Published 20 January 2021
Let’s face it: after one year of intensive research, we have some steroids which have been shown to reduce mortality in patients with severe COVID-19 (see Corticosteroids, page 376); and we have one approved drug, remdesivir (Veklury®), which had a marginal benefit in a company-sponsored trial (Beigel 2020). There are also a few monoclonal antibodies, showing modest effects on viral load. And the JAK inhibitor baricitinib, in combination with remdesivir, in special patient populations. That’s the COVID-19 treatment armamentarium as of January 2021.
So, the next pages will discuss many drugs that have so far shown NO effect. So why read this chapter? Because doctors need to know the state-of-the-art – even the ‘state-of-the-non-art’. Doctors must know why substances have shown NO effect and why there may still be new, innovative and creative ideas; why the senior physician has been less enthusiastic about tocilizumab over the last few weeks and why the 89-year-old diabetic on Ward 1 still gets remdesivir and famotidine; and why the plasma therapy did not work in the 51-yr-old obese woman who died on Ward 2.
Hopefully, within a year or so, this chapter will be only ten pages. We only need one good drug (or, for that matter, five me-too-drugs). Only one drug that must not even be perfect but could become a game changer in this pandemic (perhaps even more so and even sooner than a vaccine) because it is good enough to prevent people from becoming seriously ill. One drug to downgrade SARS-CoV-2 to the rank of its stupid seasonal common cold siblings that nobody was really interested in in the last decades (except Christian Drosten, who would keep us all in lockdown indefinitely).
Research activity is immense. A brief look at ClinicalTrials.gov illustrates the efforts that are underway. On April 18, the platform listed 657 studies, with 284 recruiting, among them 121 in Phase III randomized clinical trials (RCTs). On October 14, these numbers increased to 3598, 1880 and 230. Unfortunately, many trials exclude those patients most in need: the elderly. A data query of ClinicalTrials.gov on June 8 revealed that 206/674 (31%) COVID-19 interventional trials had an upper age exclusion criterion. The median upper age exclusion was 75 years. Exclusion of older patients dramatically increases the risk of non-representative trial populations compared with their real-world counterparts (Abi Jaoude 2020).
Different therapeutic approaches are under evaluation: antiviral compounds that inhibit enzyme systems, those inhibiting the entry of SARS-CoV-2 into the cell and, finally, immune therapies, including convalescent plasma and monoclonal antibodies. Some immune modulators may enhance the immune system, others are supposed to reduce the cytokine storm and associated pulmonary damage that is seen in severe cases. In this chapter, we will discuss the most promising agents (those for which at least a bit of clinical data is available). We will not mention all compounds that may work in cell lines or that have been proposed from virtual screening models. We will also forget some.
On the following pages, the following agents will be discussed:
|1.||Inhibitors of viral RNA synthesis|
|RdRp Inhibitors||Remdesivir, favipiravir, sofosbuvir|
|2.||Other antiviral agents|
|Various||APN1, camostat, umifenovir Hydroxy/chloroquine|
|Monoclonal antibodies||Bamlanivimab, etesevimab, casiri-vimab/imdevimab and other mAbs|
|JAK inhibitors||Baricitinib, ruxolitinib|
|Cytokine blockers and anticomplement therapies||Anakinra, canakinumab, infliximab, mavrilimumab, tocilizumab, siltuximab, sarilumab, vilobelimab|
|5..||Various treatments (with unknown or unproven mechanisms of action)||Acalabrutinib, ibrutinib, colchicine, famotidine, G-CSF, iloprost|
Please enjoy reading the following pages. Most of the options are ineffective (in the end, page 388, we will make some brief recommendations).
SARS-CoV-2 is a single-stranded RNA betacoronavirus. Potential targets are some non-structural proteins such as protease, RNA-dependent RNA polymerase (RdRp) and helicase, as well as accessory proteins. Coronaviruses do not use reverse transcriptase. There is only a total of 82% genetic identity between SARS-CoV and SARS-CoV-2. However, the strikingly high genetic homology for one of the key enzymes, the RdRp which reaches around 96%, suggests that substances effective for SARS may also be effective for COVID-19.
Remdesivir (RDV) is a nucleotide analog and the prodrug of an adenosine C nucleoside which incorporates into nascent viral RNA chains, resulting in premature termination. It received an “Emergency Use Authorization” from the FDA in May and a so-called “conditional marketing” authorization from the EMA in July.
In vitro experiments have shown that remdesivir has broad anti-CoV activity by inhibiting RdRp in airway epithelial cell cultures, even at sub-micromolar concentrations. This RdRp inhibition works in rhesus macaques (Williamson 2020). The substance is very similar to tenofovir alafenamide, another nucleotide analogue used in HIV therapy. Remdesivir was originally developed by Gilead Sciences for the treatment of the Ebola virus but was subsequently abandoned, after disappointing results in a large randomized clinical trial (Mulangu 2019). Resistance to remdesivir in SARS was generated in cell culture but was difficult to select and seemingly impaired viral fitness and virulence. However, there is a case report describing the occurrence of a mutation in the RdRp (D484Y) gene following failure of remdesivir (Martinot 2020). Animal models suggest that a once-daily infusion of 10 mg/kg remdesivir may be sufficient for treatment; pharmacokinetic data for humans are still lacking.
Safety was shown in the Ebola trial. In the Phase III studies on COVID-19, an initial dose of 200 mg was started on day 1, similar to the Ebola studies, followed by 100 mg for another 4-9 days. The key trials are listed here:
- Compassionate Use Program: this was a fragmentary cohort (Grein 2020) on some patients (only 53/61 patients were analyzed) with varying disease severity. Some improved, some didn’t: random noise. We believe, for a number of reasons, that this case series published in the New England Journal of Medicine is a cautionary tale for “science in a hurry”, arousing false expectations. It might have been preferable to postpone the publication (Hoffmann 2020).
- NCT04257656: This multicentre RCT at ten hospitals in Hubei (Wang 2020) randomized a total of 237 patients with pneumonia, oxygen saturation of 94% or lower on room air and within 12 days of symptom onset to receive 10 days of single infusions or placebo. Clinical improvement was defined as the number of days to the point of a decline of two levels on a six-point clinical scale (from 1 = discharged to 6 = death). Patients were 65 years old (IQR 56–71), and many were co-treated with lopinavir (28%) and corticosteroids. The trial did not attain the predetermined sample size because the outbreak was brought under control in China. However, remdesivir was not associated with a difference in time to clinical improvement. Day 28 mortality was 14% versus 13%. Of note, the viral load decreased similarly in both groups. Some patients with remdesivir had dosing prematurely stopped due to adverse events (12% versus 5%, mainly gastrointestinal symptoms and increases of liver enzymes). The positive message from this trial is that time to recovery was “numerically” shorter in the remdesivir group, particularly in those treated within 10 days of symptom onset.
- SIMPLE 1: in this randomized, open-label RCT in 397 hospitalized patients with severe COVID-19 and not requiring IMV, clinical improvement at day 14 was 64% with 5 days and 54% with 10 days of remdesivir (Goldman 2020). After adjustment for (significant) baseline imbalances in disease severity, outcomes were similar. The most common adverse events were nausea (9%), worsening respiratory failure (8%), elevated ALT level (7%), and constipation (7%). Because the trial lacked a placebo control, it was not a test of efficacy for remdesivir. An expansion phase will enroll an additional 5600 (!) patients around the world.
- The second open-label SIMPLE trial, NCT04292730 (GS-US-540-5774), evaluated the efficacy of two remdesivir regimens compared to standard of care (SOC) in 584 hospitalized patients with moderate COVID-19, with respect to clinical status assessed by a 7-point ordinal scale on day 11. Clinical status distribution was significantly better for those randomized to a 5-day course of remdesivir compared with those randomized to SOC (Spinner 2020). According to the authors, however, this “difference was of uncertain clinical importance”. The difference for those randomized to a 10-day course (median length of treatment, 6 days) compared with standard of care was not significant. By day 28, 9 patients had died: 2 (1%) and 3 (2%) in the 5-day and 10-day remdesivir groups, and 4 (2%) in the SOC group, respectively. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients, compared with SOC.
- ACTT (Adaptive COVID-19 Treatment Trial): The conclusion of the final report for this double-blinded RCT that had randomized 1062 patients throughout the world, was remarkably short: remdesivir “was superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection” (Beigel 2020). Median recovery time was 10 versus 15 days. On an eight-category ordinal scale, patients who received remdesivir were more likely to improve at day 15. The benefit in recovery persisted when adjustment was made for glucocorticoid use. The Kaplan–Meier estimates of mortality were 6,7% with remdesivir and 11,9% with placebo by day 15. Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24,6%) and in 163 of the 516 patients who received placebo (31,6%).
