a signal track passing information between proteins in the cell that assists in immune reactions, cell proliferation, cell death, and cancer cell formation.

There are four categories of JAK, namely JAK1, JAK2, JAK3, and JAK4, based on the involvement with cytokines (immune modulators).

What Are JAK Inhibitors?

Janus kinase inhibitors are a kind of medicine formulated to hinder the action of one or more JAK enzymes, thereby retarding the JAK-STAT pathway.Their main function is to alter the immune reaction by suppressing cytokine activity. Janus kinase inhibitors are commonly called JAK inhibitors or jakinibs. Some of the FDA (Food and drug administration)-approved and commercially available JAK inhibitors are,

• Abrocitinib.

• Barictinib.

• Delgocitinib.

• Fedratinib.

• Filgotinib.

• Oclacitinib.

• Peficitinib.

• Pacrtinib.

• Ruxolitinib.

• Tofacitinib.

• Upadacitinib.

What Are the Uses of JAK Inhibitors?

JAK inhibitors play a crucial role in reducing inflammation and mitigating the symptoms of autoimmune diseases.

• JAK 1 inhibitors are used in the treatment of pruritic dermatitis (chronic itchy skin with inflammation), allergic rhinitis, asthma, and inflammatory bowel disease.

• A combined JAK 1 and JAK 2 inhibitory activity is used to control rheumatoid arthritis, psoriasis, and pruritis.

• Selective JAK-3 inhibitors are efficient in the management of rheumatoid arthritis.

• JAK inhibitors have merged as a potential therapeutic agent against myeloproliferative neoplasms (blood cancer).

• Some other JAK inhibitors are in the clinical trial phase studied for the treatment of alopecia (hair loss) and systemic lupus erythematosus.

How Are the JAK-STAT Pathway and COVID-19 Infection Related?

COVID-19, or coronavirus 2019, is a contagious disease caused by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), which is responsible for the ongoing global pandemic of coronavirus that was first identified in 2019. COVID-19 infected patients can be asymptomatic or present with mild manifestations to severe organ failures.

One of the important suggested mechanisms attributed to the severe form of COVID-19 is cytokine storm. Cytokine storm refers to the sudden and severe response of immune cells, delivering a huge concentration of cytokines, eventually leading to multiple organ failures and even death. These cytokines exert their actions by binding to the cytokine receptors present in the cell membrane. They aid in the development of acute respiratory distress syndrome (ARDS).

Since a lot of cytokine receptors use the JAK-STAT pathway for signal transmission, the inhibition of JAK has become a target and opened a route for the management of severe COVID-19 infection.

How Are JAK Inhibitors Useful in Treating COVID-19?

Non-selective JAK inhibitor- Barictinib has been approved to treat patients with severe or critical COVID-19.

• JAK inhibitors inhibit the JAK-STAT pathway of the cells hosted by SARS-CoV-2, thereby decreasing the infectivity of the cells (especially lung cells).

• Non-selective JAK inhibitors reduce the action of cytokines and prove to be beneficial as a whole, instead of blocking only one cytokine at a time.

• The kinase inhibitors are recommended in severe COVID-19 patients because they prevent phosphorylation of key proteins that pass signals to activate proinflammatory cytokine - interleukin-6 for immunity and inflammation.

• Barictinib reduces inflammation and reduces the severity of acute respiratory distress syndrome.

• Unlike other JAK inhibitors, Barictinib also restricts endocytosis - intake of the substance into the cells, which will also prevent virus cell entry, thus having a direct antiviral activity.

• By combining directly-acting antivirals and Barictinib, there is a marked decrease in viral infection and unwanted inflammatory responses.

• Since SAR-CoV-2-infected patients will require only short-term treatment with JAK inhibitors, their long-term side effects are less likely to be considered in the case of COVID-19.

What Are the Facts Available to Support JAK Inhibitors as a New Treatment Strategy for COVID-19?

Barictinib was the most common JAK inhibitor evaluated in the studies against COVID-19. The review of research literature has provided the following evidence to support JAK inhibitors as a new treatment strategy for COVID-19.

ACTT trial - 2:

• ACTT (adaptive COVID-19 treatment) trial - 2 investigated Barcitinib-4mg in 1033 COVID-19 patients who showed severe symptoms for 14 days. The study demonstrated the efficiency of Baricitnib in combination with Remdesiver (antiviral drug).

• Trials have demonstrated the efficacy of Barictinib in improving the recovery time in patients with COVID-19 who required supplemental oxygen therapy. There was a significant improvement in recovery time seen in patients compared with those administered with placebo at a ratio of 1:16.

COV-BARRIER trial:

• COV-BARRIER was another largest randomized trial conducted with 1525 hospitalized COVID-19 patients with Barictinib 4mg orally or placebo for 14 days.

• The trails results showed the overall added benefit of survival when combined with corticosteroids.

• Also, the trial extended with the same regimen to COVID-19 patients with mechanical ventilation or ECMO (extracorporeal membrane oxygenation). Baricitinib used as an adjuvant therapy along with the usual COVID-19 care has probably reduced the death rates up to 28 days and 60 days than in the placebo arm.

STOP-COVID trial:

• This study has concluded that Tofacitinib can be used as an alternative to Barictinib with similar clinical benefits.

Other JAK inhibitors like Ruxolitinib and Upadacitinib and their efficacy in the treatment of COVID-19 are under clinical trials.

As per the recent guidelines, the world health organization (WHO) has strongly recommended the usage of Barictinib in patients with severe or critical COVID-19. The recommendation was based on the cumulative data from the above studies.

What Are the Limitations of JAK Inhibitors?

• JAK inhibitors suppress the immune system, paving the way for opportunistic infections (infections from microbes that are usually harmless).

• There are concerns about thromboembolic events (blood vessel blockage).

• There is no evidence to show its efficacy in patients with mild to moderate COVID-19 disease.

• There is no data to evaluate their risk in pregnant and breastfeeding women and in patients taking other medications.

• With the latest update, Barictinib use is restricted to patients needing supplemental oxygen but is not recommended in patients requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

• Various studies have used different approaches to assess and report their effects, hence inconclusive of specificity.

Conclusion:

Short-term studies have shown a positive outcome for the use of JAK inhibitors in the treatment of COVID-19. Further research will be required to explore the mechanism of JAK inhibitors in a substantial way, especially the timing of administration, course of the medication, and their interaction with other drugs.

The evaluation of the prospective part and the risk of JAK inhibitors in the treatment of severe COVID-19 is more complex and is considered a demanding area for active investigation.