Treatment for Coronavirus? Remdesivir, Hydroxycholorquine, Actemra Update

MedMaven

by Dr. C.H. Weaver M.D. 6/22/2020

To date, no specific antiviral drugs to prevent or treat human coronaviruses (HCoVs) infections are widely available. Treatment of the virus and its consequences will likely be the most effective approach to limit the pandemic given that a vaccine is well over a year away and there is no guarantee it will be effective. Currently available medications that can be used to treat patients diagnosed with novel coronavirus pneumonia include Remdesivir, chloroquine or hydroxychloroquine and Actemra, over 70 others are being developed. Early results from small trails suggest each might improve the success rate of treatment, shorten hospital stay and improve patient outcomes, especially for individuals with lung complications. (1,2)

About Coronaviruses

Coronaviruses are large, enveloped, single-stranded, positive-sense RNA viruses that have been recognized as human pathogens for about 50 years, but no effective treatment strategy has been approved. This shortcoming became evident during the SARS-CoV outbreak which was the start of numerous studies (1,2) and has been amplified by the recent global Coronavirus COVID-19 pandemic.

About Remdesivir

Remdesivir is an antiviral medication that was developed to treat Ebola by Gilead and works by inserting directly into viral RNA. Remdesivir appears to facilitate a more rapid recovery from COVID-19 infections and based on the results of the first placebo controlled clinical trial will likely get expedited FDA approval around May 1.

University of Chicago Medicine enrolled 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials evaluating Remdesivir. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of Remdesivir. Rapid recoveries in fever and respiratory symptoms leading to nearly all patients being discharged from the hospital in less than a week has being reported.

Results from the preliminary trial comparative trial released April 29 show Remdesivir improved recovery time for coronavirus patients from 15 to 11 days which is similar to the effect that the influenza drug Tamiflu has on flu. In addition to reducing the duration of the illness treatment also decreases "viral shedding" rendering people less likely to transmit the infection to others. Remdesivir also may reduce the likelihood that patients will die - the mortality rate was 8.0% for the group receiving Remdesivir versus 11.6% for the placebo group. (15)

These results are preliminary and full trial trial analyses is necessary before conclusions can be drawn – the investigation of five- and 10-day treatment courses of Remdesivir is ongoing and the primary study endpoint is a statistical comparison of patient improvement between the two treatment arms. (14)

Dexamethasone

Low-dose dexamethasone used as a treatment for COVID-19 has been reported to reduce the risk for death by one-third in ventilated patients and also lowered risk in patients receiving oxygen, according to early results from the RECOVERY trial. Dexamethasone is a commonly used "steroid" medication thought to exert its benefit by reducing inflammation. (20)

About Chloroquine

The Food and Drug Administration (FDA) said the drugs hydroxychloroquine and chloroquine are unlikely to be effective in treating the novel coronavirus on June 12. Citing reports of heart complications, the FDA said the drugs' unproven benefits “do not outweigh the known and potential risks”. In addition based on a non-clinical laboratory study in which remdesivir was administered with either chloroquine phosphate or hydroxychloroquine sulfate, the FDA revised its fact sheet for health care providers so that co-administration of these drugs is no longer recommended. The change in recommendation is based on the suggestion that co-administration diminishes remdesivir’s antiviral activity. The FDA admits the anti-viral effect was only seen in a non-clinical setting. It has not been observed among patients.

Chloroquine is a clinically approved drug effective against malaria, and it is known to elicit antiviral effects against several viruses including human immunodeficiency virus type 1, hepatitis B virus, and herpes simplex virus type 1. (3-10) Chloroquine is also reported to inhibit the replication of some HoCov (10) and SARS-CoV (11) in vitro. Chloroquine can affect virus infection in many ways. Besides having a direct antiviral effect, chloroquine is endowed with immunomodulatory activity, suppressing the production and release of tumor necrosis factor alpha and interleukin 6, which mediate the inflammatory complications of several viral diseases. (13)

Physicians routinely use FDA approved medications to treat conditions for which they are not approved if it's in their judgement that the medication might benefit their patient, especially in "life threatening" situations. Hydroxychloroquine is are already FDA approved and has been in use for decades - the side effects at recommended doses are well documented. Patients with certain autoimmune conditions have been routinely taking hydroxychloroquine medications for years. In oncology patients are often treated with non FDA approved treatments because the "available" data suggests the treatment may benefit an individual patient and following a discussion a shared decision can be made between a patient and their physician.

Researchers have investigated the anti-corona viral properties of chloroquine and demonstrated that it inhibit some HCoV replication. Chloroquine has also been shown to prevent HCoV induced death in newborn mice. These results have led to recent testing of chloroquine and hydroxychloroquine in humans impacted with the current COVID-19 strain implicated in the global pandemic with encouraging results. (13) Clinical trials are ongoing and results are being reported.

