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Cresswell Advisors David Allan Advisory

Cresswell Advisors

An Essential COVID-19 Primer           Q1 2022
 - Expectations and realities                                        

Updated as @2022-04-9

“Dans les champs de l’observation le hasard ne favorise que les esprits préparés”
(In the field of observation, chance favours only the prepared mind)

Louis Pasteur  

Inaugural Address as newly appointed Professor and Dean at the opening of the new Faculté des Sciences at Lille (7 Dec 1854)

Current status of the COVID-19 pandemic

More than two years after its announced emergence in Wuhan, China, the coronavirus disease 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, remains alarmingly contagious, resulting in an important number of hospitalizations for Acute Respiratory Distress Syndrome (ARDS), generalized coagulopathy and, critically and largely and incomprehensibly underappreciated, severe multiorgan failure (1). COVID-19 was belatedly recognized as a Global Pandemic by WHO (2), had reached 224 countries, provoked over 411.3 million identified cases and 5,831,008 confirmed deaths by January 13, 2022, of which the single largest number of 942,944 being in the USA (3).

 

The implementation of preventive measures, and regulations to limit the contagion and the spread of the disease globally, have been insufficient (5,6) and prompted an unprecedented global mobilization of research and other experimental measures to actively control the epidemic. This, either by the standardization of protocols for supporting treatment, repurposing of therapies in use for other diseases (infectious or not), design of new antiviral molecules, battling the immunological storm caused by the virus, or attempting to transfer immunity from convalescent patients. In parallel, major initiatives are involved in an accelerated search for vaccine candidates.

 

Epidemiologic data suggest that the contagion principally occurs through airborne spread from person to person via droplets expelled from infected individuals coughing, and through aerosolization from exhaling and vocalization, or contact with infected surfaces (1,4). Notwithstanding the political and media hype regarding expectations for the current rollout of vaccines, or subsequently approved ones, completely resolving the viral challenge (43), such a resolution is unlikely. This virus is expected to be both ubiquitous and latent; vaccines, as well-established with influenza, have variable efficacy and require reengineering as the virus mutates (44).  There are antecedents with previous vaccines designed to protect elderly populations where the efficacy has been marginal or almost non-existent in ages over 75 years (46).

The race for an effective vaccine against COVID-19 is principally reliant on the success of messenger RNA (mRNA) or adenoviral vector-based technologies. Other candidates include inactivated vaccines or vectors (67). Four vaccines are already approved as an Emergency Use Authorization (EUA) in North America: Pfizer-Biontech’s mRNA vaccine, and Moderna’s similar candidate (68,69), have been approved by US FDA and Health Canada. Oxford-AstraZeneca’s adenoviral-based product, currently approved in the European Union, UK, and a dozen other nations, is still under review by FDA, but was recently approved by Health Canada (70,71,74). Janssen’s (Johnson & Johnson) adenoviral-based vaccine has been approved as EUA by US FDA and Health Canada on February 27th and March 5th respectively (74,75). We remain cautious on not exceeding the expectation for a rapid and ubiquitous vaccine solution and for the purpose of this report, we substantiate our position that therapeutics will command a permanent place in the remedial process.  

 

Here we describe the current status of treatment options for COVID-19, which options may raise readers’ concerns about a great deal that is not yet known regarding delayed multi-organ failure. We anticipate that, during 2021, much of the delayed impact on the vascular system and lung function will become evident, and particularly in patients treated with antivirals alone. Antivirals alone are already reported (1) to risk increasing morbidity and mortality, notwithstanding that molecules to counteract such risks are available, as we describe below.    

Standard of Care for Clinical Management of COVID-19

While most people with COVID-19 develop only mild (40%) or moderate (40%) disease, approximately 15% develop severe disease that requires oxygen support, and 5% have critical disease with complications such as respiratory failure, ARDS, sepsis and septic shock, thromboembolism, and/or multiorgan failure, including acute kidney injury and cardiac injury (7). Older age, smoking (8), and underlying noncommunicable diseases, such as diabetes, hypertension, cardiac disease, chronic lung disease, and cancer, have been reported as risk factors for severe disease and death, and these conditions are then required to be carefully monitored and controlled during hospitalization (9,10).

 

The standard of care for the clinical management of COVID-19 cases, as per WHO and the National Guidelines adopted by numerous countries, focuses on supportive care and sustaining the respiratory function, whilst introducing other therapeutic processes: repurposing antiviral drugs or other compounds, immunomodulators, anti-inflammatories and even certain natural remedies (1,11-14).

 

Over 75% of patients hospitalized with COVID-19 require supplemental oxygen therapy in a non-invasive or invasive process depending upon their clinical status. Prone positioning, a higher positive end-expiratory pressure, or neuromuscular blockade (1,14), may assist the patient’s impaired physiology.

 

A relatively high percentage of patients with ARDS are treated with broad spectrum antibiotics, even when bacterial or fungal infections are not confirmed, notwithstanding that WHO Guidelines discourage such use, except in the evidence of bacterial infection or in those immunologically compromised (11), since that  results in higher bacterial resistance rates. That resistance then impacts the morbidity and mortality both during the COVID-19 pandemic and beyond.

  • Targeting the virus

The most extensively-tested antivirals in COVID-19 are remdesivir (Gilead Sciences - USA) and favipiravir (Toyama Chemical – Japan, in clinical development in the USA and Canada by Appili Therapeutics).  Since October 22, 2020, Remdesivir is the first FDA-approved treatment for use in adult and pediatric patients 12 years of age and older, requiring hospitalization (61).

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Remdesivir has shown in vitro antiviral activity against the causative agents of SARS, MERS and Ebola and has been administered under clinical trial protocols during outbreaks of the latter and SARS-CoV-2 (15).  Results of a Phase III trial, published on October 9, 2020 (16), demonstrated superiority of remdesivir over placebo in shortening the time to recovery in adults hospitalized with COVID-19, and evidence of lower respiratory-tract infection. The death rate was also lower; but met no statistically-significant difference. The US Food and Drug Administration (FDA), had previously issued an Emergency Use Authorization (EUA) for use of remdesivir in COVID-19 patients hospitalized with severe symptoms, based on preliminary results of this study, and the early results of another Phase III trial (17), which was updated in August 2020 for the use on all hospitalized patients, even those without severe symptoms (18). FDA issued also an EUA for the use of remdesivir in combination with Eli Lilly’s JAK inhibitor baricitinib (73).

