Author Name: SUSHMITA KUSWA*
Designation: Senior Manager
Institution Name: ARISTO PHARMACEUTICALS PVT. LTD.
Coronavirus disease (COVID-19), which appeared in December 2019, hasbeen declared pandemic and new treatments are urgently needed as we enter a phase beyond containment. With no vaccine or antiviral therapeutic agent available for COVID-19 treatment, there is an urgent need to identify novel measures for its treatment and prevention. Since vaccine development could take well over a year and novel treatment even longer, researchers are looking to drug repurposing as another solution. Drug repurposing is a strategy where existing drugs, that have already been tested safe in humans, are redeployed to combat difficult-to-treat diseases. The current article is a review article based on the recent repurposed drugs used in India. More drugs may be repurposed to fight the COVID-19 pandemic in the future.
Keywords: COVID-19, pandemic, management strategy, drug repurposing
The COVID-19 i.e. a Coronavirus disease 2019 is a respiratory tract infection caused by the novel coronavirus which was first identified in Wuhan State of China at the end of 2019. Genetically this virus closely resembles to severe acute respiratory syndrome (SARS) virus. 1 On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency.2, 3 On March 11, 2020, the WHO declared COVID-19 a global pandemic, its first such designation since declaring H1N1 influenza a pandemic in 2009.4 It spread across the globe (More than 190 counties) within a short period, i.e. 45 to 90 days of its inception. The SARS-CoV-2 (COVID-19) created the devastating situation not only in developing countries but also in the developed counties. Till date, there is no specific treatment available to treat COVID-19 infection.5, 6
As India’s COVID-19 positive cases approach the fifteen lakh count, we are the third most affected country by the SARS-CoV-2 virus. 7 While the spread has been contained in some countries, the lack of an actual treatment puts many patients at risk of death and long-term injury. Although infected people can develop antibodies and overcome this disease, many young and old are not able to fight back. With no vaccine or antiviral therapeutic agent available for COVID-19 treatment, there is an urgent need to identify novel measures for its treatment and prevention. Since vaccine development could take well over a year and novel treatment even longer, researchers are looking to drug repurposing as another solution.
Defining Drug Repurposing
Drug repurposing is a strategy where existing drugs, that have already been tested safe in humans, are redeployed to combat difficult-to-treat diseases.8
There are a number of different definitions of drug repurposing. All of them contain two key elements:• taking existing scientific or medical knowledge and technology that is “approved” for human use in one disease or condition; and• applying this knowledge and technology to another disease or condition.9
Drugs repurposed to treat COVID-19
Since developing an effective drug can take several years, scientists have been looking at drugs currently in the market that could be repurposed to treat COVID-19 patients. Are there any that have been successful or at least show potential? The answer is yes and no.
Most drugs considered for repurposing in the therapy of the COVID-19 outbreak are commercially available and their dosage and toxicity in humans is well known, due to years (or even decades) of clinical use. This can allow their fast-track evaluation in phase II–III clinical trials, or even within straightforward compassionate use.10
Potentially suitable drugs for repurposing are essentially those affecting signal transduction, synthesis of macromolecules and/or bioenergeticpathways, those able to interfere with the host immune response, in particular, the life-threatening cytokine storm associated with severe COVID-19 and finally antiviral compounds are occasionally effective in fighting cancer. A single molecule can present more than one of the above-mentioned mechanisms.10
Recent Repurposed Drugs in India for COVID-19 Management
Based on severity of symptoms, Covid-19 can be categorised into three groups: mild, moderate and severe.1. Hydroxychloroquine (HCQ): Hydroxychloroquine belongs to a class of drugs called antimalarials. Hydroxychloroquine may also be used to treat rheumatoid arthritis and systemic lupus erythematosus.11
Initially, HCQ was authorized for emergency use to address COVID-19 by the FDA in Apr’20 but only to be revoked two months later on 15 Jun’20. The FDA has said that there is no evidence that ensures that oral administration of HCQ or chloroquine may be effective in treating the disease. On the other hand there is evidence that it could instead pose heart risks for some patients.
In India, the Drug Controller General of India (DCGI) has approved the protocol recommended by the ICMR National Task Force for restricted use in emergency situation in March 2020. A revised government advisory has recommended use of HCQ as a preventive medication for asymptomatic healthcare workers working in non-COVID-19 hospitals, frontline staff on surveillance duty in containment zones and paramilitary/police personnel involved in coronavirus infection related activities. HCQ against COVID-19 is also recommended for all asymptomatic healthcare workers involved in containment and treatment of COVID-19 and household contacts of laboratory confirmed cases. The revised advisory issued by the ICMR, however, cautioned that the intake of the medicine should not instil a sense of false security. The Updated National Clinical Management Protocol, issued by MoHFW, mentions the use of HCQ for management of mild to moderate cases of COVID-19.12
The combination of Azithromycin and HCQ was earlier recommended by the ICMR for mild, moderate and severe cases of COVID-19. However, as per the new protocol for treatment, use of Azithromycin in combination with HCQ has been removed. In March’20, a study done in France suggested that Azithromycin supplemented the effects of HCQ in reducing viral load in COVID-19 patients. However, another French study and a study done in the US said that the combination of the two drugs was ineffective. The US study is still in the preprint phase and is yet to be peer-reviewed.2. Remdesivir: Remdesivir is a broad-spectrum antiviral drug. 11
After HCQ, Remdesivir has emerged as one of the most promising drug candidates for the treatment of COVID-19 patients. On 1 May2020, the US FDA issued Emergency Use Approval (EUA) of remdesivir to allow its emergency use for severe COVID-19 (confirmed or suspected) in hospitalized adults and children. This drug has shown only moderate potency with no statistically significant effect on deaths. However, detailed studies have revealed a very specific mechanism of action by blocking the viral machinery in charge of its replication. Alternate ways to make this drug viable i.e. as powder for inhalation or injected subcutaneously, is currently underway. Remdesivir is currently administered intravenously as it cannot be degraded in the liver. Remdesivir has been rapidly advanced into several clinical trials for COVID-19, and early informal data being released from those trials suggest that Remdesivir is effective, but such datasets need to be used cautiously for generalizing the understanding of either safety or efficacy.
In India, the DCGI approved Remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalised with severe disease on 1 June 2020. This approval has been granted under “restricted emergency use”.12 Remdesivir has to be used with extreme caution for Covid-19 treatment due to its potential for serious adverse effects including liver and kidney injury.3. Favipiravir: Favipiravir is an antiviral drug.11
Favipiravir was developed for influenza and approved in Japan in 2014, specifically for new pandemic influenza outbreaks. Favipiraviris in the clinical trial stage for the treatment of Covid-19 not only in Japan, where the drug is approved for treating influenza but also in the US and Europe. While Japan has commenced phase 3 clinical trials, in the United States a phase 2 trial will start.
On 19 June 2020, the DCGI has approved Favipiravir in COVID-19 patients with co-morbid conditions such as diabetes and heart disease with mild to moderate COVID-19 symptoms. Favipiravir has been approved for emergency medical use under the fast-tracked approval process.12 Favipiravir is now the first oral approved medication in India for the treatment of COVID-19.4. Dexamethasone: Dexamethasone is a corticosteroidal drug.
Dexamethasone is widely used in many other diseases to reduceinflammation. This widely available and economical drug was the only one in a pool of five treatments (Lopinavir Ritonavir, Azithromycin, Dexamethasone, