Months after the COVID-19 pandemic began, researchers are still working to identify effective treatments to help people who develop this new disease. While many people with COVID-19 will only get mild symptoms, those who experience moderate and severe symptoms need more effective treatment options.
Researchers have not yet identified a truly promising treatment option, but what is becoming clear is that treatment with a combination of agents is likely to be our best approach.
Severe cases of COVID-19 already receive supportive care to relieve their symptoms and new treatments are being tested in combination with this level of care. Supportive care includes monitoring, oxygen therapy, fluid management, antibiotics (if a bacterial infection also develops) and other measures, which may include antivirals and other drug therapies. New treatments are also being tested in patients with mild or moderate COVID-19 symptoms.
Here’s an update on the 7 drugs we looked at back in March and some other new options that are now under investigation.
Remdesivir has not yet proven to be a game changer in the fight against COVID-19. It is thought to be of most benefit to patients who require oxygen supplementation, but who do not need mechanical ventilation.
Patients treated with remdesivir had a shorter time to recovery compared with patients who received placebo (11 days vs 15 days), according to preliminary results from 1059 patients in a trial, but patients in both groups still died at the same rate. The randomized, double-blind, placebo-controlled trial in hospitalized COVID-19 patients was initiated by the National Institute for Allergy and Infectious Diseases (NIAID).
Gilead Sciences continues to investigate the potential of remdesivir and is now set to test the drug in combination with other therapeutics to see if this improves patient outcomes. The Adaptive COVID-19 Treatment Trial 2 (ACTT-II) trial, for example, will evaluate remdesivir in combination with baricitinib.
The optimal dosing regimen and duration of treatment (5-days or 10-days) for remdesivir are still under investigation and the drug is also being tested in patients with less severe COVID-19 symptoms. Gilead’s phase III SIMPLE trials are evaluating remdesivir in patients with moderate and severe disease, and the SOLIDARITY trial being conducted by the World Health Organization (WHO) is also investigating the drug.
On May 1, 2020 the US Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for use of remdesivir to treat hospitalized patients with severe COVID-19. This was to enable wider use of the drug at more hospitals across the US. The EUA is a temporary measure and does not replace full FDA approval. Remdesivir (Veklury), has also been granted an exception approval in Japan.
Remdesivir was used to treat the first patient in the US who was hospitalized with COVID-19. It is an experimental nucleotide analog which works by blocking an enzyme (RNA-dependent RNA polymerase, RdRps) necessary for viral replication.
2. Lopinavir + ritonavir
The combination drug lopinavir + ritonavir (Kaletra, Aluvia) is also being investigated for COVID-19. Initial results from a randomized trial conducted in 199 patients with severe COVID-19 suggested that lopinavir + ritonavir does not provide any benefit in patients with severe COVID-19. In June 2020, researchers from the RECOVERY trial also reported that lopinavir + ritonavir provided no clinical benefit to hospitalized patients with COVID-19, confirming the findings of the early study. The RECOVERY trial is being run in the UK and has enrolled almost 12,000 patients to test different COVID-19 treatments. The lopinavir + ritonavir arm enrolled 1596 patients to receive the drug combination and compared them with 3376 patients who received standard care.
Triple therapy with lopinavir + ritonavir, interferon beta-1b and ribavirin, however, has appeared to be beneficial, according to the results of a phase II trial conducted in Hong Kong. The combination of lopinavir + ritonavir, interferon beta-1b and ribavirin shortened the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19 treated in the phase II trial. Patients receiving triple therapy tested negative for SARS-CoV-2 after 7 days of treatment, compared with 12 days for those in the control group. The trial enrolled 127 patients and 86 of them were randomly assigned to receive triple therapy, while the rest were part of the control group.
Lopinavir + ritonavir is being investigated in the SOLIDARITY trial being conducted by WHO and other trials, including some investigating its potential to prevent COVID-19. The drug which combines two protease inhibitors, is already used for the treatment of human immunodeficiency virus (HIV).
Favipiravir (Avigan) is an anti-influenza drug that has been under investigation since February. Results from China suggest favipiravir is safe and effective in patients with mild to moderate COVID-19. In one clinical trial, patients taking the drug in combination with interferon alpha (IFN-α) testing negative after a median of 4 days compared with 11 days for those in the control group. Patients treated with favipiravir in another trial were also reported to have recovered from fevers and coughs more quickly than those who did not receive it. They also needed less respiratory aids.
Interim results from Japan, however, have not been positive. It was hoped that favipiravir would be approved in Japan for the treatment of COVID-19 by the end of May, but favipiravir has not been found to be effective in the trials conducted so far in patients with mild or no COVID-19 symptoms. There are also concerns about the potential for the drug to cause fetal abnormalities in pregnant women.
A number of trials of the drug are continuing or planned at various sites around the world, including some investigating it in combination with other medications.
Fingolimod (Gilenya) is an immunomodulator that is also under investigation. It is able to alter the way the immune system works, by acting as a sphingosine 1-phosphate receptor modulator. Fingolimod is already used to treat relapsing forms of multiple sclerosis. A phase II trial of fingolimod in patients with COVID-19 was initiated in China in February 2020 and was still recruiting patients in May 2020.