 

Besides these results, other Phase III clinical studies with remdesivir have been less encouraging, and statistically-significant differences on days-to-improvement of symptoms were not demonstrated (19,20). Remdesivir has not been approved by the FDA for any use, except under the EUA, and the safety and efficacy of remdesivir for the treatment of COVID-19 are not yet established (57).  Accordingly, remdesivir in our opinion, remains far from label approval.

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Favipiravir (Avigan) is approved in China and Japan for the treatment of Influenza and has demonstrated in vitro activity against SARS-CoV-2(21). In North America, Appili Therapeutics is currently conducting a FDA-cleared Phase II trial with favipiravir tablets (48) as a first-line drug against COVID-19 to control outbreaks following exposure to the virus in long-term care facilities and a Phase III application has been made to the FDA for the conduct  of a study evaluating favipiravir in the early treatment outpatient setting for adult COVID-19 infections (53).

 

It is also an investigational drug in more than 70 clinical trials in various indications, from which 28 are registered in the ClinicalTrials.gov database; but of which only a few reports have been published. In a small trial comparing it to Lopinavir/Ritonavir in China, a shorter viral clearance time was reported for the favipiravir arm versus the control arm, as well as significant improvement in chest imaging (22). The study results have been criticized because of its methodological flaws and absence of randomization (23). Another randomized study demonstrated that favipiravir, compared to another antiviral, did not significantly improve the clinical recovery rate of COVID-19 patients at Day 7 (24).

 

In December 22, 2021, U.S. Food and Drug Administration issued a EUA for Pfizer’s Paxlovid tablets,  containing a combination of the antivirals nirmatrelvir tablets and ritonavir (77) for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

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Whilst nirmatrelvir inhibits a SARS-CoV-2 protein stopping the virus replication,  ritonavir acts slowing down the breakdown of the former, and prolongs its circulation at higher concentrations (78). Paxlovid is not authorized for use for longer than five consecutive days.

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The primary data supporting this EUA for Paxlovid are from EPIC-HR, a randomized, double-blind, placebo-controlled clinical trial studying Paxlovid for the treatment of non-hospitalized symptomatic adults with a laboratory confirmed diagnosis of SARS-CoV-2 infection (79). Patients were adults 18 years of age and older with a prespecified risk factor for progression to severe disease or were 60 years and older regardless of prespecified chronic medical conditions. All patients had not received a COVID-19 vaccine and had not been previously infected with COVID-19. The main outcome measured in the trial was the proportion of people who were hospitalized due to COVID-19 or died due to any cause during 28 days of follow-up. Paxlovid significantly reduced the proportion of people with COVID-19 related hospitalization or death from any cause by 88% compared to placebo among patients treated within five days of symptom onset and who did not receive COVID-19 therapeutic monoclonal antibody treatment. The safety and effectiveness of Paxlovid for the treatment of COVID-19 continue to be evaluated(80).

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Hydroxychloroquine (HCQ) and Chloroquine (CQ), two drugs that had been extensively used to treat malaria and other autoimmune diseases, such as rheumatoid arthritis and lupus, were also identified as potential drug candidates due to their reported antiviral effect (25). Both HCQ and CQ interfere with the glycosylation of Angiotensin Converting Enzyme-2 (ACE2) receptor, a receptor that is essential for the viral entry to the host cell. Also, HCQ/CQ are immunomodulatory agents that reduce pro-inflammatory cytokines importantly involved in the pathogenesis of the complications (26).  

 

More than 200 clinical trials of HCQ/CQ were initiated; but early data from trials in hospitalized patients with COVID-19 have not demonstrated clear benefit (1). Two retrospective studies found no effect on risk of intubation or mortality among hospitalized patients (1,27). As adverse effects of these two drugs are common, most notably QT interval prolongation indicating an increased risk of cardiac complications in vulnerable populations, this rapidly caused the FDA to revoke a previously-issued EUA (28). Controversy about its benefit continues although some trials are still ongoing. 

 

Azithromycin is an antibiotic commonly used to treat bacterial respiratory infections. It has been shown to be effective in vitro against viruses such as Zika and rhinovirus, in addition to SARS- CoV-2, and to have antiviral effects in bronchial epithelial cells (29).  Azithromycin has also been shown to be immunomodulatory (30).

 

The results of the concluded COALITION II clinical trial corroborated that azithromycin might not provide benefit to patients once the disease has progressed to the point that patients require hospitalization. Separately, results of a randomized clinical trial on the effects of Azithromycin in outpatients with SARS-CoV-2 released on July 2021 indicated that treatment with a single dose of oral azithromycin compared with placebo did not result in a greater likelihood of being free of symptoms at day 14 (76).

 
Because azithromycin is currently the most commonly-prescribed outpatient therapy for COVID-19, establishing whether it is helpful earlier in the disease course is an important research priority because, if this antibiotic has no role in the treatment of COVID-19, avoiding its use would reduce unnecessary antibiotic consumption and the consequent emergence of bacterial resistance (30).

 

Antiviral molecules that have been previously approved or researched for several viral infections, such as influenza, HIV, Ebola, yellow fever, Zika, Marburg, and others, have also been included in therapeutic emergency protocols or investigator-sponsored trials. The list includes oseltamivir (Tamiflu), Lopinavir/Ritonavir (Kaletra), umifenovir (Arbidol), galidesivir (31). Although some still continue in trials, not one has emerged as an effective tool to significantly reduce the associated symptomatology or complications.

 

Similarly, some other pharmacological compounds in use to treat inflammatory diseases or parasitic infections such as dexamethasone, approved to treat COVID-19 in the UK and Japan (72), colchicine or ivermectin, are currently in ongoing clinical trials (1).

