key: cord-349210-8t4a5qqo authors: Ji, Ping; Chen, Jianmeng; Golding, Amit; Nikolov, Nikolay P.; Saluja, Bhawana; Ren, Yunzhao R.; Sahajwalla, Chandrahas title: Immunomodulatory Therapeutic Proteins in COVID‐19: Current Clinical Development and Clinical Pharmacology Considerations date: 2020-08-10 journal: J Clin Pharmacol DOI: 10.1002/jcph.1729 sha: doc_id: 349210 cord_uid: 8t4a5qqo The COVID‐19 pandemic caused by infection with SARS‐CoV‐2 has led to more than 600,000 deaths worldwide. Patients with severe disease often experience acute respiratory distress characterized by upregulation of multiple cytokines. Immunomodulatory biological therapies are being evaluated in clinical trials for the management of the systemic inflammatory response and pulmonary complications in patients with advanced stages of COVID‐19. In this review, we summarize the clinical pharmacology considerations in the development of immunomodulatory therapeutic proteins for mitigating the heightened inflammatory response identified in COVID‐19. This article is protected by copyright. All rights reserved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It belongs to the beta-coronavirus family and is phylogenetically close to the severe acute respiratory syndrome (SARS) virus. 1 As of August 1, 2020, SARS-CoV-2 infection has been confirmed in over 17 million people worldwide and caused 680, 894 deaths as reported on the World Health Organization website. About 5-10% of COVID-19 patients developed lung injury and respiratory distress that progressed to acute respiratory distress syndrome (ARDS). 2 According to statistics emerging from around the world, different demographics may have different susceptibilities to COVID-19. Patients who are male, elderly or with pre-existing medical conditions are facing worse outcomes with higher death rates in this pandemic. 3 Other potential risk factors that have been identified to date include race/ethnicity, background co-medications, and poverty and crowding, among others. 4 At this time, no drugs or other therapeutics have been approved by the U.S. Food and Drug Administration (FDA) to prevent or treat COVID-19. 5 In May 2020, the FDA issued an emergency use authorization for the drug remdesivir authorizing its emergency use by licensed health care providers to treat adults and children hospitalized with severe COVID- 19. 6, 7 Current clinical management includes secondary infection prevention, symptom control and supportive care, such as supplemental oxygen and mechanical ventilatory support when indicated. 4 While most drug development programs take years before an effective drug can reach the market, drug development programs and regulatory review of potential COVID-19 therapies consider the urgent need for treatment and prevention options while adhering to the FDA's robust standards for demonstrating the safety and effectiveness of drug products. Clinical pharmacology is playing an increasingly crucial role in assessing the drug activity, efficacy and safety during development and regulatory review. Although COVID-19 presents a significant challenge both from drug development and regulatory review standpoints, it offers a unique opportunity for the clinical pharmacology community to facilitate clinical development of therapies. 8 In this review, we summarize the role of clinical pharmacology during the COVID-19 pandemic, focusing on immunomodulatory therapeutic proteins. This article is protected by copyright. All rights reserved. Currently, no drugs, biologics or other therapeutics have been approved by the FDA to prevent or treat COVID- 19 . Because clinical information about the optimal management of COVID-19 is evolving quickly, recommendations by the COVID-19 Treatment Guidelines Panel on the use of any agents for pre-or post-exposure prophylaxis against SARS-CoV-2 in patients with COVID-19 outside of the clinical trial setting are updated frequently as published data and other authoritative information become available. 9 In the clinical trial setting, consideration of clinical manifestation is critical to any antiviral or immunomodulatory treatment strategy. Patients infected with SARS-CoV-2 can experience a range of clinical manifestations, from no symptoms to critical illness. 10 The symptomatic phases include: 1) mild illness, with such signs and symptoms as fever, cough, sore throat, malaise, headache, muscle pain without shortness of breath or abnormal imaging; 2) moderate illness, with evidence of lower respiratory disease; 3) severe illness, with dyspnea, hypoxia or evidence of greater than 50% lung involvement on imaging tests; and 4) critical illness, with respiratory failure, septic shock and/or multiple organ dysfunction. The Chinese Center for Disease Control and Prevention reported that of 44,500 confirmed infections, most infected patients (80%) experienced mild or moderate forms of the illness, 14% developed severe illness and 5% developed critical illness. 