4. Immunomodulators

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• Another RCT on 338 hospitalized adult patients with severe COVID-19 pneumonia from Argentina did not find any difference in clinical status or overall mortality or in prespecified subgroups (Simonovich 2020). • So it may depend on the patients – and on the level of antibody titers.

Among 3082 patients hospitalized with COVID-19, the efficacy was moderated by mechanical ventilation status (Joyner 2020). In patients who were not receiving mechanical ventilation, transfusion of plasma with higher antibody levels was associated with a lower risk of death than transfusion of CP with lower antibody levels. • In an RCT on early administration of high titer CP to 160 mildly ill older adults, severe respiratory disease developed in 16% who received CP and in 31% who received placebo (Lipster 2020). • CP may be also very helpful in patients with humoral deficiency induced by anti-CD20 monoclonal antibodies such as rituximab. In 17 consecutive patients with profound B cell lymphopenia and prolonged COVID-19 symptoms, all but one patient experienced an improvement of clinical symptoms within 2 days.

While antiviral drugs are most likely to prevent mild COVID-19 cases from becoming severe, adjuvant strategies will be needed, particularly in severe cases. Coronavirus infections may induce excessive and aberrant, ultimately ineffective host immune responses that are associated with severe lung damage (Channappanavar 2017). Similar to SARS and MERS, some patients with COVID-19 develop acute respiratory distress syndrome (ARDS), often associated with a cytokine storm. This is characterized by increased plasma concentrations of various interleukins, chemokines and inflammatory proteins. Various host-specific therapies aim to limit the immense damage caused by the dysregulation of pro-inflammatory cytokine and chemokine reactions (Zumla 2020). Immunosuppressants, interleukin blocking agents such as anakinra or JAK-2 inhibitors are also an option (Mehta 2020). These therapies may potentially act synergistically when combined with antivirals. Numerous drugs are discussed, including those for lowering cholesterol, for diabetes, arthritis, epilepsy and cancer, but also antibiotics. They are said to modulate autophagy, promote other immune effector mechanisms and the production of antimicrobial peptides. Other immunomodulatory and other approaches in clinical testing include bevacizumab, brilacidin, cyclosporin, fedratinib, fingolimod, lenadilomide and thalidomide, sildenafil, teicoplanin and many more. However, convincing clinical data is pending for most strategies.

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Corticosteroids

Corticosteroids are thus far the only drugs which provide a survival benefit in patients with severe COVID-19. During the first months of the pandemic, according to current WHO guidelines, steroids were controversially discussed and were not recommended outside clinical trials. With a press release on June 16, 2020 reporting the results of the UK-based RECOVERY trial, the treatment of COVID-19 underwent a major change. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation. The RECOVERY results had a huge impact on other RCTs around the world. The therapeutic value of corticosteroids has now been shown in numerous studies: • RECOVERY: In this open-label trial (comparing a range of treatments), hospitalized patients were randomized to receive oral or intravenous dexa (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. Overall, 482 patients (22,9%) in the dexa group and 1110 patients (25,7%) in the usual care group died within 28 days (age-adjusted rate ratio, 0,83). The death rate was lower among patients receiving invasive mechanical ventilation (29,3% vs. 41,4%) and among those receiving oxygen without invasive mechanical ventilation (23,3% vs. 26,2%) but not among those who were receiving no respiratory support (17,8% vs. 14,0%). • REMAP-CAP (different countries): In this Bayesian RCT, 384 patients were randomized to fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone. Treatment with a 7-day fixed-dose course or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority, respectively, with regard to the odds of improvement in organ support free days within 21 days. However, due to the premature halt of the trial, no treatment strategy met pre-specified criteria for statistical superiority, precluding definitive conclusions. • CoDEX (Brazil). A multicenter, open-label RCT in 299 COVID-19 patients (350 planned) with moderate-to-severe ARDS (Tomazini 2020). Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard of care (n = 151) or standard of care alone (n = 148). Patients randomized to the dexamethasone group had a mean 6,6 ventilator-free days during the first 28 days vs 4,0 ventilator-free days in the standard of care group (difference, 2,26; 95% CI, 0,2-4,38; p = 0,04). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free

