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Treatment

COVID-19 Treatment Research Brief

11/18/20 - The section Pfizer has been updated to reflect new efficacy data. (See Pfizer)

11/18/20 - The section Moderna has been updated to reflect new information from a phase 3 trial. (See Moderna)

11/09/20 - The section Pfizer Vaccine has been updated to reflect new information from the first interim efficacy analysis of results from the phase 3 trial. (See Pfizer)

The global research and scientific response to the SARS-CoV-2 virus identified at the beginning of 2020 has been active. At least 319 treatments and 213 vaccines are in varying stages of development.1 They range from preclinical efforts to emergency authorizations, with no clear home runs at this stage. Researchers are sifting through past work to repurpose compounds that may show efficacy in treating issues such as respiratory problems and cytokine storms, so as to shorten the disease course and lower mortality rates. As the medical and scientific communities better understand how the virus affects the body, they can better target treatments. Vaccine development has been in overdrive. This process typically takes a minimum of several years, but more than 50 efforts are already in human trials, including almost a dozen in phase 3.2 We present some of the most promising and advanced efforts to date to combat SARS-CoV-2.

Navigate this resource by topic:

I. REPURPOSED TREATMENTS FOR COVID-19

     a. Corticosteroids
          i. Dexamethasone

     b. Antivirals
          i. Hydroxychloroquine
          ii. Remdesivir
          iii. Other antiviral and anti-inflammatory drugs

     c. Convalescent plasma

     d. Anticoagulants

 

II. NEW TREATMENTS FOR COVID-19

     a. Monoclonal antibodies
          i. REGN10933 + REGN10987
          ii. LY-CoV555

     b. Complement inhibitors
          i. IFX-1 (vilobelimab)

     c. Cell-based therapies
          i. RLF-100 (aviptadil)

 

III. VACCINES FOR COVID-19

     a. In late-phase trials
          i. AstraZeneca
          ii. Moderna
          iii. Pfizer
          iv. Johnson & Johnson

     b. Approved for limited use
          i. CanSino Biologics
          ii. Sinovac Biotech
          iii. Wuhan Institute of Biological Products
          iv. Gamaleya Research Institute

 

IV. References

 

REPURPOSED TREATMENTS FOR COVID-19

It is not only easier, but also faster to look first at existing treatments, whether used today or in the past. These therapies have been studied for various conditions, and researchers understand at least some of the mechanisms of action. These treatments have gone through the regulatory process, with postmarketing information available.

Corticosteroids

Corticosteroids depress inflammation, and COVID-19 is a disease that both affects the respiratory system and can cause severe inflammation. A meta-analysis of studies on corticosteroid use in patients with acute respiratory distress syndrome (ARDS) showed that usage reduced the risk of all-cause mortality and reduced mechanical ventilation duration.3 Several corticosteroids are in clinical trials alone or in combination with other drugs for COVID-19 treatment.

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Dexamethasone

Dexamethasone was the first to show effectiveness in reducing mortality in severely ill patients with COVID-19. The multicenter, open-label RECOVERY trial in hospitalized patients in the United Kingdom with COVID-19 enrolled 2104 patients to receive dexamethasone and 4321 to receive standard care.4 Researchers found that the drug lowered mortality by one-third for patients on ventilators and by one-fifth for patients on oxygen. Researchers did not find a benefit to giving dexamethasone to patients needing no respiratory support. Patients in the dexamethasone arm also experienced a shorter hospitalization duration compared with the usual-care group. The findings suggest that corticosteroids may modulate inflammation-mediated lung injury, reducing a patient’s progression to respiratory failure and death. The National Institutes of Health recommends giving dexamethasone to hospitalized patients under these conditions and recommends against giving it to patients who are not receiving supplemental oxygen.5 Alternative corticosteroids (prednisone, methylprednisolone, or hydrocortisone) could be given if dexamethasone is unavailable.5 More studies are under way internationally.