11 The four clinical manifestations seem to be controlled by the underlying two distinct but overlapping pathologic subsets: viral pathogenicity and host inflammatory response, based on which Siddiqui et al. proposed a staging system to characterize the disease course of COVID-19. 12 During the first week of infection, the innate immunity reaction is involved, followed by the adaptive immunity reaction starting at about the second week, including antigen-specific T cells and antibodies which are produced for more efficient viral clearance and blocking. At the initial stage of the illness, most patients experience mild to moderate forms of illness and recover on their own with minimal intervention. A minority of COVID-19 patients will transition into the severe and critical stages of the illness, which manifest as an extrapulmonary systemic hyperinflammation syndrome. The aggravation of symptoms often is associated with increased levels of acute phase reactants (erythrocyte sedimentation rate, C-reactive protein (CRP), ferritin), coagulopathy (elevated titers of D-dimers, disseminated intravascular coagulation) and cell lysis (serum creatine kinase, lactate dehydrogenase). 13, 14 These clinical and laboratory parameters are correlated with increased levels of This article is protected by copyright. All rights reserved. proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α. 15, 16, 17 Massive and rapid release of these detrimental proinflammatory mediators identified as so-called "cytokine storm" is associated with ARDS and multiple organ failure. 18 As such, the potential of immunomodulatory therapeutic proteins in blocking the inflammatory pathway has been hypothesized to prevent or mitigate disease progression of COVID-19. These also likely provide additional benefits in conjunction with the standard of care, and with other potential treatments such as high doses of polyvalent immunoglobulins or convalescent serum. 15 These hypotheses of immunomodulatory therapeutic proteins in COVID-19 are being evaluated in various clinical settings and are elaborated below. In this review, we classify immunomodulatory therapeutic proteins in two categories: 1) FDAapproved drug products, and 2) drug products that have not been FDA-approved but are currently under investigation for illnesses other than COVID-19 (Table 1 ). Both categories involve repurposed drugs being evaluated for their ability to control the underlying hyperinflammatory syndrome in advanced stages of COVID-19. The available nonclinical and clinical experience is helpful for scientists in selecting candidate therapeutic proteins. For therapeutic proteins already approved for other indications, the known or anticipated benefits and risks for the approved indication (s), as well as reasonably anticipated adverse events, can be used to aid the benefit/risk assessment in COVID-19-related clinical trials. For novel investigational therapeutic proteins still in early development stages, information on benefits and risks mostly is obtained from limited early clinical data and nonclinical assessment; therefore, they likely involve a higher degree of uncertainty than do the repurposed approved therapeutic proteins. At this writing, over 110 COVID-19-related clinical studies evaluating immunomodulatory therapeutic proteins have been registered in clinicaltrials.gov (Supplemental Table) . We categorize these registered clinical studies by the corresponding immunomodulatory targets ( Figure 1 ) and summarize them below. This article is protected by copyright. All rights reserved. IL-6 is considered a key driver of the uncontrolled hyperinflammatory response/cytokine release storm (CRS) that accompanied ARDS in some COVID-19 patients. 19 A recent retrospective analysis that evaluated 201 patients with confirmed COVID-19 showed that the level of IL-6 was significantly higher (2.9-fold) in patients with ARDS compared with patients without ARDS. 20 As such, targeting the IL-6 pathway is one of the approaches that has gained substantial attention for the potential treatment of COVID-19-associated ARDS. Currently, IL-6 pathway inhibitors evaluated in one or more clinical trials for COVID-19 include anti-IL-6 receptor monoclonal antibodies tocilizumab, sarilumab and levilimab; and anti-IL-6 monoclonal antibodies clazakizumab, olokizumab and siltuximab. Targetmediated clearance can be observed at low drug concentrations for the three anti-IL-6 receptor antibodies, but not for the three anti-IL-6 antibodies. Tocilizumab has been evaluated in multiple clinical trials, either alone or in combination with other drugs in patients with COVID-19. Although the studied population overall fit in the moderate-critical criterion level, individual studies varied slightly in their patient enrollment criteria, for example, patients with at least moderate pneumonia, patients with severe pneumonia, patients hospitalized in intensive care, patients hospitalized with high risk of progression, and patients with confirmed infection and with evidence of systemic inflammation. The approved dosing regimen of tocilizumab for RA is 4 mg/kg IV every four weeks with an option of increasing to 8 mg/kg IV based on the clinical situation. In some COVID-19 trials, the