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days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. • CAPE COD: Multicenter double-blinded RCT, in 149 (290 planned) critically-ill patients admitted to the intensive care unit (ICU) for COVID-19–related acute respiratory failure (Dequin 2020). The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42,1%) in the hydrocortisone group compared with 37 of 73 (50,7%) in the placebo group (p = 0,29). • A prospective WHO meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The fixed-effect summary odds ratios for the association with mortality were 0,64 (95% CI: 0.50-0.82; p < 0,001) for dexamethasone compared with usual care or placebo, 0,69 (95% CI: 0,43-1,12; p = 0,13) for hydrocortisone and 0.91 (95% CI: 0,29-2.87; p = 0,87) for methylprednisolone, respectively. There was no suggestion of an increased risk of serious adverse events.

• Another study with 206 patients suggested that the effect of corticosteroids on viral shedding may be in a dose-response manner. High-dose (80 mg/d) but not low-dose corticosteroids (40 mg/d) delayed viral shedding of patients with COVID-19 (Li 2020). • Treatments for respiratory disease, specifically inhaled corticosteroids (ICSs) do not have a protective effect. In 148,557 persons with COPD and 818,490 persons with asthma who were given relevant respiratory medications in the 4 months before the index date (March 1), people with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA–LAMA combinations (adjusted HR 1,39) (Schultze 2020). Compared with those prescribed short acting beta agonists only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1,55, 1,10-2,18]), whereas those given a low or medium dose were not. Sensitivity analyses showed that the apparent harmful association could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS. Conclusions: WHO suggests NOT to use corticosteroids in the treatment of patients with non-severe COVID-19. The WHO recommends systemic corticosteroids for the treatment of patients with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). However, the WHO panel noted that the oxygen saturation threshold of 90% to define severe COVID-19 was arbitrary and should be interpreted cautiously when used for determining which patients should be offered systemic corticoster-

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oids. For example, clinicians must use their judgement to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient suffering from chronic lung disease. Similarly, a saturation above 90–94% on room air may be abnormal if the clinician suspects that this number is on a downward trend.

Interferons

The interferon (IFN) response constitutes the major first line of defense against viruses. This complex host defense strategy can, with accurate understanding of its biology, be translated into safe and effective antiviral therapies. In a recent comprehensive review, the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses is described (Park 2020). IFN may work on COVID-19 when given early. Several clinical trials are currently evaluating synthetic interferons given before or soon after infection, in order to tame the virus before it causes serious disease (brief overview: Wadman 2020). In vitro observations shed light on antiviral activity of IFN-β1a against SARS-CoV-2 when administered after the infection of cells, highlighting its possible efficacy in an early therapeutic setting (Clementi 2020). In patients with coronaviruses such as MERS, however, interferon studies were disappointing. Despite impressive antiviral effects in cell cultures (Falzarano 2013), no convincing benefit was shown in clinical studies in combination with ribavirin (Omrani 2014). • A Phase II, multicentre, open-label RCT from Hong Kong randomized 127 patients with mild-to-moderate COVID-19 (median 5 days from symptom onset) to receive lopinavir/r only or a triple combination consisting of lopinavir/r, ribavirin and interferon (Hung 2020). This trial indicates that the triple combination can be beneficial when started early. Combination therapy was given only in patients with less than 7 days from symptom onset and consisted of lopinavir/r, ribavirin (400 mg BID), and interferon beta-1b (1-3 doses of 8 Mio IE per week). Combination therapy led to a significantly shorter median time to negative results in nasopharyngeal swab (7 versus 12 days, p = 0,001) and other specimens. Clinical improvement was significantly better, with a shorter time to complete alleviation of symptoms and a shorter hospital stay. Of note, all differences were driven by the 76 patients who started treatment less than 7 days after onset of symptoms. In these patients, it seems that interferon made the difference.

Up to now, this is the only larger RCT showing a virological response of a specific drug regimen.