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Antivirals

Hydroxychloroquine

Early in the pandemic, hydroxychloroquine and chloroquine were considered a possible treatment for COVID-19, because researchers found that they stopped coronavirus replication in cells. Hydroxychloroquine, approved for use in the 1950s, is a compound related to the antimalarial drug chloroquine, which was first synthesized in the 1930s. Hydroxychloroquine is currently used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus.6 Approximately 180 clinical trials,7 including one from the World Health Organization (WHO),8 found that hydroxychloroquine and/or chloroquine did not reduce mortality compared with standard of care in patients with COVID-19. The WHO’s SOLIDARITY trial of remdesivir, hydroxychloroquine, lopinavir (fixed-dose combination with ritonavir), and interferon beta-1a included patients from more than 35 countries and 400 hospitals.8 The US Food and Drug Administration (FDA) revoked the emergency use authorization (EUA) of hydroxychloroquine and chloroquine in June 2020; in July 2020, the FDA reported safety issues including serious heart rhythm problems.9

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Remdesivir

The drug that arguably has made the biggest splash is remdesivir (Veklury), an intravenous treatment previously developed as a broad-spectrum antiviral. It was tested previously during the outbreaks of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), Ebola, and other infectious diseases.10 A phase 3 open-label randomized trial compared remdesivir with standard of care, with 312 patients receiving the treatment and 818 patients receiving stand of care.11 The remdesivir arm was associated with significantly greater recovery and a 62% reduced risk of mortality compared with standard of care at day 14.11 The ACTT-1 trial, which ran from mid-February to mid-April 2020, evaluated 1062 hospitalized patients with varying levels of illness severity.12 The trial was conducted at 60 sites in multiple countries, with most in the United States. Eligible patients were randomly assigned in equal numbers to remdesivir or placebo for up to 10 days. The median time to recovery (hospital discharge, not needing supplemental oxygen, or not needing ongoing medical care) was 10 days for the remdesivir group and 15 days for the standard of care group. Patients receiving remdesivir experienced improvement in mortality, but it was not statistically significant.12

In May 2020, remdesivir was the first COVID-19 treatment to receive EUA from the FDA. As of late August 2020, the FDA’s authorized use covered all hospitalized patients getting COVID-19 treatment, regardless of disease severity.13 The drug, while helpful, is not felt to be independently sufficient in treating patients with COVID-19. Researchers recommended trials combining it with other antiviral medications or other treatments.12

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Other antiviral and anti-inflammatory drugs

Investigations continue, with several trials combining remdesivir with other agents. The phase 3 ACTT-2 trial is comparing remdesivir and baricitinib (Olumiant) to remdesivir plus placebo in 1000 hospitalized adults diagnosed with COVID-19.14 The hypothesis is that the drug may reduce the ability of infected cells to replicate the virus, and it may reduce the cytokine storm. The primary outcome is time-to-recovery by day 29. Baricitinib is an anti-inflammatory Janus kinase inhibitor that is currently FDA-approved to treat RA.15

The phase 3 REMDACTA trial combines remdesivir with intravenous tocilizumab (Actemra/RoActemra), an anti-interleukin-6 receptor antibody. The study is of patients aged 12 years or older who are hospitalized with severe COVID-19 pneumonia.16 The investigators are recruiting 450 patients to the randomized, double-blind study comparing the combination with placebo plus remdesivir. Results are not yet available.17 Tocilizumab is FDA-approved to treat RA and several other types of arthritis, as well as cytokine release syndrome.18 The COVACTA trial compared placebo with tocilizumab treatment for 450 patients with the same condition, from April to July 2020.19 The study found that clinical status at day 28 was not significantly different for the two arms, and there was no difference in mortality. The tocilizumab arm had a median time to discharge that was 8 days shorter than in the placebo arm.19 In July 2020, Roche reported that the COVACTA study did not meet its primary endpoint of improved clinical status or mortality at 4 weeks.20

Remdesivir is also combined with interferon beta-1a (Rebif) in the ACTT-3 trial, which opened in August 2020, to recruit 1000 hospitalized adults with lung involvement, testing the combination against remdesivir alone in a double-blind randomized study.21 Researchers note that the normal interferon response can be suppressed by the virus. Interferon beta-1a has anti-inflammatory and antiviral properties and is FDA-approved to treat multiple sclerosis.21

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Convalescent plasma

Convalescent plasma has been known as a treatment, starting even before the 1918 influenza pandemic a century ago.22 The idea is to collect antibody-rich plasma from those who have recovered from COVID-19, then give it to those who are currently ill to boost their infection-fighting ability with antibodies that can more easily recognize and neutralize the virus. The first study, from China, included 103 patients.23 Published in June 2020, it showed that convalescent plasma did not result in significant clinical improvement within 28 days, although there were study limitations that could be addressed in other trials.24

The Mayo Clinic led an Expanded Access Program (EAP) partly to determine the safety of these transfusions. The program included 35,322 patients who received a transfusion, with 52.3% in the intensive care unit and 27.5% receiving mechanical ventilation at transfer time.25 The EAP showed a lower mortality rate for those receiving plasma, with a better result for those receiving plasma earlier. Several convalescent plasma trials are under way, including one led by NYU Langone Health, with a goal of enrolling 1000 hospitalized adult patients with respiratory symptoms.26 Another trial led by Vanderbilt University Medical Center will also enroll 1000 participants.26 The FDA gave EUA for convalescent plasma in August 2020 for hospitalized patients with COVID-19.27