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Monoclonal antibodies. Regeneron Pharmaceuticals’ cocktail of human monoclonal antibodies (mAbs) targeting the spike protein of SARS-Cov-2 (54) is a mixture consisting of a human antibody cloned from a patient’s B lymphocyte and a humanized antibody genetically engineered in mouse cells. Preclinical experiments in primates intentionally infected with SARS-Cov-2 demonstrated that the cocktail could reduce the viral levels and the pathology changes caused by the virus (55).

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Regeneron has announced that it reduced viral load and time-to-alleviation of symptoms in non-hospitalized patients with COVID-19 and that it “rapidly reduced viral load through Day 7" in prior-to-inclusion seronegative patients. The reduction was greater than in patients in the control arm, although the difference was not statistically significant. The drug was well tolerated and few adverse events recorded (56). This drug could become a therapeutic option for individuals seronegative to the virus at the moment of diagnosis, who are reported as bearing high viral load and a slow rate for viral clearance in absence of treatment. 

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On November 21, 2020, US FDA issued an EUA for Regeneron’s mAb cocktail for mild to moderate COVID-19 in adults, pediatric patients who are at high risk for progressing to severe COVID-19, and those 65 years of age or older or who have certain chronic medical conditions (65). Patients hospitalized due to COVID-19 requiring high flow oxygen and mechanical ventilation have not yet been shown to benefit, and there is concern that mAbs may be associated with worse clinical outcomes in those patients. The safety and efficacy of this investigational therapy in COVID-19 continues to be evaluated. 

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Eli Lilly’s two recombinant human IgG1 monoclonal antibodies against the surface spike protein of SARS-COV-2, bamlanivimab and etesevimab, obtained Emergency Use Authorization from the FDA and Health Canada on November 9 and 20, 2020 respectively for the treatment of mild to moderate COVID-19 infection in patients over 12 years old, at high risk for progressing to severe COVID-19 and/or hospitalization (62,66).

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The EUA was based on data from BLAZE-1, a randomized, double-blind, placebo-controlled Phase 2 study in patients with recently diagnosed, mild-to-moderate COVID-19 in the outpatient setting and explicitly excludes hospitalized patients or patients requiring assisted respiration. Patients treated with bamlanivimab showed reduced viral load, rates of symptoms, and hospitalization. Adverse events in the treated and control groups were similar (63).

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Bamlanivimab is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially treating COVID-19. The IgG1 antibody was discovered by the Canadian company AbCellera from a blood sample taken from one of the first U.S. patients who recovered from COVID-19 (64) and Etesevimab was licesned from Junshi Biosciences (81).

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In light of the most recent information and data available, in January 24, 2022  the FDA revised the authorizations for these two monoclonal antibody treatments – bamlanivimab/etesevimab (administered together) and REGEN-COV  – to limit their use to only when the patient is likely to have been infected with or exposed to a variant that is susceptible to these treatments (82). 

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The decision was based on data showing that  these treatments are highly unlikely to be active against the omicron variant, which started to circulate at a very high frequency throughout the United States from November 22, 2021 (83) and just a month later was became prevalent over the Delta variant (84). In consequence, according to the previously cited statement from CDC, these treatments are not currently authorized for use in any U.S. states, territories, and jurisdictions. In the future, if patients in certain geographic regions are likely to be infected or exposed to a variant that is susceptible to these treatments, then use of these treatments may be authorized in these regions (82).  

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Most recently, FDA issued an EUA for a new monoclonal antibody for the treatment of COVID-19 that retains activity against the omicron variant (85). The EUA for Eli Lilly's bebtelovimab (86) is for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms), with a positive COVID-19 test, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by the FDA are not accessible or clinically appropriate. 

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However, bebtelovimab is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19, because so far this treatment  has not been studied in patients hospitalized due to COVID-19, and, as it happens with other monoclonal antibodies, this treatment could be associated with worse clinical outcomes if administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation (85). 

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GSK’s sotrovimab is an Fc-engineered human monoclonal antibody that contains the LS modification to enhance half-life and respiratory mucosal delivery (87). In contrast to other monoclonal antibodies, sotrovimab targets a highly conserved epitope in the SARS-CoV-2 spike protein at a region that does not compete with binding of the angiotensin-converting enzyme (88). In addition to neutralizing SARS-CoV-2, sotrovimab had demonstrated effector functions in vitro that may contribute to immune-mediated viral clearance and some data suggested that sotrovimab may prevent cell-cell fusion (ie, syncytia formation) unlike other antibodies that target the receptor-binding domain.
In a study among nonhospitalized patients with mild to moderate COVID-19 and at risk of disease progression, a single intravenous dose of sotrovimab, compared with placebo, significantly reduced the risk of a composite end point of all-cause hospitalization or death through day 29. The findings supported sotrovimab as a treatment option for nonhospitalized, high-risk patients with mild to moderate COVID-19 (89).

FDA issued a EUA in March 2022, for sotrovimab. However, in consideration of the unlikely effectiveness on the recently emerged omicron BA.2 subunit variant, this authorization was suspended on April 5th, the same year. (90)

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Convalescent plasma, obtained from individuals recently recovered from SARS-Cov-2, is expected to contain high levels of polyclonal antibodies directed against the virus. There has been evidence suggesting a mortality benefit when administered for several acute respiratory infections, and in rabies, and Ebola infections (32).

 

However, the clinical experience, so far, with COVID-19 provides very low-quality evidence to support inferences regarding the benefit of convalescent plasma to patients with COVID-19 and the matter is still in debate (32). Although the FDA approved the use of convalescent plasma for COVID-19, in March 2020, as an emergency investigational new drug (33), this did not constitute an endorsement for efficacy; but a resource in cases in which no other therapeutic options, or access to a clinical trial, were available.