tocilizumab dose selected was 8 mg/kg, with an option of one additional dose more than eight hours later, which is consistent with the dose of tocilizumab approved for the treatment of CRS. Higher total tocilizumab doses than those for autoimmune diseases such as RA evaluated in these clinical trials are likely due to concern about increased clearance under hyperinflammation in advanced stages of COVID-19. Other than the IV route, subcutaneous (SC) dosing of tocilizumab also is being explored for the treatment effect in hospitalized patients with SARS-CoV-2 infection. Tocilizumab also is being evaluated in numerous smaller clinical trials to decipher COVID-19 and explore its mechanism of action such as the role of IL-6 and soluble IL-6 receptor as predictors of efficacy in patients with severe COVID-19, the role of anti-IL-6 on calming the virus-induced cytokine storm, etc. The use of SC route of administration of sarilumab, the approved dosing route in RA, is planned in moderate-to-severe COVID-19 patients and moderate COVID-19 patients. IV dosing regimen of sarilumab, although not approved, is considered to achieve peak concentration faster and hence have been evaluated in several COVID-19 trials. The dose for siltuximab of 11 mg/kg IV evaluated in patients with severe or critical COVID-19 is consistent with the approved one for multicentric This article is protected by copyright. All rights reserved. Castleman's disease. Levilimab is currently under development for the treatment of RA; single SC administration of levilimab at a dose of 324 mg is being evaluated for its efficacy and safety in patients with severe COVID-19. The SC dosing of olokizumab, also under development for the treatment of RA, is being evaluated in patients with severe COVID-19 to assess the proportion of those responding to therapy. For clazakizumab, the SC route is being evaluated in RA and transplant patients. However, the IV route of 25 mg or 12.5 mg is being assessed in multiple clinical trials of COVID-19 for its treatment effect in patients with COVID-19. In addition to some preliminary studies, 21 26 In this trial, sarilumab was added to best supportive care and compared to best supportive care alone (placebo). A higher number of adverse events occurred in the drug-treated group than in the placebo group (80% to 77%) within the primary analysis population. It remains to be seen what the results will be in other trials, including in combination with antiviral therapy. IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses, including inflammatory and immunological responses. Patients with ARDS secondary to influenza and SARS have shown evidence of cytophagocytosis on histopathological examination. 27 Cytophagocytosis is a hallmark of macrophage activation syndrome (MAS), which is an inflammasome/IL-1-mediated disease. 28 Its levels have been elevated in COVID-19 patients with This article is protected by copyright. All rights reserved. severe illness. IL-1 has been suspected to exert a negative impact on cardiac function, which may be the link to the myocardial injury in many COVID-19 patients. 29 Pharmacodynamic (PD) assessments such as CRP, serum ferritin and D-dimer are among the many secondary outcome assessments. Canakinumab 300 or 600 mg IV is being evaluated in a study testing the proof of concept that early treatment prevents progressive heart and respiratory failure in patients with COVID-19 infection. SC dosing of 150 mg canakinumab is being assessed in COVID-19 pneumonia patients. Anakinra was approved for the treatment of RA at a daily dose of 100 mg SC and for Cryopyrin-Associated Periodic Syndromes at a daily dose of 1-2 mg/kg SC. It is being evaluated in multiple clinical trials for COVID-19, either alone, or jointly with other drug(s). Because of its short half-life of four to six hours, it is administered once daily or more frequently than daily. In a retrospective cohort study of patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the intensive care unit (ICU), treatment with high-dose anakinra of 5 mg/kg twice daily IV was safe and associated with clinical improvement in 72% of patients. 31 Another study on the off-label use of anakinra in 52 patients who were admitted to hospital for severe forms of COVID-19 with symptoms indicative of worsening respiratory function showed that anakinra reduced both need for invasive mechanical ventilation in the ICU and mortality, without serious side-effects. 32 Randomized controlled trials are being conducted in patients with moderate to critical pneumonia associated with COVID-19 at IV doses up to 400 mg daily. SC anakinra is being evaluated at 100 mg once daily or every 6 to 16 hours in patients with COVID-19. Interferons (IFNs) are a group of cytokines that communicate between cells against pathogens. They play a critical role in the immune system, such as activating natural killer cells and macrophages, as well as inducing flu-like symptoms of various diseases. 