- WHO Solidarity Trial Consortium 2020: In SOLIDARITY, 11.330 adults (405 hospitals in 30 countries) were randomized, with 2750 allocated to remdesivir, 954 HCQ, 1411 lopinavir/r, 651 interferon plus lopinavir/r, 1412 only interferon, and 4088 no study drug. Kaplan-Meier 28-day mortality was 12%. No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalization duration. 301 of 2743 patients receiving remdesivir died as did 303 of 2708 receiving the control (WHO Solidarity 2020).
On 20 November, WHO issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients (WHO Date).
What comes next? Several additional trials are ongoing, including combination therapies with other drugs such baricitinib (see below). Let’s wait for the results, before we throw remdesivir out with the bathwater. According to a recent review, remdesivir (5 days) should be prioritized for hospitalized patients requiring low-flow supplemental oxygen as it appears that these patients derive the most benefit (Davis 2020). The data also support some benefit in hospitalized patients breathing ambient air (if there is adequate drug supply). Current data do NOT suggest benefit for those requiring high-flow oxygen or mechanical ventilation (non-invasive or invasive). It has become “clear that treatment with an antiviral drug alone is not likely to be sufficient for all patients” (Beigel 2020).
Of note, some new ideas on remdesivir as an inhalation therapy have been published (Contini 2020). Local instillation or aerosol in the first phase of infection, both in asymptomatic but nasopharyngeal swab positive patients, together with antiseptic-antiviral oral gargles and povidone-iodine eye drops for conjunctiva would attack the virus directly through the receptors to which it binds, significantly decreasing viral replication and the risk of severe COVID-19. Gilead is working on this (knowing that “early intravenous infusions” are not feasible).
Favipiravir is another broad antiviral RdRp inhibitor that has been approved for influenza in Japan (but was never brought to market) and other countries. Favipiravir is converted into an active form intracellularly and recognized as a substrate by the viral RNA polymerase, acting like a chain terminator and thus inhibiting RNA polymerase activity (Delang 2018). In the absence of scientific data, favipiravir has been granted five-year approval in China under the trade name Favilavir® (in Europe: Avigan®). A loading dose of 2400 mg BID is recommended, followed by a maintenance dose of 1200-1800 mg QD. However, in 7 patients with severe COVID-19, the favipiravir trough concentration was much lower than that of healthy subjects in a previous clinical trial (Irie 2020). Potential drug-drug interactions (DDIs) have to be considered. As the parent drug undergoes metabolism in the liver mainly by aldehyde oxidase (AO), potent AO inhibitors such as cimetidine, amlodipine, or amitriptyline are expected to cause relevant DDIs (review: Du 2020). Some encouraging preliminary results in 340 COVID-19 patients were reported from Wuhan and Shenzhen (Bryner 2020).
- A first open-label RCT posted on March 26 (Chen 2020) was conducted in China, comparing arbidol and favipiravir in 236 patients with pneumonia. Some improvement in the primary outcome (7-day clinical recovery rate) was found only in a subgroup). In the whole study population, no difference was seen.
- No effect of viral clearance was found in a RCT on 69 patients with asymptomatic to mild COVID-19 who were randomly assigned to early or late favipiravir therapy (same regimen starting day 1 or day 6). Viral clearance occurred within 6 days in 67% and 56%. Neither disease progression nor death occurred in any of the patients (Doi 2020).
- In the pilot stage of a Phase II/III clinical trial, 60 patients hospitalized with COVID-19 pneumonia were randomized to two different dosing groups or standard of care (Ivashchenko 2020). The proportion of patients who achieved negative PCR on day 5 on both dosing regimens was twice as high as in the control group (p < 0.05).
In an RCT on 150 patients from India, the median time to the cessation of viral shedding was somewhat shorter (5 days versus 7 days) with favipiravir, compared to controls (Udwadia 2020).
Molnupiravir (MK-4482/EIDD-2801) is an orally-administered bioavailable prodrug of cytidine nucleoside analogue EIDD-1931. Originally developed for treatment of hepatitis C, some studies indicated potent activity of EIDD-1931 against SARS-CoV-2 in multiple cell types. Molnupiravir is able to mitigate SARS-CoV-2 infection and block transmission when therapeutically administered to ferrets (Cox 2020). The drug, initially developed as an inhibitor of influenza viruses, is currently in Phase II/III clinical trials (NCT04405570 and NCT04405739).
Other RdRp inhibitors: sofosbuvir, galidesivir
Some other RdRp inhibiting compounds have also been discussed. Sofosbuvir is a polymerase inhibitor which is also used as a direct-acting agent in hepatitis C. It is usually well tolerated. Modelling studies have shown that sofosbuvir could also inhibit RdRp by competing with physiological nucleotides for the RdRp active site (Elfiky 2020). Sofosbuvir could be combined with HCV PIs. The first randomized controlled trial in adult patients hospitalized with COVID-19 in Iran to evaluate the efficacy and safety of the two HCV drugs sofosbuvir and daclatasvir in combination with ribavirin (SDR) compared these drugs with standard of care (Abbaspour Kasgari 2020). Though there were trends in favor of the SDR arm for recovery and lower death rates, the trial was too small to make definite conclusions. In addition, there was an imbalance in the baseline characteristics between the arms.
Galidesivir is a nucleoside RNA polymerase inhibitor with broad-spectrum activity in vitro against more than 20 RNA viruses in nine different families, including coronaviruses and other viral families. A NIAID-funded, randomized, double-blind, placebo-controlled clinical trial to assess the safety, clinical impact and antiviral effects of galidesivir in patients with COVID-19 is underway. Of note, the drug also works against Zika: in the study presented here, galidesivir dosing in rhesus macaques was safe and offered post-exposure protection against Zika virus infection (Lim 2020).
Protease inhibitors (PIs)
A promising drug target is the viral main protease Mpro, which plays a key role in viral replication and transcription. Some HIV PIs have been extensively studied in COVID-19 patients.
Lopinavir/r is thought to inhibit the 3-chymotrypsin-like protease of coronaviruses. To achieve appropriate plasma levels, it has to be boosted with another HIV PI called ritonavir (usually indicated by “/r”: lopinavir/r). Due to some uncontrolled trials in SARS and MERS, lopinavir/r was widely used in the first months, despite the lack of any evidence. In an early retrospective study on 280 cases, early initiation of lopinavir/r and/or ribavirin showed some benefits (Wu 2020).
- The first open-label RCT in 199 adults hospitalized with severe COVID-19 did not find any clinical benefit beyond standard of care in patients receiving the drug 10 to 17 days after onset of illness (Cao 2020). There was no discernible effect on viral shedding.
- A Phase II, multi-center, open-label RCT from Hong Kong randomized 127 patients with mild-to-moderate COVID-19 (median 5 days from symptom onset) to receive lopinavir/r only or a triple combination consisting of lopinavir/r, ribavirin and interferon (Hung 2020). The results indicate that the triple combination can be beneficial when started early (see below, interferon). As there was no lopinavir/r-free control group, this trial does not prove lopinavir/r efficacy.
- After preliminary results were made public on June 29, 2020, we are now facing the full paper on the lopinavir/r arm in the RECOVERY trial: In 1616 patients admitted to hospital who were randomly allocated to receive lopinavir/r (3424 patients received usual care), lopinavir/r had no benefit. Overall, 374 (23%) patients allocated to lopinavir/r and 767 (22%) patients allocated to usual care died within 28 days. Results were consistent across all prespecified subgroups. No significant difference in time until discharge alive from hospital (median 11 days in both groups) or the proportion of patients discharged from hospital alive within 28 days was found. Although the lopinavir/r, dexamethasone, and hydroxychloroquine groups have now been stopped, the RECOVERY trial continues to study the effects of azithromycin, tocilizumab, convalescent plasma, and monoclonal antibodies.
- There was no effect in the SOLIDARITY trial of lopinavir/r (WHO Solidarity 2020)
At least two studies suggested that lopinavir/r pharmacokinetics in COVID-19 patients may differ from those seen in HIV-infected patients. In both studies, very high concentrations were observed, exceeding those in HIV-infected patients by 2-3 fold (Schoergenhofer 2020, Gregoire 2020). However, concentrations of protein-unbound lopinavir achieved by current HIV dosing is probably still too low for inhibiting SARS-CoV-2 replication. The EC50 for HIV is much lower than for SARS-CoV-2. It remains to be seen whether these levels will be sufficient for (earlier) treatment of mild cases or as post-exposure prophylaxis.