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• A retrospective multicenter cohort study of 446 COVID-19 patients, taking

“advantage of drug stock disparities” between two medical centers in Hubei. Early administration ≤ 5 days after admission of IFN-α2b was associated with reduced in-hospital mortality in comparison with no admission of

IFN-α2b, whereas late administration of IFN-α2b was associated with increased mortality (Wang 2020). • In the WHO Solidarity Trial conducted at 405 hospitals in 30 countries, 2063 were randomly assigned to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. There was no efficacy of subcutaneous interferon alone or with lopinavir/r (WHO Solidarity). • SNG001 is a formulation of recombinant interferon beta for inhaled delivery by nebulizer that is in development for the treatment of virus-induced lower respiratory tract illnesses. In this pilot trial, patients randomly assigned to SNG001 (n = 48) had greater odds of improvement versus placebo and more rapid recovery (Monk 2020). This corroborates findings from in vitro studies and animal models showing that the interferon pathway is crucial.

JAK inhibitors

Several inflammatory cytokines that correlate with adverse clinical outcomes in COVID-19 employ a distinct intracellular signalling pathway mediated by Janus kinases (JAKs). JAK-STAT signalling may be an excellent therapeutic target (Luo 2020). Baricitinib (Olumiant®) is a JAK inhibitor approved for rheumatoid arthritis. Using virtual screening algorithms, baricitinib was identified as a substance that could inhibit ACE2-mediated endocytosis (Stebbing 2020). Like other JAK inhibitors such as fedratinib or ruxolitinib, signaling inhibition may also reduce the effects of the increased cytokine levels that are frequently seen in patients with COVID-19. In rhesus macaques, viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was NOT reduced with baricitinib. However, animals treated with baricitinib showed reduced inflammation (Hoang 2020). There is some evidence that baricitinib could be the optimal agent in this group (Richardson 2020). Other experts have argued that the drug would be not an ideal option due to the fact that baricitinib causes lymphocytopenia, neutropenia and viral reactivation (Praveen 2020) as well as pancreatitis (Cerda-Contreras 2020). There is also a dose-dependent association with arterial and venous thromboembolic events (Jorgensen 2020). It is possible that

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the pro-thrombotic tendencies could exacerbate a hypercoagulable state, underscoring the importance of restricting the use of baricitinib to clinical trials. On December 28, 2020, baricitinib has been granted an FDA Emergency Use Authorization (EUA) for treatment of confirmed or suspected COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO); the EUA requires that baricitinib be used in combination with remdesivir. The EUA is based on these findings: • In a large RCT of 1033 hospitalized adults with COVID-19, baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among those receiving high-flow oxygen or non-invasive ventilation. The 216 patients receiving high-flow oxygen or non-invasive ventilation at enrollment had a time to recovery of 10 days with combination treatment (n = 103) and 18 days with control (n = 103). The 28-day mortality was 5,1% and 7,8%, respectively. • One observational study provides some evidence for a synergistic effect of baricitinib and corticosteroids (Rodriguez-Garcia 2020). Patients with moderate to severe SARS-CoV-2 pneumonia received lopinavir/r and HCQ plus either corticosteroids (controls, n = 50) or corticosteroids and baricitinib (n = 62). In the controls, a higher proportion of patients required supplemental oxygen both at discharge (62% vs 26%) and 1 month later (28% vs 13%). Ruxolitinib (Jakavi®) is a JAK inhibitor manufactured by Incyte. It is used for myelofibrosis, polycythemia vera (PCV) and certain chronic graft versus host diseases in patients following a bone marrow transplant. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19associated cytokine storm and reduce mortality. • A small placebo-controlled Phase II RCT on 43 patients with severe COVID19, ruxolitinib was not associated with significantly accelerated clinical improvement, although ruxolitinib recipients had a numerically faster clinical improvement (Cao Y 2020). • In a retrospective study, 12/14 patients achieved significant reduction of the “COVID-19 Inflammation Score” with sustained clinical improvement in 11/14 patients (La Rosée 2020). Treatment was safe with some signals of efficacy to prevent or overcome multi-organ failure. A Phase II RCT has been initiated (NCT04338958).

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• Another non-randomized study suggested a clinical benefit from ruxolitinib in 32 patients with severe COVID-19 pneumonia, compared to a control group (D’Alessio).