33 Because of their in vitro and in vivo antiviral properties, type I (IFN-α, β, ε, κ, and ω) and type II (IFN-γ) interferons are being evaluated extensively for their efficacy in patients with uncomplicated COVID-19 disease. On the other hand, the hyperproduction of pro-inflammatory IFN- during the later stages may be responsible for COVID-19-associated acute lung injury. Therefore, the removal of this cytokine by anti-IFN- antibodies during the late stage of the disease is believed to block this pathologic pathway and provide therapeutic benefit. 34 Emapalumab, a monoclonal antibody directed against IFN-γ and approved for the treatment of hemophagocytic lymphohistiocytosis (HLH), is being evaluated in a Phase 2/3, randomized trial in COVID-19 patients experiencing hyperinflammation and respiratory distress. The dosing regimen being investigated is IV 6 mg/kg on Day 1 followed by 3 mg/kg on Days 4, 7, 10 and 13, which is borrowed from the approved dosing regimen for HLH. The primary outcome measure of the trial is the proportion of patients not requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. Low-dose IL-2 IL-2, a pleiotropic cytokine, plays a key role in the development and function of regulatory T cells (Treg). 35 Low-dose IL-2 has been shown to control autoimmune and inflammatory disorders by enhancing Tregs. 36 As such, Aldesleukin (ILT-101), a human recombinant IL-2, was repurposed for COVID-19 to investigate its therapeutic benefit as a Treg inducer for controlling SARS-CoV2-related ARDS. ILT-101 was given as a once-daily SC administration for 10 consecutive days, which differs from the approved IV dosing of every 8 hours in one cycle of 14 doses in metastatic melanoma and metastatic renal cell carcinoma. IL-8, also known as CXCL8, is a proinflammatory cytokine orchestrating the recruitment of neutrophils in tissue injuries. 37 It was reported to be positively correlated with disease severity of COVID-19, with severe cases having the highest IL-8 levels. 38 IL-17 expression was reported to be elevated in patients with COVID-19 and its level was correlated with severity of lung injury. 40 This indicates that IL-17 may serve both as a biomarker of disease severity and as a potential target of therapy to mitigate the damage of SARS-CoV-2, particularly to the lung. Secukinumab, a human IgG1κ monoclonal antibody that binds to the IL-17A, is being repurposed for COVID -19 in an open-label, prospective randomized, small trial with 300 mg SC as the first dose and then 150 mg twice a day SC for 10 days. This dosing regimen is more frequent than the approved dosing regimens (150 or 300 mg once every week for the loading dose or once every four weeks) for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. TNF-α is produced during inflammation and is important in the coordination and development of the inflammatory response. Blockade of TNF-α alleviates inflammation and suppresses the production of other proinflammatory cytokines. The TNF-α level is upregulated in patients with COVID-19, especially in those with severe disease in ICU. 41 Duret 43 Currently, anti-TNF-α monoclonal antibodies such as adalimumab, infliximab and Xpro1595 are being evaluated in COVID-19 studies. A randomized, open-label, controlled trial for the efficacy and safety of adalimumab in patients with elevated TNF-α levels in the critical stages of severe COVID-19 is ongoing in Shanghai, China, with the main outcome of time to clinical improvement. 44 The dosing of adalimumab is not reported. A Phase 2 trial of the efficacy and safety of infliximab was initiated to evaluate whether early institution of TNF-α inhibitor therapy in patients with severe COVID-19 infections could prevent further clinical deterioration and reduce the need for advanced cardiorespiratory support and early mortality at a 5 mg/kg IV single dose. XPro1595, an investigational anti-TNF-α antibody, is being evaluated for prevention of disease progression in patients ≥ 65 years of age who have a diagnosed COVID-19 infection with pulmonary complications. This is a high-risk group of patients whose condition can deteriorate rapidly, requiring intensive care beds and increased respiratory support. The dose of 1 mg/kg SC once a week up to two doses in the COVID-19 trial is within the dosing range for XPro1595 evaluated in patients with Alzheimer's disease. The complement system, which is involved both in innate and in adaptive immunity, is considered an essential defense system against invading pathogens. On the other hand, an over-activated complement system has been reported to be associated with microvascular injuries and multiorgan failures in patients with COVID-19, and blocking complement overactivation may attenuate the proinflammatory sequelae of Sars-CoV-2 infection. 45 Mastaglio et al. reported a favorable course in a patient with COVID-19 severe pneumonia with systemic hyperinflammation after the treatment with the compastatin-based C3 inhibitor AMY-101. 46 Preliminary data on anti-complement C5 therapy with eculizumab as an off-label agent in four COVID-19 patients admitted to ICU showed that all four patients recovered with reduction of serum CRP levels. 