  • Impact of other antivirals on hospitalized patients with COVID-19
              The WHO SOLIDARITY trial consortium 

On October 15, 2020 (60), the WHO SOLIDARITY consortium reported interim mortality results from a large (11,266 subjects), multi-country, open-label, randomized trial on hospitalized patients. The study had been recommended by the WHO COVID-19 Research Forum with the purpose of evaluating four repurposed antiviral drugs purported to have at least a moderate effect on mortality: remdesivir, hydroxychloroquine, Lopinavir, and interferon-β1a (58).

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The trial was initiated in March 2020(59). The study protocol was adaptive and the unpromising drugs, hydroxychloroquine and Lopinavir, were dropped. The SOLIDARITY consortium concluded that none of remdesivir, hydroxychloroquine, Lopinavir or interferon regimens reported other than marginal or no effect in hospitalized COVID-19 patients on overall mortality, initiation of ventilation, or duration of hospital stay, and the mortality findings with Remdesivir and interferon, were consistent with meta-analyses of mortality in all major trials (60).

  • Battling the immunological storm

Alternative therapeutic strategies include modulating the overwhelming inflammatory response that follows the viral infection. These include monoclonal antibodies directed against key inflammatory mediators, interferons gamma and alpha, interleukins 1-6, and complement factor 5a (1).

 

When SARS-CoV-2 infects the respiratory tract, it causes a respiratory syndrome with consequent release of cytokines such as  interleukin IL-1 and IL-6, that are mediators of further lung inflammation, fever, and fibrosis (34). More than 50 randomized, controlled trials of tocilizumab, sarilumab and siltuximab, singularly or in combination, in patients with severe COVID-19, have been initiated or are proposed to be conducted, in China, Western Europe, the USA, Russia, Malaysia, and Australia (35)

 

Suppression of these pro-inflammatory cytokines has been therapeutically beneficial in many inflammatory conditions, including viral infections. Considering their role in severe COVID-19, early identification of hyperinflammation and its management, using existing, approved therapies such as steroids and intravenous immunoglobulins plus selective cytokine inhibitors, may lead to reduce the mortality, and continue to be researched. However, safety can be a major deterrent for the use of these drugs alone or in combination, because of the risk of concomitant serious infections, multiorgan damage, and other adverse effects (34).

  • Damage control: Mitigating the hyperinflammation (Angiotensin 1-7, ACE2, and bradykinin inhibitors)

The pathophysiology of SARS-CoV-2 infection is unique and very complex. Early in the infection, SARS-CoV-2 targets nasal and bronchial epithelial cells and pneumocytes, where the viral structural spike(S) will bind to the ACE2 receptor (36). The binding of SARS-CoV-2 to the membrane-bound enzyme, ACE2, results in a decrease in enzymatic activity and subsequent reduction in the peptide angiotensin 1-7 (Ang1-7), the principal product of the action of ACE2 on angiotensin II (Ang II). This results in a loss of Ang1-7’s intrinsically-protective effects and an excess of Ang II.

 

The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems, and SARS-CoV-2 utilizes and interrupts this pathway directly (37). When Ang II accumulates in excess, this leads to pulmonary vasoconstriction, inflammation, and cytokine-induced organ damage secondary to increased membrane permeability and increased epithelial cell apoptosis (37). Ang1-7 depletion, and increase of bradykinin, occur simultaneously, causing more hyperinflammation, increase of vascular permeability, HAL disbalance, etc. (38).  

 

This furthers recognition that treatment of moderate or complicated cases must be supplemented with therapies that mitigate the impact of the events resulting principally from ACE2 downregulation.  We emphasize that ACE2 downregulation will occur even in the course of treatment with most of the antiviral compounds assayed to date in COVID-19, because those are designed to interfere with the viral replication inside the host cell, after the virus has already bound to the ACE2 receptor and caused its downregulation (39)

 

Both acute lung injury and the acute respiratory distress syndrome caused by the SARS-CoV-2 infection are accompanied by a cytokine storm and an overwhelming inflammatory response. Introducing Ang1-7 as imperative in protecting against lung inflammation and fibrosis inhibiting alveolar cell apoptosis, attenuating the endothelial cell activation and the loss of barrier function and edema, and limiting the synthesis of proinflammatory and profibrotic cytokines(40),  has more recently been espoused by numerous papers to prove highly-promising hypotheses (45) .

 

It has been observed in experimental models that restoring the depletion in ACE2 caused by the SARS-CoV-2 infection reduces the concentration of Ang II and leads to an increased generation of protective Ang 1-7 (37,41,45). Recombinant, soluble ACE2 trials to treat ARDS were conducted prior to the COVID-19 pandemic. In a 2017 study, an infusion of recombinant ACE2 resulted in the expected changes in RAAS biomarkers and was well tolerated in subjects with ARDS. (49) A Chinese Phase II study with human recombinant ACE2 in COVID-19 was registered in ClinicalTrials.gov in February 2020; but the study was withdrawn before enrolling any patient (50). 

 

Soluble ACE2 is still regarded as a potential attenuator of the lung injury, and could probably slow the virus entering the host cells, and spreading (51). However, its short life in vivo is a limitation to its efficacy. Notwithstanding the product being available from GlaxoSmithKline, and other sources, its clinical development as a COVID-19 therapeutic has not been continued. 

 

Constant Therapeutics (Boston, USA) is undertaking a clinical development program aimed to include its proprietary pharmaceutical formulation of Ang1-7, TXA127, as a complementary intervention in the management of both moderate and severe cases of COVID-19.  The first two single-center trials will be investigator led at Columbia University Irving Medical Center in New York City and Rambam Health Care Campus in Israel.  A third, multi-center trial, is currently under discussion between Constant and the National Heart Lung and Blood Institute (NHLBI), a division of the United States’ National Institute of Health (NIH). The trial at Columbia is currently recruiting patients, and the Israeli trial is expected to begin in October, while the NHLBI trial, with the agreement concluded, could initiate by year-end 2020 (42).

 

Successful clinical trial outcomes would corroborate the protective effect of restoring the RAAS disbalance caused by SARS-CoV-2, lead to a reduction of inflammation, and improvement of the pulmonary symptoms in moderate to severe COVID-19 patients. This would, in turn, reduce the duration of hospitalization, need for ventilation, and mortality.