For another HIV PI, darunavir, there is no evidence from either cell experiments or clinical observations that the drug has any prophylactic effect (De Meyer 2020).
It is hoped that the recently published pharmacokinetic characterization of the crystal structure of the main protease SARS-CoV-2 may lead to the design of optimized protease inhibitors. Virtual drug screening to identify new drug leads that target protease which plays a pivotal role in mediating viral replication and transcription, have already identified several compounds. Six compounds inhibited M(pro) with IC50 values ranging from 0.67 to 21.4 muM, among them two approved drugs, disulfiram and carmofur (a pyrimidine analog used as an antineoplastic agent) drugs (Jin 2020). Others are in development but still pre-clinical (Dai 2020).
Most coronaviruses attach to cellular receptors via their spike (S) protein. Within a few weeks after the discovery of SARS-CoV-2, several groups elucidated the entry of the virus into the target cell (Hoffmann 2020, Zhou 2020). Similar to SARS-CoV, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a key receptor, a surface protein that is found in various organs and on lung AT2 alveolar epithelial cells. The affinity for this ACE2 receptor appears to be higher with SARS-CoV-2 than with other coronaviruses. The hypothesis that ACE inhibitors promote severe COVID-19 courses through increased expression of the ACE2 receptor remains unproven (see chapter Clinical Presentation, page 293).
Human recombinant soluble ACE2 (APN01)
HrsACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. It may act by binding the viral spike protein (thereby neutralizing SARS-CoV-2) and by interfering with the renin–angiotensin system. APN01 has been shown to be safe and well-tolerated in a total of 89 healthy volunteers and patients with pulmonary arterial hypertension (PAH) and ARDS in previously completed Phase I and Phase II clinical trials. It is developed by APEIRON, a privately-held European biotech company based in Vienna, Austria. There is a report of an Austrian case of a 45-year-old woman with severe COVID-19 who was treated with hrsACE2. The virus disappeared rapidly from the serum and the patient became afebrile within hours (Zoufaly 2020). Several Phase II/III studies of hrsACE2 are ongoing.
In addition to binding to ACE2, priming or cleavage of the spike protein is also necessary for viral entry, enabling the fusion of viral and cellular membranes. SARS-CoV-2 uses the cellular protease transmembrane protease serine 2 (TMPRSS2). Compounds inhibiting this protease may therefore inhibit viral entry (Kawase 2012). The TMPRSS2 inhibitor camostat, approved in Japan for the treatment of chronic pancreatitis (trade name Foipan®), may block the cellular entry of SARS-CoV-2 (Hoffmann 2020). Clinical data are pending. Some trials are ongoing, mostly in mild-to-moderate disease.
Umifenovir (Arbidol®) is a broad-spectrum antiviral drug approved as a membrane fusion inhibitor in Russia and China for the prophylaxis and treatment of influenza. Chinese guidelines recommend it for COVID-19 – according to a Chinese press release it is able to inhibit the replication of SARS-CoV-2 in low concentrations of 10-30 μM (PR 2020). In a small retrospective and uncontrolled study in mild to moderate COVID-19 cases, 16 patients who were treated with oral umifenovir 200 mg TID and lopinavir/r were compared with 17 patients who had received lopinavir/r as monotherapy for 5–21 days (Deng 2020). At day 7 in the combination group, SARS-CoV-2 nasopharyngeal specimens became negative in 75%, compared to 35% with lopinavir/r monotherapy. Chest CT scans were improving for 69% versus 29%, respectively. Similar results were seen in another retrospective analysis (Zhu 2020). However, a clear explanation for this remarkable benefit was not provided. Another retrospective study on 45 patients from a non-intensive care unit in Jinyintan, China failed to show any clinical benefit (Lian 2020). There is a preliminary report of a randomized study indicating a weaker effect of umifenovir compared to favipiravir (Chen 2020).
Oseltamivir (Tamiflu®) is a neuraminidase inhibitor that is approved for the treatment and prophylaxis of influenza in many countries. Like lopinavir, oseltamivir has been widely used for the current outbreak in China (Guan 2020). Initiation immediately after the onset of symptoms may be crucial. Oseltamivir is best indicated for accompanying influenza co-infection, which has been seen as quite common in MERS patients at around 30% (Bleibtreu 2018). There is no valid data for COVID-19. It is more than questionable whether there is a direct effect in influenza-negative patients with COVID-19 pneumonia. SARS-CoV-2 does not require neuramidases to enter target cells.
Hydroxychloroquine (HCQ) and chloroquine (CQ)
HCQ is an anti-inflammatory agent approved for certain autoimmune diseases and for malaria. The story of HCQ in the current pandemic is a warning example of how medicine shouldn’t work. Some lab experiments, a mad French doctor, bad uncontrolled studies, many rumors and hopes, reports without any evidence and an enthusiastic tweet that this had “a real chance to be one of the biggest game changers in the history of medicine” – hundreds of thousands people received an ineffective (and potential dangerous) drug. Moreover, many turned away from clinical trials of other therapies that would have required them to give up HCQ treatments. In some countries, the HCQ frenzy prompted serious delays in trial enrolment, muddled efforts to interpret data and endangered clinical research (Ledford 2020). Some countries stockpiled CQ and HCQ, resulting in a shortage of these medications for those that need them for approved clinical indications. Only a few months later, we are now facing an overwhelming amount of data strongly arguing against any use of both HCQ and CQ. So please, let’s forget it. Completely. But let us learn from the bad HQC story which should never happen again (Kim 2020, Ledford 2020).
|No clinical benefit from Hydroxychloroquine (HCQ)
· In an observational study from New York City (Geleris 2020) of 1376 hospitalized patients, 811 received HCQ (60% received also azithromycin, A). After adjusting for several confounders, there was no significant association between HCQ use and intubation or death.
· Another retrospective cohort of 1438 patients from 25 hospitals in the New York metropolitan region (Rosenberg 2020), there were no significant differences in mortality for patients receiving HCQ + Azithromycin (A), HCQ alone, or A alone. Cardiac arrest was significantly more likely seen with HCQ + A (adjusted OR 2.13).
· A randomized, Phase IIb trial in Brazil on severe COVID-19 patients was terminated early (Borba 2020). By day 13, 6/40 patients (15%) in the low-dose CQ group had died, compared with 16/41 (39%) in the high-dose group. Viral RNA was detected in 78% and 76%, respectively.
· In a study of 251 patients receiving HCQ plus A, extreme new QTc prolongation to > 500 ms, a risk marker for torsades, occurred in 23% (Chorin 2020).
· In 150 patients with mainly persistent mild to moderate COVID-19, conversion to negative PCR by day 28 was similar between HCQ and SOC (Tang 2020). Adverse events were recorded more frequently with HCQ (30% vs 9%, mainly diarrhea).
· Symptomatic, non-hospitalized adults with lab-confirmed or probable COVID-19 and high-risk exposure were randomized within 4 days of symptom onset to HCQ or placebo. Among 423 patients, change in symptom severity over 14 days did not differ. At 14 days, 24% receiving HCQ had ongoing symptoms compared with 30% receiving placebo (p = 0.21). Adverse events occurred in 43% versus 22% (Skipper 2020).
· HCQ does not work as prophylaxis. In 821 asymptomatic participants randomized to receive HCQ or placebo within 4 days of exposure, incidence of confirmed SARS-CoV-2 was 12% with CQ and 14% with placebo. Side effects were more common (40% vs 17%) (Boulware 2020).
· No, HCQ does not work as prophylaxis, even in HCW. This double-blind, placebo-controlled RCT included 132 health care workers and was terminated early. There was no significant difference in PCR-confirmed SARS-CoV-2 incidence between HCQ and placebo (Abella 2020).
· And finally, the RECOVERY Collaborative Group discovered that among 1561 hospitalized patients, those who received HCQ did not have a lower incidence of death at 28 days than the 3155 who received usual care (27% vs 25%).