47 These four patients received eculizumab 900 mg IV for two doses. Eculizumab is being evaluated in a randomized controlled clinical trial at a dosing regimen of 1200 mg IV on Days 1, 4 and 8 then at 1200 mg or 900 mg on Day 12 in patients with COVID-19 infection to assess its efficacy and safety. Ravulizumab, an approved anti-C5 monoclonal antibody, also is being repurposed to evaluate its potential for treatment of COVID-19 disease. The approved dosing for ravulizumab in paroxysmal nocturnal hemoglobinuria and in atypical hemolytic uremic syndrome is being used in the COVID-19 patients. Further, the safety and efficacy assessment of avdoralimab (anti-C5aR) and IFX-1 (anti-C5a) in patients with severe COVID-19-induced pneumonia is underway. Immunostimulants: TLR Agonist, IL-15 Agonist, PD-1 Inhibitor and TIM-3 Inhibitor PD-1 (programmed cell death protein-1) is a lymphoid cell surface protein of the immunoglobin superfamily and a member of the extended CD28/CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) family of T cell regulators. It is known to act as a mature T cell checkpoint for the modulation of apoptosis. PD-1 interaction with either of its ligands constitute significant negative immune checkpoints in the pathway responsible for blunting cell-mediated immune responses, specifically CD8+ responses, and for upregulating resulting pathologies (e.g., COVID-19) and malignancies. 48, 49, 50, 51 T lymphocytes (LT) counts are decreased in patients with COVID-19, which is responsible for host anergy towards viral infection, leading to increased risk of severe forms of COVID-19. It has been shown that healing from COVID-19 is associated with LT PD1 expression normalization. 52 Nivolumab, a PD-1 blocker, was approved for metastatic melanoma at 3 mg/kg IV given once every two weeks. It is being evaluated for its efficacy and safety nivolumab in This article is protected by copyright. All rights reserved. Toll-like receptors (TLRs) in innate immunity participate in the first line of defense against invading pathogens and play a significant role in inflammation, immune cell regulation, survival, and proliferation. 53 BDB-001, a TLR agonist with potential immune-stimulating and antineoplastic activities, is being assessed in COVID-19 patients with severe pneumonia, or acute lung injury/ARDS. IL-15 is a pleiotropic cytokine that plays a key role in immunotherapy. 54 Its overexpression promotes innate immune responses via the induction of natural killer cells, CD8 + T and Treg cells that may suppress the induced T helper type 2 (Th2)-related cytokines. This results in decreased levels of IL-4, IL-5, and IL-13, thus mitigating SARS-CoV-2 induced inflammation and fibrosis via IFN-γ and IL-10, which inhibit viral replications and reduce viral loads. 55 IL-15 agonist N-803, a fusion protein, is being evaluated in a Phase 1b, randomized, blinded, placebo-controlled study in adult subjects with COVID-19 to assess its safety and immunostimulatory activity, such as changes in lymphocyte counts. Hematopoietic cytokines: IL-7 and GM-CSF IL-7 is important for differentiation of hematopoietic stem cells into lymphoid progenitor cells and activation of cytotoxic T lymphocyte (CTL) responses. Paradoxically, its expression is reported to be depleted during certain viral infections. 56 As such, IL-7-based therapies also are proposed to restore the lymphopenic status in patients with COVID-19. Indeed, treatment with CYT107 in lymphopenic COVID-19 patients improved the absolute lymphocyte count from randomization to Day 30 when administered IM at 10 μg/kg twice a week for two weeks. In another trial, administration of IL-7 was reported not to affect the plasma concentrations of TNF-α, IL-1β and IL-12p70 in 12 COVID-19 patients. 57 GM-CSF (granulocyte-macrophage colony stimulating factor) is used as a medication to stimulate the production of white blood cells following chemotherapy. This strategy may prove useful for stabilizing alveolar macrophage and epithelial cell function, increasing SARS-CoV-2 clearance, protecting against secondary infection and contributing to lung repair mechanisms. 58 CCR5 (C-C chemokine receptor type 5) plays a central role in modulating immune cell trafficking to sites of inflammation, inhibition of which may suppress the hyperactive immune response observed in COVID-19 patients. 59 Leronlimab, a CCR5 antagonist, is being evaluated in patients who experience respiratory illness as a result of COVID-19 at a single dose of 700 mg IV, consistent with the dose used in the ongoing breast cancer trial. CD147, a receptor on host cells, is considered a novel route for SARS-CoV-2 invasion, and it is hypothesized that there exists an inhibitory potential for drugs interfering CD147 on SARS-CoV-2 invasion. 60 Meplazumab, a humanized anti-CD147 monoclonal antibody, is in the early clinical development stage for the potential to mediate both treatment and prophylaxis of falciparum malaria. It is known to inhibit both T cell chemotaxis and virus cell entry. In an open-label study in patients with COVID-19 pneumonia, the time to virus eradication in the meplazumab group given two doses of 10 mg IV once daily was significantly shorter than in the control group. 