 

Not as widely discussed as angiotensin, the bradykinin (BK) system is another potent regulator of blood pressure that can be considered an essential   extension of the RAAS (38).  BK and RAAS are integrated because the ACE2 degrades and inactivates BK. As with the RAAS, the ACE2 downregulation will severely impair the BK system during COVID-19. It has been hypothesized that the inherent complications could be mitigated though interventions with blockers of the BK system that are currently in use for treating other conditions, if repurposed as a complementary treatment (38).

 

Disconcertingly, it must be noted that a number of those blockers have well-documented, serious adverse side-effect profiles, including androgenic side effects; risk of airway obstruction by laryngeal swelling attacks; risk of anaphylaxis, amongst others.

 

In marked contrast, Ang1-7 would compare favourably as a mediator that acts on the same system, RAAS, having the same potential for improvement of the complications, whilst showing an importantly-better safety record in the various studies in which it has been clinically tested. Propitiously, it offers the mediation of pulmonary manifestations and other generalized vascular disfunctions – all now becoming widely recognized.

 

Soluble ACE2, a recombinant protein requiring multiple IV dosing, together with its being a larger and more complex molecule than Ang1-7 (which is only a peptide), may lead to the occurrence of more adverse events (52). This further qualifies TXA127 as a preferable therapeutic candidate. 

Concluding remarks

The complex pathophysiology of the SARS-CoV-2 infection, and its subsequent clinical expression as COVID-19, has made the selection of therapeutics to effectively resolve the lung systemic damages, the extended hospitalization, and the high mortality rates, extremely uncertain.  We reiterate our concern about the widely-held expectations that vaccines will resolve the pandemic. Critically, the duration of immunization from the novel vaccines in development is unknown and may be temporary. Consequently, antivaxxers may still have an impact as the immunization wears off and, equally critically, the over-60 population will likely rely on therapeutic intervention rather than vaccine efficacy.

 

Some antivirals, alone or in combination (such the recently-approved for emergency use Paxlovid) can exert an effect decreasing the possibility of progression to severe disease; in non hospitalized patients. But at the same time, it has become more evident from the results of numerous clinical trials, compassionate-use protocols, and from the WHO SOLIDARITY that this may not necessarily occurs when the treatment is provided to already-hospitalized COVID-19 patients. We must consider that a disease mechanism of such complexity cannot be targeted solely by inhibiting or blocking the viral replication, and that it is clearly necessary to focus on the cascade of immunological and biochemical events unchained following the interaction of the virus with its primary host cells.

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There is increasing consensus in the scientific community that antivirals alone are insufficient to prevent the induced lung injury and the hyperinflammation (19,20), and that they may, conversely, increase morbidity and mortality. With this in mind, the medical and scientific community worldwide keeps testing drugs approved for other conditions,  in the search of repurposed treatments that can reduce the morbidity and mortality of COVID-19.

​

The RAAS is crucial to the homeostasis of both the cardiovascular and respiratory systems and SARS-CoV-2 utilizes and interrupts this pathway directly via the downregulation of ACE2. Many researchers have already realized the need to leverage this to mitigate indirect viral-induced lung injury secondary to the viral infection, which occurs even after attacking, or directly blocking the virus. Thus, compounds such as  Ang1-7, already in use for other diseases, and with a well-established safety profile and a potential for rapid regulatory approval, may importantly contribute to improve the existing standard of care in the near future. 

 

Incorporating a treatment such as TXA127 into the protocols of care for moderate and severe cases of COVID-19 could transform the disease from an international crisis to a manageable illness. Such a complementary therapy has a high prospect of reducing disease severity, acute and chronic morbidity, and mortality, and would also decrease the need for scarce hospital and ICU resources, taking pressure off the development timelines for vaccines and antivirals. It is crucial to corroborate this approach through rapidly advancing controlled clinical trials and securing rapid regulatory approval for its use.

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To develop treatments that act on the consequences of the infection rather than on the causative agent alone – the focus of many current approaches – is crucial, not only to face the challenges imposed by this pandemic, but in order to be prepared to manage other novel viruses predicted to emerge, which may have a similar pathogenesis, and against which no vaccine protection will be available.

Dr. Germán Rogés, MD.
Senior Scientist
Cresswell Advisors

David G. P. Allan
Principal
Cresswell Advisors

Updated April 9, 2022

DISCLAIMER: 

The Principal at Cresswell Advisors holds an investment in each of Appili Therapeutics, Constant Therapeutics , Gilead Sciences, and Regeneron Pharmaceuticals that may constitute a conflict of interest and a bias in the primer toward the attributes of those companies. Cresswell’s Senior Scientist holds no such investments.

The prospective advantage that these two companies’ approaches hold for Covid-19 patients that encouraged the Principal to invest, compel the sharing of these analyses with Society through this primer.

REFERENCES

  1. Wiersinga W. J; Rhodes A.; Cheng, A.C; Peacock, S.J.; Prescott, C. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19) A Review.  JAMA. doi:10.1001/jama.2020.12839. Published online July 10, 2020

  2. World Health Organization declares COVID-19 a ‘pandemic’. Here is what it means.
    March 11, 2020. https://time.com/5791661/who-coronavirus-pandemic-declaration/

  3. COVID-19 Coronavirus Pandemic. Worldometer.
    In: https://www.worldometers.info/coronavirus/

  4. Doremalen, N.V. et al. Aerosol and surface stability of HCov-19 (SARS-Cov-2) compared to SARS-Cov-1.  NEJM Original Article, first reprinted March 9 2020 in:

  5. Pan A, Liu L, Wang C, et al. Association of Public Health Interventions with the Epidemiology of the COVID-19 Outbreak in Wuhan, China. JAMA. 2020;323(19):1915–1923. doi:10.1001/jama.2020.6130

  6. Kolifarhood G, Aghaali M, Mozafar Saadati H, et al. Epidemiological and Clinical Aspects of COVID-19; a Narrative Review. Arch Acad Emerg Med. 2020;8(1):e41. Published 2020 Apr 1.