The development of highly successful monoclonal antibody-based therapies for cancer and immune disorders has created a wealth of expertise and manufacturing capabilities. As long as all other therapies fail or have only modest effects, monoclonal antibodies are the hope for the near future. There is no doubt that antibodies with high and broad neutralizing capacity, many of them directed to the receptor binding domain (RBD) of SARS-CoV-2, are promising candidates for prophylactic and therapeutic treatment. On the other hand, these antibodies will have to go through all phases of clinical trial testing programs, which will take time. Safety and tolerability, in particular, is an important issue. The production of larger quantities is also likely to cause problems. Finally, there is the issue that mAbs are complex and expensive to produce, leaving people from poor countries locked out (Ledford 2020). Moroever, now that vaccines, cheaper and easier to administer, are being deployed—with priority for the most vulnerable populations—the question is what role remains for monoclonals in the first place (Cohen 2020). One potential drawback is that these antibodies could undermine the effectiveness of vaccines. According to some experts, they might be important for the elderly and other people with compromised immune systems who do not have vigorous responses to vaccines. Another growing concern is that at least some of the new variants from the UK and South Africa are less susceptible to monoclonal antibodies (see the chapter on variants).
However, the ‘COVID-19 antibodysphere’ (Amgen, AstraZeneca, Vir, Regeneron, Lilly, Adagio) is still very active, building partnerships. Several mAbs entered clinical trials in the summer of 2020. Trials include treatment of patients with SARS-CoV-2 infection with varying degrees of illness to block disease progression. Given the long half-life of most mAbs (approximately 3 weeks for IgG1), a single infusion should be sufficient. In November 2020, the FDA issued emergency use authorizations (EUA) for the investigational monoclonal antibody combination casirivimab plus imdevimab (REGN-CoV-2) and for bamlanivimab (from Lilly).
Casirivimab plus Imdevimab (REGN-COV2)
The antibodies given to Trump. Casivirimab (REGN10933) binds at the top of the RBD, extensively overlapping the binding site for ACE2, while the epitope for imdevimab (REGN10987) is located on the side of the RBD, away from the REGN10933 epitope, and has little to no overlap with the ACE2 binding site. Proof of principle was shown in in a cell model, using vesicular stomatitis virus pseudoparticles expressing the SARS-CoV-2 spike protein. Simultaneous treatment with both mAbs precluded the appearance of escape mutants (Baum 2020, Hansen 2020). Thus, this cocktail called REGN-COV2 did not rapidly select for mutants, presumably because escape would require the unlikely occurrence of simultaneous viral mutation at two distinct genetic sites, so as to ablate binding and neutralization by both antibodies in the cocktail.
On 21 November, the FDA issued an emergency use authorization for both mAbs to be administered together for the treatment of mild-to-moderate COVID-19 in patients 12 years of age or older (weighing at least 40 kilograms) and who are at high risk for progressing to severe COVID-19 (65 years of age or older or certain chronic medical conditions). Neither antibody is authorized for patients hospitalized due to COVID-19 or who require oxygen therapy due to COVID-19. Regeneron will distribute REGN-COV2 in the US and Roche is responsible for distribution outside the US.
Clinical data is still limited:
- An interim analysis of an ongoing Phase I–III trial randomly assigning 275 non-hospitalized patients to receive placebo, 2,4g or 8,0g of REGN-COV2 (Weinreich 2020). The least-squares mean difference (REGN-COV2 dose groups vs. placebo group) in the time-weighted average ∆ in viral load from day 1 through day 7 was minus 0,56 log10 copies/mL among patients who were serum antibody–negative at baseline and minus 0,41 log10 copies/mL in the overall trial population. But did this translate into a clinical benefit? Maybe. At least one medical attended visit was necessary in 3% vs 6% (placebo) overall and in 6% vs 15% (placebo) in serum antibody-negative at baseline. Both doses were well-tolerated. Infusion reactions and severe adverse events were balanced across all groups, no deaths occurred.
Bamlanivimab (LY-CoV555, BAM) from Lilly is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. On 9 November, the FDA issued an emergency use authorization (EUA) for the treatment of mild to moderate COVID-19 in patients who are 12 years of age and older weighing at least 40 kilograms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization. These are elderly patients but also with a BMI ≥ 35, chronic kidney disease, diabetes, immunosuppressive status, cardiovascular disease and others (depending on age). Of note, BAM is not authorized for patients who are hospitalized due to COVID-19 or who require oxygen therapy due to COVID-19.
As with REGN-2, clinical data is still limited with BAM:
- The interim analysis of an ongoing Phase II study (BLAZE-1) in 452 patients with mild to moderate COVID-19 showed some clinical benefit (Chen 2020). Those who received a single dose BAM (three different dosages) had fewer hospitalizations (1,6% versus 6,3%) and a lower symptom burden than those who received placebo, with the most pronounced effects observed in high-risk cohorts.
- The final data set of BLAZE-1 in 577 outpatients (Gottlieb 2020) revealed that there was no significant difference in change in viral load with 3 different doses of BAM compared with placebo. However, treatment with a combination of BAM and another mAb (etesevimab, LY-CoV016) significantly decreased SARS-CoV-2 viral load by -0.57 log at day 11 compared with placebo. Further ongoing clinical trials will focus on assessing the clinical benefit.
- In another RCT involving 314 hospitalized patients, BAM did not demonstrate efficacy among hospitalized patients who had COVID-19 without end organ failure. The trial was stopped (ACTIV 2020).
Other mAbs, some key papers:
- The first report of a human monoclonal antibody that neutralizes SARS-CoV-2 (Wang 2020). 47D11 binds a conserved epitope on the spike RBD explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using a mechanism that is independent of receptor-binding inhibition. This antibody could be useful for development of antigen detection tests and serological assays targeting SARS-CoV-2.
- From 60 convalescent patients, 14 potent neutralizing antibodies were identified by high-throughput single B cell RNA-sequencing (Cao 2020). The most potent one, BD-368-2, exhibited an IC50 of 15 ng/mL against SARS-CoV-2, displaying strong therapeutic efficacy in mice. The epitope overlaps with the ACE2 binding site.
- Several mAbs from ten convalescent COVID-19 patients. The most interesting mAb, named 4A8, exhibited high neutralization potency but did not bind the RBD (like most other mAbs). Cryo-EM revealed that the epitope of 4A8 seems to be the N terminal domain (NTD) of the S protein (Chi 2020).
- Isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells of eight SARS-CoV-2 infected individuals. Some antibodies showed potent anti-SARS-CoV-2 neutralization activity that correlates with their competitive capacity with ACE2 for RBD binding (Ju 2020).
- CR3022 tightly binds the RBD and neutralizes SARS-CoV-2 (Huo 2020). The highly conserved, structure-stabilising epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. The mechanism of neutralisation is new and was not seen for coronaviruses.
- H014 neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nanomolar level by engaging the S receptor binding domain. In the hACE2 mouse model, H014 prevented pulmonary pathology. H014 seems to prevent attachment of SARS-CoV-2 to its host cell receptors (Lv 2020).
- Four human neutralizing monoclonal antibodies were isolated from a convalescent patient. B38 and H4 blocked the binding between the virus S protein RBD and the cellular receptor ACE2. A competition assay indicates their different epitopes on the RBD. In a mouse model, both antibodies reduced viral titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity (Wu 2020).
- Of a total of 178 S1 and RBD binding human monoclonal antibodies from the memory B cells of 11 recently recovered patients, the best one, 414-1, showed neutralizing IC50 at 1.75 nM (Wan J 2020). Epitope mapping revealed that the antibodies bound to 3 different RBD epitopes, and epitope B antibody 553-15 could substantially enhance neutralizing abilities of most other neutralizing antibodies.
- Isolation and characterization of two ultra-potent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that were identified among almost 800 screened Abs isolated from 12 COVID-19 patients (Tortorici 2020). Both nAbs protected hamsters against SARS-CoV-2 challenge.
- Using a high-throughput rapid system for antibody discovery, more than 1000 mAbs were isolated from 3 convalescent donors by memory B cell selection using SARS-CoV-2 S or RBD recombinant proteins. Of note, only a small fraction was neutralizing, highlighting the value of deep mining of responses to access the most potent Abs. RBD-nAbs that directly compete with ACE2 are clearly the most preferred for prophylactic and therapeutic applications, and as reagents to define nAb epitopes for vaccine. With these nABs, Syrian hamsters were protected from weight loss. However, animals that received higher doses also showed body weight loss, possibly indicating antibody-mediated enhanced disease (Rogers 2020).
- Antibodies from convalescent patients had low levels of somatic hypermutation. Electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites. In total, 19 neutralizing antibodies were identified that target a diverse range of antigenic sites on the S protein, of which two showed picomolar (very strong!) neutralizing activities (Brouwer 2020).