Cytokine blockers and anticomplement therapies

The hypothesis that quelling the cytokine storm with anti-inflammatory therapies directed at reducing interleukin-6 (IL-6), IL-1, or even tumor necrosis factor TNF alpha might be beneficial has led to several ongoing trials. It is suggestive that interleukin blocking strategies might improve the hyperinflammatory state seen in severe COVID-19. A recent review on this strategy, however, was less enthusiastic and urged caution (Remy 2020). Past attempts to block the cytokine storm associated with other microbial infections and with sepsis have not been successful and, in some cases, have worsened outcomes. Moreover, there is concern that suppressing the innate and adaptive immune system to address increased cytokine concentrations, could enable unfettered viral replication, suppress adaptive immunity, and delay recovery processes. There is growing recognition that potent immunosuppressive mechanisms are also prevalent in such patients. Following, we will briefly discuss the evidence on cytokine blockers. Anakinra (Kineret®) is an FDA-approved treatment for rheumatoid arthritis and neonatal onset multisystem inflammatory disease. It is a recombinant human IL-1 receptor antagonist that prevents the binding of IL-1 and blocks signal transduction. Anakinra is thought to abrogate the dysfunctional immune response in hyperinflammatory COVID-19 and is currently being investigated in almost 20 clinical trials. Some case series have reported on encouraging results and anakinra is considered to be included as an option in the RECOVERY trial.

• A study from Paris, comparing 52 “consecutive” patients treated with anakinra with 44 historical patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 25% of patients in the anakinra group and 73% of patients in the historical group. The treatment effect of anakinra remained significant in the multivariate analysis (Hayem 2020).

According to the authors, their study was “not perfect from a statistical point of view…” • Of 120 patients with hyperinflammation (33% on mechanical ventilation), 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 14% in treated patients and 36% in controls (p = 0,005). Unadjusted and adjusted risk of

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death was significantly lower for treated patients com-pared to controls (Bozzi 2020). • An RCT from France, however, was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: anakinra did not improve outcomes in patients with mildto-moderate COVID-19 pneumonia (CORIMUNO 2020). Some experts still argue that a true test of anakinra would be in patients with more severe

COVID-19, or with evidence of IL-1-mediated hyperinflammation (Cavalli 2020). Canakinumab (Illaris®) is human monoclonal antibody against IL-1β, approved for the treatment of juvenile rheumatoid arthritis and other chronic autoinflammatory syndromes. In a pilot trial, 10 patients with hyperinflammation (defined as CRP ≥ 50 mg/L) and respiratory failure showed a rapid improvement in serum inflammatory biomarkers and an improvement in oxygenation (Ucciferri 2020). There are other uncontrolled studies on 83 patients (Landi 2020) and on 17 patients (Katia 2020), suggesting clinical benefits. However, RCTs are pending. Infliximab (Remicade®) is a chimeric monoclonal anti-TNF antibody, approved to treat a number of autoimmune diseases, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis and psoriasis. As a major component of deteriorating lung function in patients with COVID-19 is capillary leak, a result of inflammation driven by key inflammatory cytokines such as TNF, making TNF-blocking agents an attractive strategy (Robinson 2020). Administration of anti-TNF to patients for treatment of autoimmune disease leads to reductions in all of these key inflammatory cytokines. A small case series of seven patients who were treated with a single infusion of IFX (5 mg/kg body weight) has been reported (Stallmach 2020). Mavrilimumab is an anti-granulocyte–macrophage colony-stimulating factor (GM-CSF) receptor-α monoclonal antibody. GM-CSF is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases (Mehta 2020). In small uncontrolled pilot trial on 13 patients, mavrilimumab treatment was associated with improved clinical outcomes compared with standard of care in non-mechanically ventilated patients with severe COVID-19 pneumonia and systemic hyperinflammation. Treatment was well tolerated (De Luca 2020). Tocilizumab (TCZ, RoActemra® or Actemra®) is a monoclonal antibody that targets the interleukin-6 receptor. It is used for rheumatic arthritis and has a good safety profile. The initial dose should be 4-8 mg/kg, with the recommended dosage being 400 mg (infusion over more than 1 hour). Of note, the

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current level of evidence supporting the use of TCZ is weak, and many guidelines recommend against the use of TCZ except in the context of a clinical trial. TCZ continues to be tested in the RECOVERY trial while results are still pending. • A large multicenter cohort included 3924 critically ill patients admitted to

ICU at 68 hospitals across the US (Gupta 2020). The risk of in-hospital death was lower with TCZ (29% versus 41%). However, TCZ patients were younger and had fewer comorbidities. According to the authors, the findings “may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed”.