  7. Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. Vital surveillances: the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) – China. China CDC Weekly. 2020;2(8):113-22.

  8. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091. Epub 2020/03/29.

  9. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Epub 2020/01/28. 18.

  10. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. Epub 2020/03/15.

  11. World Health Organization. Clinical Management of COVID-19. Interim Guidance. 27 May 2020. WHO reference number: WHO/2019-nCoV/clinical/2020.5 Available at: https://www.who.int/publications/i/item/clinical-management-of-COVID-19

  12. NUS Saw Swee Hock School of Public Health. COVID019 Science Report: Therapeutics. DOI: 10.25540/qqrk-bp3cs

  13. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health website. Updated September 1, 2020.  https://www.COVID19treatmentguidelines.nih.gov/

  14. China is encouraging herbal remedies to treat COVID-19. But scientists warn against it.  In: NBC News, published April 5, 2020. https://www.nbcnews.com/news/world/china-encouraging-herbal-remedies-treat-COVID-19-scientists-warn-against-n1173041

  15. Pardo J, Shukla AM, Chamarthi G, Gupte A. The journey of remdesivir: from Ebola to COVID-19. Drugs Context. 2020;9:2020-4-14. Published 2020 May 22. doi:10.7573/dic.2020-4-14

  16. Beigel et. al. Remdesivir for the Treatment of COVID-19 -Preliminary Report. NJEM May 22, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

  17. Food and Drug Administration Fact Sheet for Patients And Parents/Caregivers Emergency Use Authorization (EUA) Of Veklury® (remdesivir) For Coronavirus Disease 2019 (COVID-19).  https://www.fda.gov/media/137565/download

  18. FDA news release: COVID-19 Update: FDA Broadens Emergency Use Authorization for Veklury (remdesivir) to Include All Hospitalized Patients for Treatment of COVID-19 https://www.fda.gov/news-events/press-announcements/COVID-19-update-fda-broadens-emergency-use-authorization-veklury-remdesivir-include-all-hospitalized

  19. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. Published online August 21, 2020. doi:10.1001/jama.2020.16349

  20. Wang, Y et, al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. Vol. 395(10236) 1569-1578, May 16, 2020. https://doi.org/10.1016/S0140-6736(20)31022-9

  21. Shannon A, Selisko B, Le N, et al. Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase. Preprint. bioRxiv. 2020;2020.05.15.098731. Published 2020 May 15. doi:10.1101/2020.05.15.098731

  22. Quinxian Cai et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering, In Press, Available online from March 18, 2020. https://doi.org/10.1016/j.eng.2020.03.007

  23. Chachaima-Mar J, Pérez-Castilla J. Comment on: Favipiravir, an antiviral for COVID-19? [published online ahead of print, 2020 Sep 4]. J Antimicrob Chemother. 2020; dkaa378. doi:10.1093/jac/dkaa378

  24. Chang Chen, Yi Zhang, Jianying Huang, Ping Yin, Zhenshun Cheng, Jianyuan Wu, Song Chen, Yongxi Zhang, Bo Chen, Mengxin Lu, Yongwen Luo, Lingao Ju, Jingyi Zhang, Xinghuan Wang. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial medRxiv 2020.03.17.20037432; doi: https://doi.org/10.1101/2020.03.17.20037432

  25. Kumar R, Gupta N, Kodan P, Mittal A, Soneja M, Wig N. Battling COVID-19: using old weapons for a new enemy. Trop Dis Travel Med Vaccines. 2020;6:6. Published 2020 May 20. doi:10.1186/s40794-020-00107-1

  26. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;12:105938.

  27. Rosenberg, ES, Dufort EM, Udo T et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020 323(24): 2493-2502. https://doi:10.1001/jama/2020.8630

  28. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. July 1, 2020.  https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-COVID-19-outside-hospital-setting-or

  29. Oldenburg, C. Azithromycin for severe COVID-19. The Lancet. Published online September 4, 2020 https://doi.org/10.1016/S0140-6736(20)31863-8

  30. Rizk JG, Kalantar K, Mehra MR, Lavie CJ, Rizk Y, Forthal DN. Pharmaco-immunomodulatory therapy in COVID-19. Drugs 2020; published online July 21. https://doi.org/10.1007/s40265-020-01367-z.

  31. Şimşek Yavuz S, Ünal S. Antiviral treatment of COVID-19. Turk J Med Sci. 2020;50(SI-1):611-619. Published 2020 Apr 21. doi:10.3906/sag-2004-145

  32. Niveditha Devasenapathy, Zhikang Ye, Mark Loeb, Fang Fang, Borna Tadayon Najafabadi, Yingqi Xiao, Rachel Couban, Philippe Bégin, Gordon Guyatt. Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis. CMAJ Jul 2020, 192 (27) E745-E755; DOI: 10.1503/cmaj.200642

  33. Recommendations for investigational COVID-19 convalescent plasma. Silver Sprint (MD): US Food and Drug Administration; September 2, 2020. Available: www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption -ide-process-cber/investigational-COVID-19-convalescent-plasma-emergency -inds

  34. Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020 doi: 10.23812/CONTI-E

  35. Atal S, Fatima Z. IL-6 Inhibitors in the Treatment of Serious COVID-19: A Promising Therapy? Pharmaceut Med. 2020;34(4):223-231. doi:10.1007/s40290-020-00342-z

  36. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280. doi:10.1016/j.cell.2020.02.052

  37. Ingraham NE, Barakat AG, Reilkoff R, et al. Understanding the Renin-Angiotensin-Aldosterone-SARS-CoV-Axis: A Comprehensive Review. Eur Respir J 2020; in press (https://doi.org/10.1183/13993003.00912-2020).

  38. Garvin M, Alvarez C , Miller I ,et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020; 9: e59177. DOI:https://doi.org/10.7554/eLife.59177

  39. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS: Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020, 46(4):586-590.

  40. Peiró C, Moncada S. Substituting Angiotensin-(1-7) to Prevent Lung Damage in
    SARS-CoV-2. Infection?  Circulation. 2020;141 (21):1665-1666.