A report released by Chinese researchers on April 2 suggests hydroxychloroquine helped to speed the recovery of a small number of patients who were mildly ill from the coronavirus. Cough, fever and pneumonia all recovered quicker, and the disease seemed less likely to become severe in people who received hydroxychloroquine than in a comparison group not given the drug. Another recent study in Brazil has raised concerns about toxicity to the heart however the dose of the drug utilized was higher than the approved dose. Results from other recent larger observational trials have not been supportive of the early trial results. It's important to remember however that none of the published trials are well controlled comparative trials evaluating the medication in comparison to a placebo. Comparative trial results will be available soon and will help determine whether these medications ultimately have a role in management of COVID-19.

About Actemra

Individuals with more severe COVID-19 infection experience shortness of breath and cough and respiratory complications are the main cause of death. If the immune system is excessive in its response to a lung infection, a cytokine storm may occur. A cytokine storm occurs when immune factors that initiate and maintain an immune response are not inhibited. This excessive response will cause extensive lung tissue damage. Membranes will become swollen and impair oxygen exchange. With that change in lung function, individuals need to be placed on ventilators to produce positive back pressure to allow the membranes of the lung to work.

Interleukin (IL) – 6 is a cytokine identified to be a major factor in the immune process. IL-6 activates T cells, B, cell, macrophages, osteoclasts, and the production of liver factors that result in fever. IL-6 is thought to be one of the prime mediators of cytokine storm. Inhibition of IL-6 in COVID-19 patients with respiratory distress has the potential to quiet the storm and allow the lungs to heal.

IL-6 is a cytokine that also mediates the inflammatory response in rheumatoid arthritis. Therapy of rheumatoid arthritis includes Anti-IL-6 biologic drugs. These are currently available for the treatment of RA but may also be of use in the treatment of COVID -19 infection.

Tocilizumab (Actemra) is a humanized anti-human IL-6 receptor antibody that can be administered intravenously or subcutaneously. In severe cases of COVID -19 pulmonary involvement, intravenous Actemra has been utilized with some success. (18) Results from the first clinical trial evaluating Actemra in COVID -19 pneumonia were published in early May.

The preliminary report suggests that Actemra may benefit COVID-19 hospitalized patients with moderately-to-severely ill COVID-19 pneumonia. Patients were enrolled if hospitalized for moderate or severe COVID-19 pneumonia. The primary endpoint was the combination of the need for ventilation (mechanical or non-invasive) or death on D14. Patients were randomized to received Actemra + standard-of-care (SOC) treatment (65 patients) or SOC alone (64 patients). The primary objective was met with Actemra treated patients having significantly fewer deaths or ventilation, compared to the SOC arm. The results will be submitted for later publication, but the " researchers and the sponsor felt obliged, from an ethical point of view, to communicate this information, while awaiting peer review while continuing the longer follow-up of these patients" (17)

Unfortunately, research reports offer conflicting views on the potential benefits and adverse outcomes of Actemra therapy in patients with severe COVID-19 infection. A recent Italian study grabbed the headlines with a press release stating Actemra did not improve respiratory symptoms and a report last month from Sanofi also showed no beneft, while higher doses were potentially beneficial. Preliminary reports of several other studies may suggest benefit when TCZ was given to SARS-CoV-2 patients. (21,22,23)

The vast majority of individuals with COVID -19 infection will be asymptomatic or will be mildly ill. About 20% will have a noticeable infection and may require medical care. A lower number will be hospitalized. In these individuals with more severe disease, the use of anti-IL6 antibodies has the potential to prevent lung damage and result in decreased mortality from this illness.

Regeneron is testing an approved drug, called Kevzara, against COVID -19. The drug, targets inflammation, not the virus itself. A similar drug from Roche, Actemra, showed early promise in a study in China. Answers from that study might be available in weeks to months, if patients respond quickly.

Regeneron said in a press release that its scientists have isolated hundreds of virus-neutralizing antibodies from mice, and patients who have recovered from COVID-19. It will choose two of these based on their potency and other qualities like to be manufactured easily, and durability in the body. The antibodies target a protein on the virus’ outer shell, called the spike protein. Having two antibodies targeting the spike protein in the treatment, not one, should mean that it is more difficult for the virus to mutate in a way that will allow it to evade both antibodies.

Creating antibody drugs against the COVID -19 virus is seen as one of the more promising approaches. Teams of researchers at Biogen, Regeneron, Gilead, Eli Lilly and others have all announced plans to develop antibody drugs against the virus.

Study Results from Ongoing Trials

The anti-viral drug combination of Lopinavir-Ritonavir does not appear to benefit patients with advanced COVID-19 infections, the combination of these drugs into a triple antiviral therapy looks promising for mild to moderate COVID-19.