• COVACTA: On July 29, Hoffmann-La Roche announced disappointing results from its much-anticipated Phase III COVACTA trial. TCZ did not improve patient mortality, although patients spent roughly a week less in hospital compared with those given placebo. However, it may be too early to quit this strategy (Furlow 2020). Cautious interpretation of COVACTA is needed, in view of the study’s broad patient selection criteria. • EMPACTA: In 249 hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation, tocilizumab did not improve survival, but it reduced the likelihood of progression to the composite outcome of mechanical ventilation or death. Death from any cause by day 28 occurred in 10,4% of the patients in the tocilizumab group and 8,6% of those in the placebo group (Salama 2020). • CLORIMUNO: In this RCT that included 130 patients with moderate-tosevere pneumonia, tocilizumab did not reduce the WHO Scale scores at day 4. The proportion of patients with non-invasive ventilation, intubation, or death at day 14 was 36% with usual care and 24% with tocilizumab.

No difference in mortality over 28 days was found (Hermine 2020). • BACC Bay Trial: In this double-blind, placebo-controlled RCT in 243 moderately ill hospitalized patients (BACC Bay Trial), TCZ was not effective for preventing intubation or death (Stone 2020). • In an open label RCT in 126 patients hospitalized with COVID-19 pneumonia, the rate of the primary clinical endpoint (clinical worsening) was not significantly different between the control group and the TCZ group (Salvarani 2020). The proportion of patients discharged within 14 and 30 days was the same. • An open-label RCT from Brazil (Veiga 2020) among patients who were receiving supplemental oxygen or mechanical ventilation was stopped early, after 129 patients had been enrolled, because of an increased number of

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deaths at 15 days in the TCZ group, compared to standard of care (17% vs 3%). Siltuximab (Sylvant®) is another anti-IL-6-blocking agent. However, this chimeric monoclonal antibody targets interleukin-6 directly and not the receptor. Siltuximab has been approved for idiopathic multicentric Castleman’s disease (iMCD). In these patients it is well tolerated. First results of a pilot trial in Italy (“SISCO trial”) have shown encouraging results. According to interim interim data, presented on April 2 from the first 21 patients treated with siltuximab and followed for up to seven days, one-third (33%) of patients experienced a clinical improvement with a reduced need for oxygen support and 43% of patients saw their condition stabilise, indicated by no clinically relevant changes (McKee 2020). Sarilumab (Kevzara®) is another recombinant human IL-6 receptor antagonist. An open-label study of sarilumab in severe COVID-19 pneumonia with hyperinflammation. Sarilumab 400 mg was administered intravenously in addition to standard of care to 28 patients and results were compared with 28 contemporary matched patients treated with standard of care alone. At day 28, 61% of patients treated with sarilumab experienced clinical improvement and 7% died. These findings were not significantly different from the comparison group. However, sarilumab was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline (Della-Torre 2020). Vilobelimab is an anaphylatoxin and complement protein C5a blocking monoclonal antibody. In an open-label, randomized Phase II trial (part of the PANAMO trial), 30 patients with severe COVID-19 were randomly assigned 1:1 to receive vilobelimab (up to seven doses of 800 mg intravenously) or best supportive care only (control group). At day 5 after randomization, the primary endpoint of mean relative change in the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) was not significantly different between groups. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0–31) for the vilobelimab group and 27% (4–49) for the control group. The frequency of serious adverse events was similar between groups and no deaths were considered related to treatment assignment. According to the authors, the secondary outcome results support the investigation of vilobelimab in a Phase III trial using 28-day mortality as the primary endpoint. Pharmacokinetic and pharmacodynamic data, including C5a, have not yet been published (Campbell 2020). Investigators using the other C5 complement pathway inhibitors eculizumab and ravulizumab have significantly increased their dose and dosing frequency in