  41. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11:875–879. doi:10.1038/nm1267

  42. Constant Therapeutics. Personal communication. October 2020

  43. Coronavirus vaccine: What's happening now and everything you need to know.   https://www.cnet.com/how-to/coronavirus-vaccine-whats-happening-now-and-everything-you-need-to-know/

  44. Thompson MG, Clippard J, Petrie JG, et al. Influenza Vaccine Effectiveness for Fully and Partially Vaccinated Children 6 Months to 8 Years Old During 2011-2012 and 2012-2013: The Importance of Two Priming Doses. Pediatr Infect Dis J. 2016;35(3):299-308. doi:10.1097/INF.0000000000001006

  45.  Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020 May 2;395(10234):1417-1418. doi: 10.1016/S0140-6736(20)30937-5. Epub 2020 Apr 21. PMID: 32325026; PMCID: PMC7172722.

  46. Haralambieva IH, Painter SD, Kennedy RB, Ovsyannikova IG, Lambert ND, Goergen KM, Oberg AL, Poland GA. The impact of immunosenescence on humoral immune response variation after influenza A/H1N1 vaccination in older subjects. PLoS One. 2015 Mar 27;10(3):e0122282. doi: 10.1371/journal.pone.0122282. PMID: 25816015; PMCID: PMC4376784.

  47. Cross, R. Adenoviral vectors are the new COVID-19 vaccine front-runners. Can they overcome their checkered past? Chemical and Engineering News. Vol 98, Issue 19. May 12,2020. https://cen.acs.org/magazine/98/09819.html

  48. FDA Clears Appili Therapeutics to Expand its Phase 2 Clinical Trial of Favipiravir for the Potential Prevention of COVID-19 at U.S. Long-Term Care Facilities.   https://www.appilitherapeutics.com/newsfeed/FDA-Clears-Appili-Therapeutics-to-Expand-its-Phase-2-Clinical-Trial-of-Favipiravir-for-the-Potential-Prevention-of-COVID-19-at-U.S.-Long-Term-Care-Facilities

  49. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, Hall R, Poirier G, Ronco JJ, Tidswell M, Hardes K, Powley WM, Wright TJ, Siederer SK, Fairman DA, Lipson DA, Bayliffe AI, Lazaar AL. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017 Sep 7;21(1):234. doi: 10.1186/s13054-017-1823-x.

  50. Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a treatment for patients with COVID-19. ClinicalTrials.gov Identifier: NCT04287686

  51. Pang X, Cui Y, Zhu Y. Recombinant human ACE2: potential therapeutics of SARS-CoV-2 infection and its complication. Acta Pharmacol Sin. 2020;41(9):1255-1257. doi:10.1038/s41401-020-0430-6

  52. Roshanravan N, Ghaffari S, Hedayati M. Angiotensin converting enzyme-2 as therapeutic target in COVID-19. Diabetes Metab Syndr. 2020;14(4):637-639. doi:10.1016/j.dsx.2020.05.022 

  53. Appili Submits Protocol for a Phase 3 Study Evaluating Favipiravir for the Treatment of Patients with COVID-19 Infections to the US FDA https://www.appilitherapeutics.com/newsfeed/Appili-Submits-Protocol-for-a-Phase-3-Study-Evaluating-Favipiravir-for-the-Treatment-of-Patients-with-COVID-19-Infections-to-the-US-FDA-

  54.  Baum, A et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies SCIENCE21 AUG 2020 : 1014-1018
    https://science.sciencemag.org/content/sci/suppl/2020/06/15/science.abd0831.DC1/abd0831_Baum_SM.pdf

  55. Baum, A et al. REGN-COV2 antibody cocktail prevents and treats SARS-CoV-2 infection in rhesus macaques and hamsters. bioRxiv preprint (not peer reviewed) August 3, 2020 https://doi.org/10.1101/2020.08.02.233320.

  56. Regeneron's REGN-COV2 antibody cocktail reduced viral levels and improved symptoms in non-hospitalized COVID-19 patients, September 29,2020. Company Press release. In:
    https://investor.regeneron.com/news-releases/news-release-details/regenerons-regn-cov2-antibody-cocktail-reduced-viral-levels-and

  57. U.S. Food and Drug Administration. Veklury (remdesivir) EUA Letter of Authorization, 10-01-2020. https://www.fda.gov/media/137564/download

  58. World Health Organization, R&D Blueprint. Informal consultation on prioritization of candidate therapeutic agents for use in novel coronavirus 2019 infection https://www.who.int/teams/blueprint/covid-19

  59. Trial of Treatments for COVID-19 in Hospitalized Adults (DisCoVery). ClinicalTrials.gov Identifier: NCT04287686

  60. Repurposed antiviral drugs for COVID-19 – interim WHO SOLIDARITY trial results. WHO SOLIDARITY trial results. WHO Solidarity Trial Consortium. Hongchao Pan, Richard Peto, Quarraisha Abdool Karim, Marissa Alejandria, Ana Maria Henao Restrepo, Cesar Hernandez Garcia, Marie Paule Kieny, Reza Malekzadeh,Srinivas Murthy,  John Arne Rottingen, Soumya Swaminathan (not peer review certified preprint) medRxiv 2020.10.15.20209817; doi: https://doi.org/10.1101/2020.10.15.20209817

  61. U.S. Food and Drug Administration. FDA Approves First Treatment for COVID-19. October 22, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19

  62. FDA News Release: Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibody for Treatment of COVID-19. November 9, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibody-treatment-covid-19

  63. Chen, P. et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. NEJM, October 28, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2029849

  64. Interim Data Reported for AbCellera-Discovered COVID-19 Antibody in Phase 2 Clinical Trials. https://www.abcellera.com/news/2020-09-16-interim-data-phase-2-clinical-trials

  65. Regulatory Decision Summary - Bamlanivimab - Health Canada. https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detailTwo.php?linkID=RDS00719

  66. Regulatory Decision Summary - Bamlanivimab - Health Canada. https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detailTwo.php?linkID=RDS00719