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Anticoagulants

COVID-19–induced coagulopathy (CID) is found to cause venous thromboembolism (VTE) in some patients. Guidelines for anticoagulant administration during and after hospitalization for prophylaxis and treatment have been published.28 These guidelines note that one study29 showed that without VTE prophylaxis, 25% of COVID-19 patients developed lower-extremity deep vein thrombosis (DVT), a figure higher than in medically ill hospitalized patients, who had a 5% to 15% incidence in earlier studies. The guidelines also report that early studies showed that pharmacologic VTE prophylaxis was associated with up to a 60% reduction in VTE incidence without a major bleeding increase.28 The guidelines note that an Italian study reported a 21% cumulative rate of VTE and arterial thromboembolic events in hospitalized patients with COVID-19.30 The guidelines recommend pharmacologic VTE prophylaxis with anticoagulants such as enoxaparin or heparin for hospitalized nonpregnant patients diagnosed with or highly suspected of having COVID-19.28

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NEW TREATMENTS FOR COVID-19

Monoclonal antibodies

REGN10933 + REGN10987

Monoclonal antibodies (mAb) are produced in the laboratory to mimic those produced by the body’s immune system to neutralize viruses or pathogens. Regeneron announced initial data from 275 patients in a phase 1/2/3 trial of the antibody cocktail REGN10933 + REGN10987 (REGN-COV2) compared with placebo.31 The investigators found the greatest treatment benefit from those who had not yet developed their own antibodies. Patients were randomly assigned to receive placebo or one of two infusion doses. Patients in this laboratory trial were confirmed positive for COVID-19 and treated in the outpatient setting, with serology tests to see whether they were seropositive or negative. The researchers found that for seronegative patients, the cocktail reduced viral load through the key virologic endpoint, day 7. It also alleviated symptoms faster (6-8 days for treatment arms, 13 days for placebo). In this first cohort, 56% were Hispanic, 13% were Black, and 64% had at least one underlying risk factor. The investigators are recruiting at least 1300 patients into the phase 2/3 portion of the outpatient trial, as well as a trial for hospitalized patients.31 Another REGN-COV2 trial began recruiting in July 2020 to enroll 2000 asymptomatic adults who are household contacts with someone infected with the virus.32 The combination is thought to bind to the virus’s spike protein in two spots, preventing it from entering healthy cells. The study will evaluate efficacy 1 month after administration.32 This cocktail received attention in October 2020 when it was given to President Trump shortly after he had tested positive for COVID-19.33

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LY-CoV555

Another phase 3 trial will evaluate LY-CoV555, a mAb isolated from a recovered person with COVID-19.32 The trial will assess whether the mAb can prevent the virus from infecting individuals at high risk due to living or working in skilled-nursing or assisted-living facilities. Participants will be enrolled within a week of someone at their facility getting infected. The study will evaluate prevention efficacy and safety of the mAb compared with placebo over 8 weeks and will evaluate efficacy in preventing symptoms in those already infected. The study will enroll up to 2400 participants.32

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Complement inhibitors

IFX-1 (vilobelimab)

An open-label phase 2 randomized controlled trial (part of the adaptive phase 2/3 PANAMO trial) evaluated the monoclonal antibody IFX-1 (vilobelimab) to selectively block the anaphylatoxin and complement protein C5a in patients with severe and diagnosed disease.34 Targeted patients were adults with severe pneumonia, a history of shortness of breath within 14 days, or those needing noninvasive or invasive ventilation. Researchers defined severe disease as 100 mm Hg to 250 mm Hg, the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) in the supine position. Thirty patients at 3 hospitals in the Netherlands were randomly assigned in equal numbers to receive either up to 7 doses of IFX-1 plus best supportive care or best supportive care alone. The primary outcome was the percentage change in Pao2/Fio2 in the supine position between baseline and day 5, but during the study, researchers changed to assessing in any position due to severe hypoxemia in some patients. Patients in the treatment arm had a smaller proportion of serious pulmonary embolisms and fewer serious infections than patients in the control group. Researchers found IFX-1 to be safe, and preliminary secondary outcome results favored the treatment arm for further investigation.34

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Cell-based therapies

RLF-100 (aviptadil)

