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.