  67. Craven, J. COVID-19 vaccine tracker.  Regulatory Focus. New Articles, 2020,3. Posted December 10, 2020. https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker

  68. FDA News Release: FDA Takes Additional Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for Second COVID-19 Vaccine. December 18, 2020https://www.fda.gov/news-events/press-announcements/fda-takes-additional-action-fight-against-covid-19-issuing-emergency-use-authorization-second-covid

  69. Health Canada News Release: Health Canada authorizes MODERNA COVID-19 vaccine. December 23, 2020.
    https://www.canada.ca/en/health-canada/news/2020/12/health-canada-authorizes-moderna-covid-19-vaccine.html

  70. Medicines & Healthcare products Regulatory Agency (UK) Decision: Conditions of Authorisation for COVID-19 Vaccine AstraZeneca. https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca/conditions-of-authorisation-for-covid-19-vaccine-astrazeneca

  71. Treble. P. AstraZeneca is likely the next vaccine coming to Canada. What do we know about it? In: Maclean’s accessed February 2, 2021 https://www.macleans.ca/news/astrazeneca-is-likely-the-next-vaccine-coming-to-canada-what-do-we-know-about-it/

  72. Craven J. COVID-19 Therapeutics tracker. Regulatory Focus. New Articles 2020 (3)
    https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-therapeutics-tracker

  73. FDA. Letter of Authorization: EUA for baricitinib (Olumiant) in combination with remdesivir. November 19, 2020
    https://www.fda.gov/media/143822/download

  74. Government of Canada. Drug and vaccine authorizations for COVID-19: List of authorized drugs, vaccines and expanded indications. Accessed March 6th, 2021. https://www.canada.ca/en/health-canada/services/drugs-health-products/covid19-industry/drugs-vaccines-treatments/authorization/list-drugs.html

  75. FDA News Release: FDA Issues Emergency Use Authorization for Third Covid Vaccine. Feb 27, 2021. https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-third-covid-19-vaccine

  76. Oldenburg CE, Pinsky BA, Brogdon J, et al. Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA. 2021;326(6):490–498. doi:10.1001/jama.2021.11517

  77. FDA NEWS RELEASE: Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19, December 22, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19

  78. Mahase E. Covid-19: Pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ. 2021 Nov 8;375:n2713. doi: 10.1136/bmj.n2713. PMID: 34750163.

  79. EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Non-hospitalized High Risk Adults With COVID-19.  https://clinicaltrials.gov/ct2/show/NCT04960202

  80. Pfizer’s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death by 89% in Interim Analysis of Phase 2/3 EPIC-HR Study https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate

  81. Lilly's bamlanivimab (LY-CoV555) administered with etesevimab (LY-CoV016) receives FDA emergency use authorization for COVID-19" (Press release). Eli Lilly and Company. 9 February 2021. Retrieved 9 February 2021 – via PR Newswire.

  82. FDA STATEMENT: Coronavirus (COVID-19) Update: FDA Limits Use of Certain Monoclonal Antibodies to Treat COVID-19 Due to the Omicron Variant. January 24 2022.
    https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-limits-use-certain-monoclonal-antibodies-treat-covid-19-due-omicron

  83. US Department of Health and human Services. Center for Disease Control and Prevention. Media Statement: First Confirmed Case of Omicron Variant Detected in the United States. Released December 1, 2021.

  84. US Department of Health and human Services. Center for Disease Control and Prevention. Potential Rapid Increase of Omicron Variant Infections in the United States.
    Dec. 20, 2021. https://www.cdc.gov/coronavirus/2019-ncov/science/forecasting/mathematical-modeling-outbreak.html

  85. FDA NEWS RELEASE: Coronavirus (COVID-19) Update: FDA Authorizes New Monoclonal Antibody for Treatment of COVID-19 that Retains Activity Against Omicron Variant. February 11, 2022.
    https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-monoclonal-antibody-treatment-covid-19-retains

  86. Westendorf K, Wang L, Žentelis S, Foster D, Vaillancourt P, Wiggin M, Lovett E, van der Lee R, Hendle J, Pustilnik A, Sauder JM, Kraft L, Hwang Y, Siegel RW, Chen J, Heinz BA, Higgs RE, Kallewaard N, Jepson K, Goya R, Smith MA, Collins DW, Pellacani D, Xiang P, de Puyraimond V, Ricicova M, Devorkin L, Pritchard C, O'Neill A, Dalal K, Panwar P, Dhupar H, Garces FA, Cohen C, Dye J, Huie KE, Badger CV, Kobasa D, Audet J, Freitas JJ, Hassanali S, Hughes I, Munoz L, Palma HC, Ramamurthy B, Cross RW, Geisbert TW, Menacherry V, Lokugamage K, Borisevich V, Lanz I, Anderson L, Sipahimalani P, Corbett KS, Yang ES, Zhang Y, Shi W, Zhou T, Choe M, Misasi J, Kwong PD, Sullivan NJ, Graham BS, Fernandez TL, Hansen CL, Falconer E, Mascola JR, Jones BE, Barnhart BC. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. bioRxiv [Preprint]. 2022 Jan 7:2021.04.30.442182. doi: 10.1101/2021.04.30.442182. PMID: 33972947; PMCID: PMC8109210.

  87. Pinto  D, Park  YJ, Beltramello  M,  et al.  Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.   Nature. 2020;583(7815):290-295. doi:10.1038/s41586-020-2349

  88. Liu  H, Wei  P, Zhang  Q,  et al.  501Y.V2 and 501Y.V3 variants of SARS-CoV-2 lose binding to bamlanivimab in vitro.   MAbs. 2021;13(1):1919285. doi:10.1080/19420862.2021.1919285

  89. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Effect of Sotrovimab on Hospitalization or Death Among High-risk Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2022;327(13):1236–1246. doi:10.1001/jama.2022.2832

  90. FDA updates sotrovimab emergency use authorization. April 5th, 2022.  https://www.fda.gov/drugs/drug-safety-and-availability/

  91. ​

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