RLF-100 (aviptadil) is in phase 2/3 trials as a synthetic human vasoactive intestinal peptide targeting the VPAC1 receptor of the alveolar type II cells in the lungs. RLF-100 binds to cells in the alveoli, blocking cytokine actions and upregulating surfactant production.35 The drug has shown dramatic effect in a small number of patients with critical disease.36 The drug received Orphan Drug Designation for ARDS, as well as Emergency Use Investigational New Drug (IND) authorization and Fast Track designation this year for COVID-19.35 The manufacturer submitted a request for EUA in September 2020 based on a study comparing RLF-100 with placebo in 51 patients. Researchers reported that the treatment arm demonstrated a survival advantage, improved recovery time, and other clinical improvements.37

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VACCINES FOR COVID-19

Globally, 11 vaccines are in phase 3 trials, with none yet approved for full use.2

In late-phase clinical trials

AstraZeneca

AstraZeneca, collaborating with Oxford University, entered global phase 3 trials of AZD1222 in April 2020.38 The 2-dose vaccines are based on a chimpanzee adenovirus, ChAdOx1. The vaccine is designed to bring the coronavirus genes into human cells, activating an immune response to the novel coronavirus. The trial will enroll 30,000 patients, with 20,000 receiving the investigational vaccine,38 and as of mid-September 2020, approximately 18,000 patients had been vaccinated.39 The trial will be considered a success if the vaccine has 50% effectiveness, confirming at least 150 people infected with SARS-CoV-2 for those receiving placebo or AZD1222 inoculations.39 AstraZeneca plans to perform an early analysis when reaching 75 cases.39

The AstraZeneca trial was paused twice, after to 2 British participants experienced neurological illnesses, both potentially transverse myelitis. The first participant was later thought to have previously undiagnosed multiple sclerosis, and the second participant has not been diagnosed. The trials resumed in several countries, including the United States.39,40

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Moderna

Moderna, collaborating with the National Institute of Allergy and Infectious Diseases, produced vaccine candidate mRNA-1273.41 The vaccine uses messenger RNA (mRNA), teaching it to produce viral proteins and allowing the immune system to build up antibodies against the novel coronavirus. The vaccine entered phase 3 clinical trials in July 2020, enrolling 30,000 healthy volunteers in the United States. The vaccine requires 2 doses a few weeks apart.41 The vaccine candidate was 94.5% effective in a recent trial.42

Moderna will assess effectiveness after a significant number of participants contract COVID-19, anticipating late 2020 or early 2021 for that stage.2 No mRNA vaccine has received FDA approval yet.43 The mRNA vaccine would need to remain frozen, making it difficult to distribute globally.44

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Pfizer

Pfizer is collaborating with BioNTech SE and Fosun Pharma for its 2-dose mRNA vaccine.2,45 Like Moderna, Pfizer began its phase 3 trial in July 2020 after testing several vaccine versions. The company chose BNT162b2, since it had significantly fewer side effects and produced antibodies and T cells in response. The trial had been initially scheduled for 30,000 participants globally, but that number was increased to 44,000 in September 2020.45 As of August 20, 2020, 11,000 participants had been enrolled.46 In October, Pfizer and its collaborators initiated a rolling submission to the European Medicines Agency following what the companies said were encouraging preliminary results.47 On November 9, 2020, Pfizer announced that the results of the first interim efficacy analysis of results from the phase 3 trial showed a vaccine efficacy of "more than 90%."48 On November 18, 2020, Pfizer and BioNTech officially announced that the vaccine is 95% effective.49

One concern with vaccines from AstraZeneca, Moderna, and Pfizer is that their definition of efficacy includes relatively mild cases of COVID-19, which could make efforts to determine whether the vaccine prevents moderate or severe illness more difficult.40

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Johnson & Johnson

Johnson & Johnson’s candidate is made from the human adenovirus 26 (Ad26), previously used as a vaccine platform for Ebola, respiratory syncytial virus (RSV), Zika, and HIV.50 The Ebola vaccine recently received European Commission marketing authorization.51 Ad26, which causes the common cold, will deliver part of the novel coronavirus spoke protein into cells, stimulating antibody production. The phase 3 trial began in September 2020, with the goal of enrolling 60,000 volunteers globally.52 The phase 2 study showed that 1 dose simulated a robust immune response with relatively few side effects, making it unique in its potential 1-dose delivery.53