61 IL-33, an inflammatory cytokine, has been identified as an endogenous alarm signal to alert various types of immune cells in reaction to trauma. 62 The population of IL-33-producing cells was found to increase with disease severity of COVID-19. 63 SC MSTT1041A, an IL-33 inhibitor, is being evaluated in asthma indication; the IV route is being assessed in a Phase 2, randomized, double-blind, placebo-controlled, multicenter study in patients hospitalized with COVID-19 pneumonia. CSF (colony stimulating factor) supports survival, clonal expansion and differentiation of hematopoietic progenitor cells. CSF-1R plays a key role in the differentiation, recruitment and This article is protected by copyright. All rights reserved. activation of tissue-associated macrophages, which has been associated with survival in classic Hodgkin's lymphoma and other lymphoma types. 64 Axatilimab (SNDX-6352), a high-affinity antibody targeting CSF-1R, is being evaluated in a randomized, double-blind, placebo-controlled, 29-day study to assess its efficacy and safety in patients with respiratory signs and symptoms secondary to COVID-19 after IV dosing on Days 1 and 15. It also is being evaluated in patients with intrahepatic cholangiocarcinoma at the same dosing route and frequency as in COVID-19 patients. CD24 is an innate checkpoint against the inflammatory response to tissue injuries or dangerassociated molecular patterns. 65 CD24Fc, a fusion protein that regulates host inflammatory response to tissue injuries, is in the Phase 2/3 clinical development stage. A single dose of CD24Fc 480 mg IV is being evaluated in hospitalized subjects with severe COVID-19. Ang2 (angiopoietin 2) levels were increased in ARDS patients. 66 LY3127804, an investigational selective monoclonal antibody against Ang2, is being evaluated in pneumonia patients hospitalized with COVID-19 who are at a higher risk of progressing to ARDS. In this trial, LY3127804 is given IV, same dosing route as in the study of CTGF (connective tissue growth factor) is involved in fibrotic and proliferative diseases and may promote vascular leakage and lead to pulmonary edema. 69 Pamrevlumab, an anti-CTGF monoclonal antibody, may mitigate or reverse this edema, and thus improve oxygenation in patients with COVID-19-induced pneumonia. It is being evaluated hospitalized patients with acute COVID-19 disease at a dosing regimen of 35 mg/kg IV on Days 1, 7, 14 and 28. The levels of LIGHT, a cytokine in the TNF superfamily that can drive inflammation and induce many other cytokines, have been shown to be elevated in COVID-19-infected patients. 70 The efficacy and safety of CERC-002 is being studied in patients with severe COVID-19 over a 28-day period as a single dose on top of standard of care at 16 mg/kg SC to a maximum dose of 1200 mg. VEGF(vascular endothelial growth factor) plays an essential role in vascular endothelial homeostasis and endothelial cell activation. 71 Significantly higher VEGF concentrations were observed in COVID-19 patients than in healthy controls, and it was shown as one important indicator related to the severity of COVID-19. 72 Bevacizumab, an anti-VEGF monoclonal antibody, is being evaluated in hospitalized COVID-19 patients at the dose level consistent with the approved doses in oncology indications for bevacizumab. The kallikrein-kinin system is a zymogen system that is known to lead to the release of the nonapeptide bradykinin after activation. Binding of bradykinin to the B2R on endothelial cells can lead to capillary leakage which causes angioedema. 73 Van de Veerdonk proposed that kallikrein-kinin blockade may have the potential to prevent ARDS in patients with COVID-19. Lanadelumab, a human monoclonal antibody targeting plasma kallikrein, was approved to prevent angioedema in patients with hereditary angioedema. It is being repurposed to evaluate its safety, PK and PD in adults hospitalized with COVID-19 pneumonia at a dose level consistent with the approved one. In general, a master protocol is designed to evaluate more than one investigational drug at a time, enabling comparison of individual drug candidates to a single control group. Few platform trials are ongoing as referenced on clinicaltrials.gov. For example, trial NCT02735707 is evaluating the effect of a range of interventions for improving outcomes of patients admitted to ICU with communityacquired pneumonia. 78 The trial has implemented a sub-platform to assess multiple interventions or treatments for COVID-19. NCT04354428 is another randomized platform trial with four drugs planned in the protocol for severe SARS-CoV-2 infection in high-risk adults not requiring hospital admission. 