Cresswell Advisors David Allan Advisory

An Essential COVID-19 Primer           Q1 2021
 - Expectations and realities                                        

Updated as @2021-08-15

“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 a year 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 221 countries, provoked over 207.7 million identified cases and 4,371,455 confirmed deaths by August 15th, 2021 of which the single largest number of 637,439 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).

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.

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).

 

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).

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).

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. 

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. 

Eli Lilly’s recombinant human IgG1 monoclonal antibody, bamlanivimab, 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).

 

The EUA is 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).

 

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).

 

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.

  • Ineffectiveness of antivirals alone in 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).

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.

 

It has become more evident from the results of numerous clinical trials, compassionate-use protocols, and now from the WHO SOLIDARITY report from October 16th 2020 describing the ineffectiveness of antivirals in hospitalized COVID-19 patients, 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.

 

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 has sought to repurpose approved drugs, or those being tested for other conditions, to 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.

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 August 15th, 2021

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.

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