The phase 3 trial will be double-blind, with half of participants getting placebo. The investigators will gauge effectiveness by whether the experimental vaccine prevents 60% of infections compared with placebo. They anticipate a verdict after 154 study volunteers get sick from the virus in their normal daily course but will evaluate effectiveness after 20 subjects get infections.43 Johnson & Johnson will also run a smaller double-dose trial. The vaccines will need refrigeration but not subzero temperature storage, unlike the Pfizer and Moderna vaccines, which need to remain frozen.44 The company anticipates that it will take less time than the Pfizer and Moderna trials, partly since patients require only one vaccination. The company anticipates having efficacy data by the end of 2020.43

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Approved for limited use

A few vaccines outside the United States have been approved for limited use. They include the following:

CanSino Biologics

This Chinese vaccine is based on adenovirus 5 (Ad5) and was approved by the Chinese military for 1 year for its own use. CanSino began phase 3 trials in several countries in August 2020, with an estimated enrollment of 40,000 participants.2,54 Phase 2 data from 508 patients showed safety and significant immune response, mostly after a single immunization.55

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Sinovac Biotech

This Chinese company launched a phase 3 trial in several countries in July 2020 for inactivated vaccine named CoronaVac.2 The Chinese government reportedly gave emergency approval for limited use in July 2020.2

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Wuhan Institute of Biological Products

The Chinese institute developed an inactivated virus 56 and initiated phase 3 tests in several countries starting in July 2020. In September 2020, the United Arab Emirates gave emergency approval to administer the vaccine to its health care workers.2

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Gamaleya Research Institute

The Russian health ministry institute began trials with 76 participants in June 2020 of Gam-COVID-Vac, which combines Ad5 and Ad26 and is engineered with the SARS-CoV-2 gene. The investigators concluded that it was safe and induced strong immune responses in all healthy participants.57 It was approved in August under the name Sputnik V prior to the beginning of phase 3 trials. The Russian government later said that the approval was conditional on positive results. The trial will enroll 40,000 participants, up from the initial plan of 2000.2,58

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REFERENCES

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  25. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. Preprint. Posted online August 12, 2020. medRxiv. doi:10.1101/2020.08.12.20169359
  26. NIH expands clinical trials to test convalescent plasma against COVID-19. News release. National Institutes of Health. September 22, 2020. Accessed October 27, 2020. https://www.nih.gov/news-events/news-releases/nih-expands-clinical-trials-test-convalescent-plasma-against-covid-19
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  28. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-81. doi:10.1007/s11239-020-02138-z
  29. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421-1424. doi:10.1111/jth.14830
  30. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi:10.1016/j.thromres.2020.04.024
  31. Regeneron's REGN-COV2 antibody cocktail reduced viral levels and improved symptoms in non-hospitalized COVID-19 patients. News release. Regeneron. September 29, 2020. Accessed October 27, 2020. https://investor.regeneron.com/news-releases/news-release-details/regenerons-regn-cov2-antibody-cocktail-reduced-viral-levels-and
  32. Clinical trials of monoclonal antibodies to prevent COVID-19 now enrolling. News release. National Institutes of Health. August 10, 2020. Accessed October 27, 2020. https://www.nih.gov/news-events/news-releases/clinical-trials-monoclonal-antibodies-prevent-covid-19-now-enrolling
  33. Thomas K, Kolata G. President Trump received experimental antibody treatment. New York Times. October 2, 2020. Updated October 22, 2020. Accessed October 27, 2020. https://www.nytimes.com/2020/10/02/health/trump-antibody-treatment.html
  34. Vlaar APJ, de Bruin S, Busch M, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol. 2020;10.1016/S2665-9913(20)30341-6. doi:10.1016/S2665-9913(20)30341-6
  35. Inhaled aviptadil for the prevention of COVID-19 related ARDS. ClinicalTrials.gov identifier: NCT04536350. Updated September 7, 2020. Accessed October 27, 2020. https://clinicaltrials.gov/ct2/show/NCT04536350
  36. Nawrat A. NeuroRx’s RLF-100: the key to treating and preventing Covid-19 respiratory failure? Pharmaceutical Technology. August 26, 2020. Accessed October 27, 2020. https://www.pharmaceutical-technology.com/features/neurorx-covid-19-respiratory-failure/
  37. NeuroRx submits request for Emergency Use Authorization for RLF-100™ (aviptadil) in the treatment of patients with critical COVID-19 and respiratory failure who have exhausted approved therapy. News release. NeuroRx. September 23, 2020. Accessed October 27, 2020. https://www.neurorxpharma.com/press-releases/neurorx-submits-request-for-emergency-use-authorization-for-rlf-100-aviptadil-in-the-treatment-of-patients-with-critical-covid-19-and-respiratory-failure-who-have-exhausted-approved-therapy/
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