- Isolation of 61 SARS-CoV-2-neutralizing mAbs from 5 hospitalized patients, among which are 19 mAbs that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus inhibitory concentrations of 0,7 to 9 ng/mL (Liu 2020).
Antibody fragments, nanobodies
- Antibody domains and fragments such as VH (heavy chain variable domain, 15 kDa) are attractive antibody formats for candidate therapeutics. They may have better tissue penetration compared to full-sized antibodies. One of those VHs, ab8, in an Fc (human IgG1, crystallizable fragment) fusion format, showed potent neutralization activity and specificity against SARS-CoV-2 both in vitro and in mice and hamsters, possibly enhanced by its relatively small size (Li 2020).
- An early inhalation of nanobodies – a future treatment? VHH antibodies or nanobodies (Nbs) are minimal, monomeric antigen-binding domains derived from camelid single-chain antibodies. Unlike IgG antibodies, Nbs are small, highly soluble and stable, readily bioengineered into bi/multivalent forms, and are amenable to low-cost, efficient microbial production. They can also be administered by inhalation, making their use against respiratory viruses very appealing. This study discovered several Nbs (Xiang 2020) with picomolar to femtomolar affinities that inhibit viral infection at sub-ng/ml concentration and determined a structure of one of the most potent in complex with RBD. Multivalent Nb constructs achieved ultra-high neutralization potency and may prevent mutational escape. While the research is still preliminary, it is hoped that Nbs might someday be the key ingredient in an antiviral drug that could be easily delivered via nasal spray.
- The ultrapotent Nb6 binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multi-valency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection (Schoof 2020).
Convalescent plasma (passive immunization)
Human convalescent plasma (CP) could be a rapidly available option for prevention and treatment of COVID-19 disease when there are sufficient numbers of people who have recovered and can donate immunoglobulin-containing serum (Casadevall 2020). Passive immune therapy appears to be relatively safe. However, an unintended consequence of receiving CP may be that recipients won’t develop their own immunity, putting them at risk for re-infection. Other issues that have to be addressed in clinical practice (Kupferschmidt 2020) are plasma supply (regulatory conderations; logistical work flow may become a challenge) and rare but relevant risks (transfusion-related acute lung injury, in which transferred antibodies damage pulmonary blood vessels, or transfusion-associated circulatory overload). Fortunately, antibodies that are found in CP are very stable. Pathogen inactivation (using psoralen and UV light) did not impair the stability and neutralizing capacity of SARS-CoV-2-specific antibodies that was also preserved at 100% when the plasma was shock frozen at −30°C after pathogen-inactivation or stored as liquid plasma for up to 9 days (Tonn 2020).
The major caveat of CP is consistency (concentration differs). In plasma from 149 patients collected on average 39 days after the onset of symptoms, neutralizing titers were extremely variable. Most plasmas did not contain high levels of neutralizing activity (Robbiani 2020). Pre-screening of CP may be necessary for selecting donors with high levels of neutralizing activity for infusion into patients with COVID-19 (Bradfute 2020). There seems to be a correlation between serum neutralizing capacity and disease severity, suggesting that the collection of CP should be restricted to those with moderate to severe symptoms (Chen 2020). Others have suggested more detailed selection criteria: 28 days after the onset of symptoms with a disease presentation of fever lasting longer than 3 days or a body temperature exceeding 38,5°C. Selection based on these criteria can ensure a high likelihood of achieving sufficiently high titers (Li 2020).
On March 26, the FDA approved the use of plasma from recovered patients to treat people who are critically ill with COVID-19 (Tanne 2020). This was a remarkable decision, because at that time data was still scarce. Now, there is growing evidence that high titer CP may have some benefit:
- The first RCT was published in June (Li 2020). Unfortunately, the study was terminated prematurely (no more patients could be recruited in China) and underpowered. Of 103 patients who were randomized, clinical improvement (on a 6-point disease severity scale) occurred within 28 days in 52% vs 43%. There was no significant difference in 28-day mortality (16% vs 24%). Of note, CP treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87% of the CP group versus 38% (OR, 11,39). Main take-homes: CP is not a silver bullet and antiviral efficacy does not necessarily lead to better survival.
- The second RCT came from India (Agarwal 2020). This open-label RCT investigated the effectiveness of CP in adults with moderate COVID-19, assigning 235 patients to two doses of 200 mL CP and 229 patients to a control arm. Progression to severe disease or all-cause mortality at 28 days occurred in 44 (19%) and 41 (18%). Moreover, CP treatment did not show anti-inflammatory properties and there was no difference between patients with and without neutralizing antibodies at baseline. The main limitation was that the antibody titers in CP before transfusion were not measured because validated, reliable commercial tests were not available when the trial started.
- Another RCT on 338 hospitalized adult patients with severe COVID-19 pneumonia from Argentina did not find any difference in clinical status or overall mortality or in prespecified subgroups (Simonovich 2020).
- So it may depend on the patients – and on the level of antibody titers. Among 3082 patients hospitalized with COVID-19, the efficacy was moderated by mechanical ventilation status (Joyner 2020). In patients who were not receiving mechanical ventilation, transfusion of plasma with higher antibody levels was associated with a lower risk of death than transfusion of CP with lower antibody levels.
- In an RCT on early administration of high titer CP to 160 mildly ill older adults, severe respiratory disease developed in 16% who received CP and in 31% who received placebo (Lipster 2020).
- CP may be also very helpful in patients with humoral deficiency induced by anti-CD20 monoclonal antibodies such as rituximab. In 17 consecutive patients with profound B cell lymphopenia and prolonged COVID-19 symptoms, all but one patient experienced an improvement of clinical symptoms within 2 days.
While antiviral drugs are most likely to prevent mild COVID-19 cases from becoming severe, adjuvant strategies will be needed, particularly in severe cases. Coronavirus infections may induce excessive and aberrant, ultimately ineffective host immune responses that are associated with severe lung damage (Channappanavar 2017). Similar to SARS and MERS, some patients with COVID-19 develop acute respiratory distress syndrome (ARDS), often associated with a cytokine storm. This is characterized by increased plasma concentrations of various interleukins, chemokines and inflammatory proteins.
Various host-specific therapies aim to limit the immense damage caused by the dysregulation of pro-inflammatory cytokine and chemokine reactions (Zumla 2020). Immunosuppressants, interleukin blocking agents such as anakinra or JAK-2 inhibitors are also an option (Mehta 2020). These therapies may potentially act synergistically when combined with antivirals. Numerous drugs are discussed, including those for lowering cholesterol, for diabetes, arthritis, epilepsy and cancer, but also antibiotics. They are said to modulate autophagy, promote other immune effector mechanisms and the production of antimicrobial peptides. Other immunomodulatory and other approaches in clinical testing include bevacizumab, brilacidin, cyclosporin, fedratinib, fingolimod, lenadilomide and thalidomide, sildenafil, teicoplanin and many more. However, convincing clinical data is pending for most strategies.
Corticosteroids are thus far the only drugs which provide a survival benefit in patients with severe COVID-19. During the first months of the pandemic, according to current WHO guidelines, steroids were controversially discussed and were not recommended outside clinical trials. With a press release on June 16, 2020 reporting the results of the UK-based RECOVERY trial, the treatment of COVID-19 underwent a major change. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation. The RECOVERY results had a huge impact on other RCTs around the world. The therapeutic value of corticosteroids has now been shown in numerous studies:
- RECOVERY: In this open-label trial (comparing a range of treatments), hospitalized patients were randomized to receive oral or intravenous dexa (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. Overall, 482 patients (22,9%) in the dexa group and 1110 patients (25,7%) in the usual care group died within 28 days (age-adjusted rate ratio, 0,83). The death rate was lower among patients receiving invasive mechanical ventilation (29,3% vs. 41,4%) and among those receiving oxygen without invasive mechanical ventilation (23,3% vs. 26,2%) but not among those who were receiving no respiratory support (17,8% vs. 14,0%).
- REMAP-CAP (different countries): In this Bayesian RCT, 384 patients were randomized to fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone. Treatment with a 7-day fixed-dose course or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority, respectively, with regard to the odds of improvement in organ support free days within 21 days. However, due to the premature halt of the trial, no treatment strategy met pre-specified criteria for statistical superiority, precluding definitive conclusions.
- CoDEX (Brazil). A multicenter, open-label RCT in 299 COVID-19 patients (350 planned) with moderate-to-severe ARDS (Tomazini 2020). Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard of care (n = 151) or standard of care alone (n = 148). Patients randomized to the dexamethasone group had a mean 6,6 ventilator-free days during the first 28 days vs 4,0 ventilator-free days in the standard of care group (difference, 2,26; 95% CI, 0,2-4,38; p = 0,04). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days.