79 Additional information on these trials is available at clinicaltrials.gov. The treatment goal of immunomodulatory therapeutic proteins in hyperinflammation management of COVID-19, as with most clinical therapeutics, is to achieve the desired benefit with minimal adverse effects. The contribution of clinical pharmacology to benefit/risk assessment largely resides in dosing regimen selection through the assessment of pharmacology, PK, PD and intrinsic and This article is protected by copyright. All rights reserved. extrinsic factors ( Route of administration: As described before, the immunomodulatory therapeutic proteins currently in clinical trials for the treatment of COVID-19 mostly are directed towards patients with moderate and severe stages of the disease. Given the acute severity of the disease, 84 especially in the advanced disease stage, rapid onset of drug action is necessary to neutralize the elevated cytokines and rebalance the immune response. IV dosing has the advantage of providing rapid onset of maximum concentration, which often is achieved at the end of the infusion, just minutes to a few hours following treatment initiation. On the other hand, the maximum concentration after SC dosing often is reached after a few days to a week, and the peak drug level often is significantly less than that after IV dosing. In this regard, SC dosing may not provide an advantage. Some researchers have hypothesized that COVID-19 patients also may benefit from certain therapeutic protein treatment earlier in the disease course -prior to progressing to severe respiratory decompensation -through early cytokine inhibition, thus preventing disease progression to the severe or critical stages. As such, SC dosing likely fits in this scenario, as a week or so may be needed for the biologic to reach the maximum concentration. Although this hypothesis appears plausible, the timing chosen should not compromise a patient's innate immune response, which is necessary for fighting off the virus and avoid the risk of infection. 85 This article is protected by copyright. All rights reserved. Comorbidity: The presence of underlying comorbidities is one important risk factor for SARS-CoV-2 infection and the fatality rate of patients with comorbidities was reported to be much higher than that of patients without comorbidities. 86 Treatment decisions related to these comorbidities are further complicated with the potential risks of clinical therapies for COVID-19, such as those posed by immunomodulatory therapeutic proteins for autoimmune diseases. It is well known that immunomodulatory therapeutic proteins are associated with increased risk of serious bacterial or opportunistic infection; however, information on their association with the risk of viral infection is limited. Nevertheless, in various academic societies, concern about the potential increased risks of immunomodulatory biological therapies for COVID-19 remains. The American College of Rheumatology recommended temporarily holding or stopping all non-IL-6 biologics in the context of documented or presumptive COVID-19, as well as in COVID-19 following known SARS-CoV-2 exposure. 87 Similarly, the American Academy of Dermatology recommended that patients discontinue or postpone biologic therapy until they recover from COVID-19. 88 The Academy also recommended benefit-risk assessment for patients currently considered candidates for biologic therapy. This highlights the importance of the treatment window in biologic therapies for COVID-19. These recommendations, however, have been debated. Data from a U.S. biologics registry showed that the rates of severe COVID-19 or complications were lower in patients prescribed ustekinumab, and that there appeared to be little difference in mild cases between patients prescribed IL-17 and IL-23 antagonists and those in corresponding placebo groups. 89, 90 As with other diseases, treatment interruption may have a profound impact as well. The treatment decision recommendation balances benefits and risks of ongoing cancer therapy during the COVID-19 pandemic. 91 Collectively, although no general rule on the treatment decision recommendation exists, caution should be taken, and the impact of treatment interruption should be evaluated carefully. In this situation, modeling and simulation could potentially be useful, as it considers such factors as covariates and facilitates decision-making. 92 Critically ill COVID-19 patients are likely to be susceptible to secondary infections and may have an increased risk of comorbid chronic infections, such as hepatitis B and tuberculosis. 93, 94 In these cases, the treatment goal is to prevent or attenuate life-threatening inflammation while minimizing the potential for secondary infection. 95 For this reason, immunomodulatory treatments should be used cautiously. The use of prophylactic antibiotics may be indicated, and bacteriologic and fungal assessments are of great importance. As discussed above, many therapeutic biologics already approved for other applications are being Pediatrics: Most COVID-19 patients have been adults. Although some children and infants have been infected with COVID-19, they generally experience mild, cold-like symptoms, such as fever, runny nose and cough. 96 However, severe outcomes have been reported in infants under one year, and children with underlying medical conditions such as chronic lung disease, moderate to severe asthma, serious heart conditions or weak immune systems might be at higher risk of serious illness from COVID-19 than are other children. 