5.1 IFN-β
Type 1 IFNs are a group of cytokines produced during viral infection. Notably, IFN-β-1a has a leading role in activating genes involved in immunomodulation, suppressing the inflammatory response and anti-viral effects (Sallard, Lescure, Yazdanpanah, Mentre, & Peiffer-Smadja, 2020). Whilst a variety of type 1 IFNs exist, in vitro evidence has shown that IFN-β-1a and IFN- β-1b are the most potent in the inhibition of SARS-CoV and MERS-CoV (Chan et al., 2013; Hensley et al., 2004). Within the lungs, IFN-β-1 has been shown to upregulate levels of the enzyme cluster of differentiation 73 (CD73), which inhibits vascular leakage, increases the secretion of anti-inflammatory adenosine and preserves pulmonary endothelial barrier function (Kiss et al., 2007; Sallard et al., 2020). However, in vivo research has revealed that timing of administration of IFN-β-1 is imperative for positive effects. When administered shortly after MERS-CoV infection, IFN-β-1 protected mice from lethal infection, whereas delayed administration failed to effectively inhibit viral replication or pro-inflammatory cytokines, leading to fatal pneumonia (Channappanavar et al., 2019). Interestingly, in vitro evidence has revealed that SARS-CoV-2 is more sensitive to IFN-β-1 treatment than MERS-CoV and SARS-CoV, and thus supports the tenet that treatment with IFN-β-1 may be beneficial for COVID-19 patients (Lokugamage, Schindewolf, & Menachery, 2020; Sheahan, Sims, Leist, Schäfer, et al., 2020; Thiel & Weber, 2008). It is assumed that treatment of COVID-19 patients with IFN-β-1 will strengthen the host immune response and prevent the worsening of severe respiratory tract manifestations.
IFN-β-1 therapy has been used for the long-term management of multiple sclerosis (MS) and has been associated with a number of AEs. When administered subcutaneously in MS patients, the most common AEs were flu-like symptoms, injection site reactions, worsening of MS symptoms, menstrual disorders, mood alterations and laboratory abnormalities (Walther & Hohlfeld, 1999). The most common laboratory abnormalities were neutropenia, leukopenia, lymphopenia and raised aminotransferases (Walther & Hohlfeld, 1999). A genome-wide association study of patients with IFN-β induced liver injury showed that rs2205986 which has been linked to differential expression of interferon regulatory factor (IRF)-6 is a predisposing factor (Kowalec et al., 2018). This may be related to the fact that IRF6 leads to apoptosis in the presence of IFN- β. Depression is a common AE reported in patients receiving subcutaneous IFN- β-1 therapy, and thus caution is needed when administering to those with a previous or current history of depressive disorder (Biogen). Whilst rare, careful monitoring of clinical manifestations such as new onset hypertension, thrombocytopenia, impaired renal function and fever are required in order to identify cases of thrombotic microangiopathy (TMA) (Biogen). TMA is rare and has been reported at different time points of IFN- β-1 therapy (Biogen; Nishio et al., 2016; Yam, Fok, McLean, Butler, & Kempster, 2018). Laboratory findings of a decreased platelet count, increased serum lactate dehydrogenase (LDH) and red blood cell fragmentation are suggestive of TMA (Biogen). If diagnosed, patients must discontinue IFN- β-1 therapy and will require plasma exchange (Biogen).
SNG001 is an inhaled form of IFN-β-1a produced by Synairgen. The company have tested the efficacy and safety of the drug for the prevention and treatment of symptoms associated with respiratory viral infection in asthma and chronic obstructive pulmonary disease (COPD) (Synairgen plc, 2018). A randomised, placebo-controlled phase 2 trial is currently ongoing to assess the safety and efficacy of inhaled SNG001 for the treatment of patients with COVID-19 (NCT04385095). Data from the asthma trials have revealed that when administered via inhalation, high levels of IFN-β-1a are achieved within the lungs with lower levels within the circulation leading to improvements in lung function, antiviral responses and better asthma control (Djukanović et al., 2014). Inhaled SNG001 seems to have a good safety profile; 5 patients within the SNG001 arm reported cardiac palpitations whereas no cases were reported in the placebo arm, but symptoms were mild and not considered clinically significant (Djukanović et al., 2014).
A clinical trial has been undertaken in hospitalised COVID-19 patients where the triple combination of IFN-β, lopinavir-ritonavir and ribavirin was compared to lopinavir-ritonavir and ribavirin (Hung et al., 2020; Shalhoub, 2020). Patients in the triple combination therapy arm achieved negative COVID-19 tests results faster than those in the control arm, with improved patient symptoms, decreased viral shedding and decreased overall length of stay in the hospital compared to those in the control group (Hung et al., 2020). AEs reported in both groups included nausea and diarrhoea. However, due to poly-pharmacy in this trial, it was difficult to determine the effect of IFN-β on SARS-CoV-2 alone.
IFN-β has reported DDIs with other COVID-19 therapies including chloroquine and hyrdroxychloroquine, and with anakinra, sarilumab and tocilizumab (Group, 2020). DDIs have also been reported with metamizole (analgesic), linezolid (antibacterial), clozapine (antipsychotic), zidovudine (HIV antiretroviral therapy) and some immunosuppressants (adalimumab, azathioprine and pirfenidone) (Group, 2020).
Table 1: Overview of safety concerns to considered drugs for the treatment of COVID-19.