- CAPE COD: Multicenter double-blinded RCT, in 149 (290 planned) critically-ill patients admitted to the intensive care unit (ICU) for COVID-19–related acute respiratory failure (Dequin 2020). The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42,1%) in the hydrocortisone group compared with 37 of 73 (50,7%) in the placebo group (p = 0,29).
- A prospective WHO meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The fixed-effect summary odds ratios for the association with mortality were 0,64 (95% CI: 0.50-0.82; p < 0,001) for dexamethasone compared with usual care or placebo, 0,69 (95% CI: 0,43-1,12; p = 0,13) for hydrocortisone and 0.91 (95% CI: 0,29-2.87; p = 0,87) for methylprednisolone, respectively. There was no suggestion of an increased risk of serious adverse events.
- Another study with 206 patients suggested that the effect of corticosteroids on viral shedding may be in a dose-response manner. High-dose (80 mg/d) but not low-dose corticosteroids (40 mg/d) delayed viral shedding of patients with COVID-19 (Li 2020).
- Treatments for respiratory disease, specifically inhaled corticosteroids (ICSs) do not have a protective effect. In 148,557 persons with COPD and 818,490 persons with asthma who were given relevant respiratory medications in the 4 months before the index date (March 1), people with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA–LAMA combinations (adjusted HR 1,39) (Schultze 2020). Compared with those prescribed short acting beta agonists only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1,55, 1,10-2,18]), whereas those given a low or medium dose were not. Sensitivity analyses showed that the apparent harmful association could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS.
Conclusions: WHO suggests NOT to use corticosteroids in the treatment of patients with non-severe COVID-19. The WHO recommends systemic corticosteroids for the treatment of patients with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). However, the WHO panel noted that the oxygen saturation threshold of 90% to define severe COVID-19 was arbitrary and should be interpreted cautiously when used for determining which patients should be offered systemic corticosteroids. For example, clinicians must use their judgement to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient suffering from chronic lung disease. Similarly, a saturation above 90–94% on room air may be abnormal if the clinician suspects that this number is on a downward trend.
The interferon (IFN) response constitutes the major first line of defense against viruses. This complex host defense strategy can, with accurate understanding of its biology, be translated into safe and effective antiviral therapies. In a recent comprehensive review, the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses is described (Park 2020).
IFN may work on COVID-19 when given early. Several clinical trials are currently evaluating synthetic interferons given before or soon after infection, in order to tame the virus before it causes serious disease (brief overview: Wadman 2020). In vitro observations shed light on antiviral activity of IFN-β1a against SARS-CoV-2 when administered after the infection of cells, highlighting its possible efficacy in an early therapeutic setting (Clementi 2020). In patients with coronaviruses such as MERS, however, interferon studies were disappointing. Despite impressive antiviral effects in cell cultures (Falzarano 2013), no convincing benefit was shown in clinical studies in combination with ribavirin (Omrani 2014).
- A Phase II, multicentre, open-label RCT from Hong Kong randomized 127 patients with mild-to-moderate COVID-19 (median 5 days from symptom onset) to receive lopinavir/r only or a triple combination consisting of lopinavir/r, ribavirin and interferon (Hung 2020). This trial indicates that the triple combination can be beneficial when started early. Combination therapy was given only in patients with less than 7 days from symptom onset and consisted of lopinavir/r, ribavirin (400 mg BID), and interferon beta-1b (1-3 doses of 8 Mio IE per week). Combination therapy led to a significantly shorter median time to negative results in nasopharyngeal swab (7 versus 12 days, p = 0,001) and other specimens. Clinical improvement was significantly better, with a shorter time to complete alleviation of symptoms and a shorter hospital stay. Of note, all differences were driven by the 76 patients who started treatment less than 7 days after onset of symptoms. In these patients, it seems that interferon made the difference. Up to now, this is the only larger RCT showing a virological response of a specific drug regimen.
- A retrospective multicenter cohort study of 446 COVID-19 patients, taking “advantage of drug stock disparities” between two medical centers in Hubei. Early administration ≤ 5 days after admission of IFN-α2b was associated with reduced in-hospital mortality in comparison with no admission of IFN-α2b, whereas late administration of IFN-α2b was associated with increased mortality (Wang 2020).
- In the WHO Solidarity Trial conducted at 405 hospitals in 30 countries, 2063 were randomly assigned to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. There was no efficacy of subcutaneous interferon alone or with lopinavir/r (WHO Solidarity).
- SNG001 is a formulation of recombinant interferon beta for inhaled delivery by nebulizer that is in development for the treatment of virus-induced lower respiratory tract illnesses. In this pilot trial, patients randomly assigned to SNG001 (n = 48) had greater odds of improvement versus placebo and more rapid recovery (Monk 2020). This corroborates findings from in vitro studies and animal models showing that the interferon pathway is crucial.
Several inflammatory cytokines that correlate with adverse clinical outcomes in COVID-19 employ a distinct intracellular signalling pathway mediated by Janus kinases (JAKs). JAK-STAT signalling may be an excellent therapeutic target (Luo 2020).
Baricitinib (Olumiant®) is a JAK inhibitor approved for rheumatoid arthritis. Using virtual screening algorithms, baricitinib was identified as a substance that could inhibit ACE2-mediated endocytosis (Stebbing 2020). Like other JAK inhibitors such as fedratinib or ruxolitinib, signaling inhibition may also reduce the effects of the increased cytokine levels that are frequently seen in patients with COVID-19. In rhesus macaques, viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was NOT reduced with baricitinib. However, animals treated with baricitinib showed reduced inflammation (Hoang 2020).
There is some evidence that baricitinib could be the optimal agent in this group (Richardson 2020). Other experts have argued that the drug would be not an ideal option due to the fact that baricitinib causes lymphocytopenia, neutropenia and viral reactivation (Praveen 2020) as well as pancreatitis (Cerda-Contreras 2020). There is also a dose-dependent association with arterial and venous thromboembolic events (Jorgensen 2020). It is possible that the pro-thrombotic tendencies could exacerbate a hypercoagulable state, underscoring the importance of restricting the use of baricitinib to clinical trials.
On December 28, 2020, baricitinib has been granted an FDA Emergency Use Authorization (EUA) for treatment of confirmed or suspected COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO); the EUA requires that baricitinib be used in combination with remdesivir. The EUA is based on these findings:
- In a large RCT of 1033 hospitalized adults with COVID-19, baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among those receiving high-flow oxygen or non-invasive ventilation. The 216 patients receiving high-flow oxygen or non-invasive ventilation at enrollment had a time to recovery of 10 days with combination treatment (n = 103) and 18 days with control (n = 103). The 28-day mortality was 5,1% and 7,8%, respectively.
- One observational study provides some evidence for a synergistic effect of baricitinib and corticosteroids (Rodriguez-Garcia 2020). Patients with moderate to severe SARS-CoV-2 pneumonia received lopinavir/r and HCQ plus either corticosteroids (controls, n = 50) or corticosteroids and baricitinib (n = 62). In the controls, a higher proportion of patients required supplemental oxygen both at discharge (62% vs 26%) and 1 month later (28% vs 13%).
Ruxolitinib (Jakavi®) is a JAK inhibitor manufactured by Incyte. It is used for myelofibrosis, polycythemia vera (PCV) and certain chronic graft versus host diseases in patients following a bone marrow transplant. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality.
- A small placebo-controlled Phase II RCT on 43 patients with severe COVID-19, ruxolitinib was not associated with significantly accelerated clinical improvement, although ruxolitinib recipients had a numerically faster clinical improvement (Cao Y 2020).
- In a retrospective study, 12/14 patients achieved significant reduction of the “COVID-19 Inflammation Score” with sustained clinical improvement in 11/14 patients (La Rosée 2020). Treatment was safe with some signals of efficacy to prevent or overcome multi-organ failure. A Phase II RCT has been initiated (NCT04338958).
- Another non-randomized study suggested a clinical benefit from ruxolitinib in 32 patients with severe COVID-19 pneumonia, compared to a control group (D’Alessio).
