In part 1 through 4 of this series we discussed the main drugs now being evaluated in the fight against SARS-CoV-2.
In this blog we wrap up the series with short descriptions of any other drugs that are currently undergoing clinical trials to assess their efficacy against SARS-CoV-2 and bring you a short list of academic experts with experience working with these drugs.
Avigan is a broad-spectrum antiviral with demonstrated activity against influenza viruses. The drug was developed by Fujifilm and has been approved in Japan and China to treat novel influenza infections. It is currently not approved in the US and Europe.
Avigan is a selective inhibitor of influenza RNA-dependent RNA-polymerase, an enzyme required for virus replication. It has shown activity not just against influenza but also other retroviruses and is therefore expected to be effective against the novel coronavirus. However, adverse events can be severe: the drug is known to be teratogenic and embryotoxic.
Clinical trials for Avigan began in Japan and China in late March and are about to start in the US. The FDA approved a phase 2 clinical study1 with about 50 COVID-19 patients in three hospitals in the Boston area.
Currently, enough of the drug is manufactured in Japan to treat approximately 700,000 people2 and the government is looking to triple production. Avigan is not commercially available and will only be made available on request by the Japanese government.
Oseltamivir is an antiviral medication approved for both treatment and prophylaxis of influenza A and B. Originally discovered by Gilead Sciences, Roche exclusively licensed the patents in 1996. A generic version of Tamiflu, Antiflu, is manufactured by Cipla.
Tamiflu3 inhibits the neuraminidase enzyme on the surface of the virion. The enzyme is used to release the viruses from the infected cells and facilitate movement in the respiratory tract. When neuraminidase is inhibited the virions can’t be released from the host cells and get entrapped in respiratory secretions. Tamiflu is highly specific to influenza virus and to date there is no evidence4 that it is effective against SARS-CoV-2.
Known side effects are nausea, vomiting, diarrhea, dizziness, headache, nosebleed, eye redness or discomfort, insomnia, cough, or other respiratory problems and in rare cases serious mental/mood changes.
Currently, three trials are in planning that evaluate oseltamivir in combination with hydroxychloroquine (NCT04303299) or ritonavir (NCT04261270) as well as a phase 4 study comparing the efficacy of oseltamivir, Arbidol hydrochloride, and lopinavir/ritonavir (NCT04255017).
Umifenovir is an antiviral drug used to treat influenza in Russia and China. The drug is not approved for use in other countries. In vitro testing has shown activity against various viruses, including coronaviruses.
Umifenovir prevents contact between the virus and the host cell making fusion between the viral envelope and the cell membrane impossible and preventing the virus from entering the host cell.
Clinical data is limited but in vitro activity against SARS-CoV-1 and SARS-CoV-2 has been reported5 in a small retrospective study in China where umifenovir combined with lopinavir/ritonavir showed more favorable outcomes than lopinavir/ritonavir alone. Two clinical trials are initiated in China (NCT04252885, NCT04260594).
Anakinra is an anti-rheumatic drug marketed by the Swedish company Orphan Biovitrum. It is a recombinant protein drug that was approved by the FDA in 2001 to treat rheumatoid arthritis, cryopyrin associated periodic syndrome, and Still’s disease.
Anakinra is a recombinant Interleukin-1 receptor antagonist that competitively binds to IL-1 alpha and beta and inhibits their binding to IL-1 receptor. As such, anakinra may be useful in combating cytokine release syndrome.
Common side effects6 include worsening of rheumatoid arthritis symptoms, nausea, vomiting, diarrhea, stomach pain, headache, joint pain, flu symptoms, cold symptoms such as stuffy nose, sneezing, and sore throat. In addition, serious infections may occur during treatment with anakinra.
There is currently no published clinical data that support the efficacy or safety of Anakinra for treating COVID-19, but encouraging preliminary results from a study in China where Anakinra was used in combination with tocilizumab. A Phase 3 randomized, open-label, multicenter trial is expected to start in Italy to evaluate efficacy and safety in reducing hyperinflammation and respiratory distress in patients with COVID-19 (NCT04324021).
Ruxolitinib is a (JAK) kinase inhibitor used to treat myelofibrosis, a cancer of the bone marrow, which results in decreased blood cell production. The drug was approved by the FDA in 2011 to treat patients with high-risk myelofibrosis and in 2014 for polycythemia vera. Ruxolitnib is marketed by Incyte in the US and Novartis elsewhere.
The drug inhibits signaling of cytokines via JAK1 and JAK2 kinases. As a consequence, ruxolitinib has a potential to combat cytokine release syndrome in severely ill patients.
And here is a surprising one: Ascorbic Acid (Vitamin C)
As an antioxidant and cofactor in many enzymatic reactions that mediate a variety of essential biological functions, Vitamin C is on the WHO List of Essential Medicines. While data does not support the claim that Vitamin C reduces the incidence of the common cold, studies7 do suggest that the duration could be shortened.
Currently, a study in China8 on Vitamin C infusions is underway to assess whether it can help improve the prognosis of patients with COVID-19. A phase 2 US study9 is assessing whether hydroxychloroquine, Vitamin C, Vitamin D, and Zinc can prevent infection with COVID-19.
Currently, there is no known published clinical trial evidence supporting efficacy or safety in patients with COVID-19, but a single arm, non-randomized, open phase 2 trial10 for front line treatment of COVID-19 patients with defined hyperinflammation is in planning. A phase 3 clinical trial evaluating ruxolitinib plus standard of care vs standard of care alone is being initiated pending FDA approval of the protocol in patients with COVID-19-associated cytokine storm (NCT04337359).
This list of drugs is bound to change as new candidates emerge or are dropped because they are not efficacious.
COVID-19 is a new disease and very few researchers have experience with studying the efficacy of these drugs in COVID-19 patients. This figure gives you a quick overview of leading experts on these drugs.