22 The Centers for Disease Control and Prevention (CDC) and its partners also are investigating reports of multisystem inflammatory syndrome in children which is associated with COVID-19 and includes features similar to those of Kawasaki disease. 97, 98, 99, 100, 101 Some ongoing clinical trials investigating immunotherapies in pediatric patients are registered in clinicaltrials.gov, and off-label use of biologics in pediatric patients has been reported. 102 The clinical management of COVID-19 complications with immunomodulatory therapeutic proteins in pediatric patients often takes body weight into consideration, since weight-based dosing regimens generally are used in these patients. It is noteworthy that as immunomodulatory therapeutic proteins often are used in many patients with more severe forms of asthma or allergies, concern exists that the treatments may compromise these patients' immune systems. Regarding treatment of severe allergic diseases with therapeutic proteins, a recent expert opinion article published by the European Academy of Allergy and Clinical Immunology suggested continuing them in otherwise healthy patients during the COVID-19 pandemic, but pausing until recovery in SARS -CoV-2-positive patients. 103 This article is protected by copyright. All rights reserved. Geriatric: According to CDC, the risk for severe illness from COVID-19 increases with age; the greatest risk for severe illness is among those aged 85 or older. 104 can be used to simulate exposures and predict relevant doses in pregnant women. 108, 109 Concomitant medications: In clinical trials, the treatment strategy for COVID-19 often combines an investigational drug with the standard of care (e.g., acetaminophen for fever reduction). Investigators manage patient care with supportive therapies as clinically indicated and per local standard practice. A theoretical concern exists regarding the potential modulation of CYP enzyme expression by cytokine level in COVID-19. The expression level of CYP450 enzymes has been shown to be suppressed by increased levels of cytokines (e.g., IL-6) in some chronic diseases. 110 Therefore, for biologics that antagonize cytokine activity, such as tocilizumab, it is expected that the expression of CYP450 enzymes could be increased to normal levels. Accordingly, RA patients treated with tocilizumab may exhibit restoration of CYP450 activities to higher levels than those in patients not COVID-19 is indicated to be associated with damages to lungs, heart, brain, kidneys and other organs. 111, 112 Elevated serum cytokine levels have been suspected to be associated with these organ damages. 113 As such, multiple immunomodulatory therapeutic proteins are being investigated in COVID-19 patients with multi-organ impairment. In this situation, biodistribution of therapeutic proteins to tissues likely is needed for neutralization of cytokines or their downstream effect. Extravascular distribution for therapeutic proteins is generally limited due to large molecular size. This article is protected by copyright. All rights reserved. However, it is unknown whether tissue distribution changes in COVID-19 patients with organ impairment due to the damage/impairment of the vascular endothelial system. Hepatic and renal damage have been reported to be associated with SARS-CoV-2 infection. Alan Kliger reported that 14% to 30% of COVID-19 patients in New York, NY and Wuhan, China ICUs lost renal function and later required dialysis. 114 This article is protected by copyright. All rights reserved. in China, CRP levels decreased significantly and returned to normal in 84.2% of patients (16 of 19) following tocilizumab treatment. 22 CRP also is being explored for the potential of a simple CRP measurement to inform decision making for which patients are to be hospitalized due to risk of developing more severe affection. 118 Immunogenicity Furthermore, the use of real-world data sources for surveillance and adverse event reporting systems around the world presents an opportunity for clinical pharmacologists to study the relationships between dose and reported outcomes of potential therapies. Using real-world data sources that are fit-for-purpose may contribute to our understanding of disease risk factors and identification potential treatment options. This article is protected by copyright. All rights reserved. We still are in the midst of this pandemic, and it is a rapidly evolving situation. Clinical trials assessing the safe and effective use of these immunomodulatory therapeutic proteins in the management of ARDS and CRS in COVID-19 are ongoing. The safe and effective use of these products in the management of ARDS and CRS in COVID-19 remains to be proven. As clinical pharmacologists, we are facing the prospect of an unprecedented timeline for COVID-19 drug development; namely, optimizing dose and dosing regimens for repurposed drug products to be evaluated in clinical trials. 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