Cytokine blockers and anticomplement therapies
The hypothesis that quelling the cytokine storm with anti-inflammatory therapies directed at reducing interleukin-6 (IL-6), IL-1, or even tumor necrosis factor TNF alpha might be beneficial has led to several ongoing trials. It is suggestive that interleukin blocking strategies might improve the hyperinflammatory state seen in severe COVID-19. A recent review on this strategy, however, was less enthusiastic and urged caution (Remy 2020). Past attempts to block the cytokine storm associated with other microbial infections and with sepsis have not been successful and, in some cases, have worsened outcomes. Moreover, there is concern that suppressing the innate and adaptive immune system to address increased cytokine concentrations, could enable unfettered viral replication, suppress adaptive immunity, and delay recovery processes. There is growing recognition that potent immunosuppressive mechanisms are also prevalent in such patients. Following, we will briefly discuss the evidence on cytokine blockers.
Anakinra (Kineret®) is an FDA-approved treatment for rheumatoid arthritis and neonatal onset multisystem inflammatory disease. It is a recombinant human IL-1 receptor antagonist that prevents the binding of IL-1 and blocks signal transduction. Anakinra is thought to abrogate the dysfunctional immune response in hyperinflammatory COVID-19 and is currently being investigated in almost 20 clinical trials. Some case series have reported on encouraging results and anakinra is considered to be included as an option in the RECOVERY trial.
- A study from Paris, comparing 52 “consecutive” patients treated with anakinra with 44 historical patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 25% of patients in the anakinra group and 73% of patients in the historical group. The treatment effect of anakinra remained significant in the multivariate analysis (Hayem 2020). According to the authors, their study was “not perfect from a statistical point of view…”
- Of 120 patients with hyperinflammation (33% on mechanical ventilation), 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 14% in treated patients and 36% in controls (p = 0,005). Unadjusted and adjusted risk of death was significantly lower for treated patients com-pared to controls (Bozzi 2020).
- An RCT from France, however, was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia (CORIMUNO 2020). Some experts still argue that a true test of anakinra would be in patients with more severe COVID-19, or with evidence of IL-1-mediated hyperinflammation (Cavalli 2020).
Canakinumab (Illaris®) is human monoclonal antibody against IL-1β, approved for the treatment of juvenile rheumatoid arthritis and other chronic autoinflammatory syndromes. In a pilot trial, 10 patients with hyperinflammation (defined as CRP ≥ 50 mg/L) and respiratory failure showed a rapid improvement in serum inflammatory biomarkers and an improvement in oxygenation (Ucciferri 2020). There are other uncontrolled studies on 83 patients (Landi 2020) and on 17 patients (Katia 2020), suggesting clinical benefits. However, RCTs are pending.
Infliximab (Remicade®) is a chimeric monoclonal anti-TNF antibody, approved to treat a number of autoimmune diseases, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis and psoriasis. As a major component of deteriorating lung function in patients with COVID-19 is capillary leak, a result of inflammation driven by key inflammatory cytokines such as TNF, making TNF-blocking agents an attractive strategy (Robinson 2020). Administration of anti-TNF to patients for treatment of autoimmune disease leads to reductions in all of these key inflammatory cytokines. A small case series of seven patients who were treated with a single infusion of IFX (5 mg/kg body weight) has been reported (Stallmach 2020).
Mavrilimumab is an anti-granulocyte–macrophage colony-stimulating factor (GM-CSF) receptor-α monoclonal antibody. GM-CSF is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases (Mehta 2020). In small uncontrolled pilot trial on 13 patients, mavrilimumab treatment was associated with improved clinical outcomes compared with standard of care in non-mechanically ventilated patients with severe COVID-19 pneumonia and systemic hyperinflammation. Treatment was well tolerated (De Luca 2020).
Tocilizumab (TCZ, RoActemra® or Actemra®) is a monoclonal antibody that targets the interleukin-6 receptor. It is used for rheumatic arthritis and has a good safety profile. The initial dose should be 4-8 mg/kg, with the recommended dosage being 400 mg (infusion over more than 1 hour). Of note, the current level of evidence supporting the use of TCZ is weak, and many guidelines recommend against the use of TCZ except in the context of a clinical trial. TCZ continues to be tested in the RECOVERY trial while results are still pending.
- A large multicenter cohort included 3924 critically ill patients admitted to ICU at 68 hospitals across the US (Gupta 2020). The risk of in-hospital death was lower with TCZ (29% versus 41%). However, TCZ patients were younger and had fewer comorbidities. According to the authors, the findings “may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed”.
- COVACTA: On July 29, Hoffmann-La Roche announced disappointing results from its much-anticipated Phase III COVACTA trial. TCZ did not improve patient mortality, although patients spent roughly a week less in hospital compared with those given placebo. However, it may be too early to quit this strategy (Furlow 2020). Cautious interpretation of COVACTA is needed, in view of the study’s broad patient selection criteria.
- EMPACTA: In 249 hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation, tocilizumab did not improve survival, but it reduced the likelihood of progression to the composite outcome of mechanical ventilation or death. Death from any cause by day 28 occurred in 10,4% of the patients in the tocilizumab group and 8,6% of those in the placebo group (Salama 2020).
- CLORIMUNO: In this RCT that included 130 patients with moderate-to-severe pneumonia, tocilizumab did not reduce the WHO Scale scores at day 4. The proportion of patients with non-invasive ventilation, intubation, or death at day 14 was 36% with usual care and 24% with tocilizumab. No difference in mortality over 28 days was found (Hermine 2020).
- BACC Bay Trial: In this double-blind, placebo-controlled RCT in 243 moderately ill hospitalized patients (BACC Bay Trial), TCZ was not effective for preventing intubation or death (Stone 2020).
- In an open label RCT in 126 patients hospitalized with COVID-19 pneumonia, the rate of the primary clinical endpoint (clinical worsening) was not significantly different between the control group and the TCZ group (Salvarani 2020). The proportion of patients discharged within 14 and 30 days was the same.
- An open-label RCT from Brazil (Veiga 2020) among patients who were receiving supplemental oxygen or mechanical ventilation was stopped early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the TCZ group, compared to standard of care (17% vs 3%).
Siltuximab (Sylvant®) is another anti-IL-6-blocking agent. However, this chimeric monoclonal antibody targets interleukin-6 directly and not the receptor. Siltuximab has been approved for idiopathic multicentric Castleman’s disease (iMCD). In these patients it is well tolerated. First results of a pilot trial in Italy (“SISCO trial”) have shown encouraging results. According to interim interim data, presented on April 2 from the first 21 patients treated with siltuximab and followed for up to seven days, one-third (33%) of patients experienced a clinical improvement with a reduced need for oxygen support and 43% of patients saw their condition stabilise, indicated by no clinically relevant changes (McKee 2020).
Sarilumab (Kevzara®) is another recombinant human IL-6 receptor antagonist. An open-label study of sarilumab in severe COVID-19 pneumonia with hyperinflammation. Sarilumab 400 mg was administered intravenously in addition to standard of care to 28 patients and results were compared with 28 contemporary matched patients treated with standard of care alone. At day 28, 61% of patients treated with sarilumab experienced clinical improvement and 7% died. These findings were not significantly different from the comparison group. However, sarilumab was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline (Della-Torre 2020).
Vilobelimab is an anaphylatoxin and complement protein C5a blocking monoclonal antibody. In an open-label, randomized Phase II trial (part of the PANAMO trial), 30 patients with severe COVID-19 were randomly assigned 1:1 to receive vilobelimab (up to seven doses of 800 mg intravenously) or best supportive care only (control group). At day 5 after randomization, the primary endpoint of mean relative change in the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) was not significantly different between groups. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0–31) for the vilobelimab group and 27% (4–49) for the control group. The frequency of serious adverse events was similar between groups and no deaths were considered related to treatment assignment. According to the authors, the secondary outcome results support the investigation of vilobelimab in a Phase III trial using 28-day mortality as the primary endpoint. Pharmacokinetic and pharmacodynamic data, including C5a, have not yet been published (Campbell 2020). Investigators using the other C5 complement pathway inhibitors eculizumab and ravulizumab have significantly increased their dose and dosing frequency in the acute setting of COVID-19 compared with the doses approved for use in atypical hemolytic uremic syndrome.
Acalabrutinib and ibrutinib
Acalabrutinib and ibrutinib are bruton tyrosine kinase inhibitors, used for CLL and lymphoma treatment. Ex vivo analysis revealed significantly elevated BTK activity (BTK regulates macrophage signalling and activation), as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. In a pilot study, 19 patients with severe COVID-19 received the BTK inhibitor acalabrutinib (Roschewski 2020). Within 10-14 days, oxygenation improved “in a majority of patients”, often within 1-3 days, and inflammation markers and lymphopenia normalized quickly in most patients. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air. These results suggest that targeting excessive host inflammation with a BTK inhibitor can be a therapeutic strategy. A confirmatory RCT is underway. Some reports have speculated about a protective effect of ibrutinib, another BTK inhibitor (Thibaud 2020).