5. Hydroxychloroquine & chloroquine
In June 2020, the World Health Organization (WHO) and the US National Institutes of Health (NIH) halted the hydroxychloroquine (Plaquenil) arm of the Solidarity trial and the ORCHID study, respectively, after results showed that hydroxychloroquine provided no benefit to hospitalized patients with COVID-19. Previously hydroxychloroquine trials had been temporarily halted over safety concerns following the publication of a multinational registry analysis in May 2020. However, the authors of the analysis later retracted their paper after the veracity of the data they used was questioned and an independent third-party peer review could not be conducted. Hydroxycholoquine trials resumed briefly after the analysis was retracted, but were stopped again after results indicated the drug was not effective.
Previously, a phase II trial of chloroquine (Resochin) in patients with severe COVID-19 was halted in Brazil. Preliminary findings suggested that high dose chloroquine (600mg twice daily for 10 days) was lethal and associated with serious heart risks in some patients.
Like remdesivir, chloroquine and hydroxychloroquine had been granted an EUA by the FDA allowing them to be used in the treatment of hospitalized teen and adult patients with COVID-19 who were unable to access them via a clinical trial. The EUA was granted in March 2020, but was revoked on June 15, 2020.
Hydroxychloroquine used in combination with an antibiotic called azithromycin (Z-Pak, Zithromax) was of particular interest in the early stages of the COVID-19 pandemic. The drugs are antimalarial and amebicidal drugs, which also possess antiviral properties.
Bevacizumab (Avastin) is a monoclonal antibody that targets vascular endothelial growth factor (VEGF). It is usually used to treat colorectal cancer and other solid tumors. In March 2020, it was undergoing investigation in China for the treatment of COVID-19. In May 2020, bevacizumab was still being investigated in patients with COVID-19 in China, as well as at a site in Italy.
Methylprednisolone is an older corticosteroid drug, which is commonly used in the treatment of a variety of disorders including allergies, endocrine disorders, rheumatic disorders and more.
The use of corticosteroids for the treatment of COVID-19 was somewhat controversial in March 2020 and WHO only recommended that it be administered to patients with COVID-19 if it was required for another reason. This was because literature reviews suggested it lacked efficacy and possibly caused harm in patients with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) who received it. Early evidence, however, suggested methylprednisolone could be of benefit in patients with COVID-19. In May 2020, methylprednisolone was still being investigated in clinical trials, including in combination with other medications, such as tocilizumab.
Results of a retrospective cohort study, indicate a role for early, low-dose, short-term methylprednisolone in patients with severe COVID-19. Treatment with methylprednisolone was associated with better clinical outcomes in such patients if used before acute respiratory distress syndrome (ARDS) occurred.
Other agents under investigation that combat inflammation
In April 2020, it became clear that inflammation was a key concern in patients with COVID-19. Researchers are now investigating a number of drugs with anti-inflammatory properties to help treat patients with COVID-19 including:
Baricitinib (Olumiant): Baricitinib is a janus kinase (JAK) inhibitor, which is already used in the treatment of rheumatoid arthritis. BenevolentAI used its artificial intelligence platform to identify this Eli Lilly drug as a potential treatment for COVID-19. It is being evaluated alone and in combination with other agents, such as remdesivir.
Inhaled beta-interferon: An inhaled formulation of beta-interferon (SNG001), assigned the code name SNG001, is also being investigated after showing promise in patients with asthma and chronic obstructive pulmonary disease (COPD) who also had lung infections, such as the flu. On May 26, Synairgen announced it was expanding it trial of SNG001 to include treating COVID-19 patients at home within 3 days of their onset of symptoms.
Opaganib (Yeliva): Redhill’s experimental drug opaganib, a selective inhibitor of sphingosine kinase-2, has shown promise in the first 6 patients with moderate to severe COVID-19 treated with the drug.
Ruxolitinib (Jakafi): Novartis’ ruxolitinib is another JAK inhibitor under investigation. It is already approved for the treatment of acute graft versus host disease (GVHD), myelofibrosis and polycythemia vera. Treatment with ruxolitinib was not associated with significantly faster clinical improvement compared with patients treated in the control group, according to the results of a phase II trial. It did, however, result in significant chest CT improvements, faster recovery from lymphopenia and significantly decreased levels of 7 cytokines.
Tocilizumab (Actemra): Roche’s anti-interleukin-6 (IL-6) receptor therapeutic, tocilizumab, is another agent of interest. It is already approved for the treatment of rheumatoid arthritis and other conditions, including severe or life-threatening cytokine release syndrome following chimeric antigen receptor T cell treatment.
MEDI-3506: Astrazenec’s interleukin-33 (IL-33) monoclonal antibody is being investigated for the treatment of COVID-19 as part of the UK’s ACCORD trial.
Acalabrutinib (Calquence): Acalabrutinib is Astrazeneca’s bruton kinase (BTK) inhibitor, which is also being evaluated. It is already approved for the treatment of mantel cell lymphoma, chronic lymphocytic leukemia and small lymphocytic lymphoma.
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