Treatment with interferon beta-1b in combination with lopinavir/ritonavir and ribavirin appears safe and superior to lopinavir/ritonavir alone for reducing the duration of viral shedding and hospital stay in adults with coronavirus disease 2019 (COVID-19). 127 adults with mild to moderate COVID-19 who were admitted to Hong Kong hospitals between February 10 and March 20, 2020 were treated with lopinavir/ritonavir and ribavirin plus up to 3 doses of of interferon beta-1b or lopinavir/ritonavir alone for 14 days. The combination therapy reduced the median time from start of treatment to negative nasopharyngeal swab by 5 days; 7 days for the combination group compared 12 days for the control group. The combination group also achieved significant clinical improvements, including shorter time to alleviation of symptoms (4 days vs 8 days) and shorter average hospital stay (9 days vs 14.5 days)

The study also did not include critically ill COVID-19 patients and suggests that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may suppress the amount of virus in a patient’s body, relieve symptoms, and reduce the risk to healthcare workers by reducing the duration and quantity of viral shedding. (19)

  • Common Flu Medication - Favipiravir
  • EIDD-1931- Researchers have provided evidence that a novel anti-viral drug compound named EIDD-1931 is effective against SARS-CoV-2, the virus that causes COVID-19. EIDD-1931 blocks replication of a broad spectrum of corona viruses and an oral form of EIDD-1931 can prevent severe lung injury in mice with COVID-19 infection. The compound was developed at the Emory Institute for Drug Development in Atlanta and appears to block replication of several coronaviruses potently by introducing lethal mutations in the virus. In the latest study, the researchers showed EIDD-1931 has antiviral activity against SARS-CoV2, MERS-CoV, SARS-CoV, and closely related bat coronaviruses. EIDD-1931 inhibits coronavirus replication in human airway cell cultures up to 100,000 fold. In mouse models infected with SARS-CoV or MERS-CoV, giving the drug before or shortly after infection prevented disease, blocked virus replication and prevented death. (16)

Vaccine Progress

There are 70 vaccines in various stages of development, most in pre-clinical trials (animal studies to assess immune response), and there are three vaccines currently in clinical human trials, with initial results expected late Summer or early Fall:

  • Moderna (Cambridge, MA): This was the first vaccine to be studied in humans with the first person receiving it in Seattle in March.
  • Inovio Pharmaceuticals (San Diego CA): One trial is underway at the University of Pennsylvania and a second trial of their vaccine is about to begin in South Korea.
  • CanSino Biological (Wuhan, China): Phase 1 completed in March, Phase 2 starting in April to look for adverse response and for antibody responses

References

  1. Antiviral Activity of Chloroquine against Human Coronavirus OC43 Infection in Newborn Mice
  2. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia
  3. Kouroumalis, E. A., and J. Koskinas. 1986. Treatment of chronic active hepatitis B (CAH B) with chloroquine: a preliminary report. Ann. Acad. Med. Singapore 15:149-152.
  4. Pardridge, W. M., J. Yang, and A. Diagne. 1998. Chloroquine inhibits HIV-1 replication in human peripheral blood lymphocytes. Immunol. Lett. 64:45-47.
  5. Rubin, M., H. N. Bernstein, and N. J. Zvaifler. 1963. Studies on the pharmacology of chloroquine. Recommendations for the treatment of chloroquine retinopathy. Arch. Ophthalmol. 70:474-481.
  6. Savarino, A., J. R. Boelaert, A. Cassone, G. Majori, and R. Cauda. 2003. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect. Dis. 3:722-727.
  7. Savarino, A., L. Gennero, K. Sperber, and J. R. Boelaert. 2001. The anti-HIV-1 activity of chloroquine. J. Clin. Virol. 20:131-135.
  8. Singh, A. K., G. S. Sidhu, R. M. Friedman, and R. K. Maheshwari. 1996. Mechanism of enhancement of the antiviral action of interferon against herpes simplex virus-1 by chloroquine. J. Interferon Cytokine Res. 16:725-731.
  9. Tsai, W. P., P. L. Nara, H. F. Kung, and S. Oroszlan. 1990. Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res. Hum. Retrovir. 6:481-489.
  10. Blau, D., and K. V. Holmes. 2001. Human coronavirus HCoV-229E enters susceptible cells via the endocytic pathway, p. 193-197. In E. Lavi (ed.), The nidoviruses, coronaviruses and arteriviruses. Kluwer, New York, NY.
  11. Fouchier, R. A., N. G. Hartwig, T. M. Bestebroer, B. Niemeyer, J. C. de Jong, J. H. Simon, and A. D. Osterhaus. 2004. A previously undescribed coronavirus associated with respiratory disease in humans. Proc. Natl. Acad. Sci. USA 101:6212-6216.
  12. Savarino, A., J. R. Boelaert, A. Cassone, G. Majori, and R. Cauda. 2003. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect. Dis. 3:722-727.
  13. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
  14. Early peek at data on Gilead coronavirus drug suggests patients are responding to treatment
  15. Gilead Announces Results From Phase 3 Trial of Investigational Antiviral Remdesivir in Patients With Severe COVID-19
  16. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice
  17. Le tocilizumab améliore significativement le pronostic des patients avec pneumonie COVID moyenne ou sévère
  18. Zhang X, Song K, Tong F, et al. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv. 2020;4(7):1307-1310.
  19. Chan JF Yao Y Yeung ML et al.Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis. 2015; 212: 1904-1913
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