Aspirin may help (a little bit). In a retrospective, observational cohort study of 412 adult patients admitted with COVID-19 to multiple US hospitals between March and July, 98 (24%) received aspirin within 24 hours of admission or 7 days prior to admission. Aspirin use had a crude association with less mechanical ventilation (36% vs. 48%, p = 0,03) and ICU admission (39% vs. 51%, p = 0,04), but no crude association with in-hospital mortality (26% vs. 23%, p = 0,51). After adjusting for 8 confounding variables, aspirin use was independently associated with decreased risk of mechanical ventilation (adjusted HR 0,56, 95% CI: 0,37-0,85, p = 0,007), ICU admission (adjusted HR 0,57, 95% CI: 0,38-0,85, p = 0,005), and in-hospital mortality (adjusted HR 0,53, 95% CI: 0,31-0,90, p = 0,02). According to the authors, a sufficiently powered randomized controlled trial is needed. The RECOVERY trial includes ASS as an option.
Colchicine is one of the oldest known drugs which has been used for over 2000 years as a remedy for acute gout flares. Given its anti-inflammatory and anti-viral properties, it is also being tested in COVID-19 patients. In a prospective, open-label RCT from Greece, 105 hospitalized patients were randomized to either standard of care (SOC) or colchicine plus SOC (Deftereos 2020). Participants who received colchicine had statistically “significantly improved time to clinical deterioration”. However, there were no significant differences in biomarkers and the observed difference was based on a narrow margin of clinical significance; according to the authors their observations “should be considered hypothesis generating” and “be interpreted with caution”. In a retrospective cohort there was some evidence on clinical benefit (Brunetti 2020). Colchicine has been included as an early immunomodulation therapy in the RECOVERY trial.
Famotidine is a histamine-2 receptor antagonist that suppresses gastric acid production. It has an excellent safety profile. Initially it was thought to inhibit the 3-chymotrypsin-like protease (3CLpro), but it seems to act rather as an immune modulator, via its antagonism or inverse-agonism of histamine signaling. While results of the randomized clinical trial on the benefits of intravenous famotidine in treating COVID-19 (NCT04370262) are eagerly awaited, we can only speculate on the potential mechanisms of action of this drug (Singh 2020).
- In a retrospective study on 1620 patients, 84 (5.1%) received different doses of famotidine within 24 hours of hospital admission (Freedberg 2020). After adjusting for baseline patient characteristics, use of famotidine remained independently associated with risk for death or intubation (adjusted hazard ratio 0.42, 95% CI 0.21-0.85) and this remained unchanged after careful propensity score matching to further balance the co-variables. Of note, there was no protective effect of PPIs. Plasma ferritin values during hospitalization were lower with famotidine, indicating that the drug blocks viral replication and reduces the cytokine storm.
- A second propensity-matched observational study included 878 consecutive COVID-19-positive patients admitted to Hartford hospital, a tertiary care hospital in Connecticut, USA (Mather 2020). In total, 83 (9.5%) patients received famotidine. These patients were somewhat younger (63.5 vs 67.5 years) but did not differ with respect to baseline demographics or pre-existing comorbidities. Use of famotidine was associated with a decreased risk of in-hospital mortality (odds ratio 0.37, 95% CI 0.16-0.86) and combined death or intubation (odds ratio 0.47, 95% CI 0.23-0.96). Patients receiving famotidine displayed lower levels of serum markers for severe disease including CRP, procalcitonin and ferritin levels. Logistic regression analysis demonstrated that famotidine was an independent predictor of both lower mortality and combined death/intubation.
Fluvoxamine (a potent agonist of the sigma-1 receptor (σ1R)), is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. In a small RCT that included 152 adult outpatients with COVID-19 and symptom onset within 7 days, clinical deterioration occurred in 0 patients treated with fluvoxamine vs 6 (8%) patients treated with placebo over 15 days (Lenze 2020). The authors acknowledge the limitations of their study: a small number of endpoint events, which makes the findings fragile. The potential advantages of fluvoxamine for outpatient treatment of COVID-19 would include its safety, widespread availability, low cost, and oral administration. Note that fluvoxamine can cause drug-drug interactions. Eagerly awaiting data from larger trials.
G-CSF may be helpful in some patients (Cheng 2020). In an open-label trial at 3 Chinese centers, 200 patients with lymphopenia and no comorbidities were randomized to standard of care or to 3 doses of recombinant human G-CSF (5 μg/kg, subcutaneously at days 0-2). Time to clinical improvement was similar between groups. However, the proportion of patients progressing to ARDS, sepsis, or septic shock was lower in the rhG-CSF group (2% vs 15%). Mortality was also lower (2% vs 10%).
Iloprost is a prostacyclin receptor agonist that promotes vasodilation of circulatory beds with minimal impact on hemodynamic parameters. It is licensed for the treatment of pulmonary arterial hypertension and is widely used for the management of peripheral vascular disease and digital vasculopathy, including digital ulcers and critical digital ischemia in systemic sclerosis. There is a case series of three morbidly obese patients with severe COVID-19 and systemic microvasculopathy who obviously benefitted from its use (Moezinia 2020).
Ivermectin, an inexpensive, over-the-counter medicine, is widely used as a preventative against COVID-19 in many South & Latin American countries. However, the evidence that ivermectin protects from COVID-19 is scant. A group from Bangladesh conducted a randomized, double-blind, placebo-controlled trial of oral ivermectin alone or in combination with doxycycline compared with placebo among 72 hospitalized patients. Virological clearance was earlier in the 5-day ivermectin treatment arm vs the placebo group (9.7 days vs 12.7 days; p = 0.02); but not in the ivermectin + doxycycline arm (11.5 days; p = 0.27) (Ahmed 2020). There were no severe adverse drug events recorded in the study. According to the authors, “larger trials will be needed to confirm these preliminary findings”.
Other treatments with no effects
Azithromycin as a macrolide antibiotic has probably no effect against SARS-CoV-2 (see the many studies above, testing it in combination with HCQ). In a large RCT conducted at 57 centers in Brazil, 214 patients who needed oxygen supplementation of more than 4 L/min flow, high-flow nasal cannula, or mechanical ventilation (non-invasive or invasive) were assigned to the azithromycin group and 183 to the control group. Azithromycin had no effect (Furtado 2020).
Leflunomide (Arava®) is an approved antagonist of dihydroorotate dehydrogenase, has some antiviral and anti-inflammatory effects and has been widely used to treat patients with autoimmune diseases. In a small RCT from Wuhan on 50 COVID-19 patients with prolonged PCR positivity, no benefit in terms of the duration of viral shedding was observed with the combined treatment of leflunomide and IFN α-2a vs IFN α-2a alone (Wang 2020).
N-acetylcysteine had no effect, even at high-doses (De Alencar 2020). In an RCT from Brazil of 135 patients with severe COVID-19, 16 patients (24%) in the placebo group were submitted to endotracheal intubation and mechanical ventilation, compared to 14 patients (21%) in the NAC group (p = 0.675). No difference was observed on secondary endpoints.
It is hoped that at least some of the options given in this overview will show positive results over time. It is also important, though, that despite the immense pressure, the basic principles of drug development and research including repurposing are not abandoned. Time is needed.
The aim of the COVID Reference textbook is to scan the literature, not to write guidelines. However, after reviewing the studies published until January 20, 2021, presented above, we would recommend reviewing the following treatment options, considering the severity of the disease:
Outpatient, mild-to-moderate (no risk factors)
- Do NOTHING, except down-talking the patient. And make sure that he or she (and their households) stays home
Outpatient, mild-to-moderate (with risk factors)
- Do NOT use dexamethasone (could be harmful) or remdesivir (daily infusions not feasible)
- Do NOT use hydroxychloroquine, chloroquine, tocilizumab, convalescent plasma or lopinavir (not efficient, plus side effects)
- Consider ASS, colchicine, vitamin D, famotidine (potential harm seems to be limited)
- In high risk patients: consider monoclonal antibodies
- Interferon may work, if given early (optimal usage and administration is unclear)
- Use dexamethasone (only a few days)
- Use remdesivir (5 days) as soon as possible (no benefit in those requiring high-flow oxygen or mechanical ventilation)
- Consider cytokine blocking agents and/or baricitinib if available
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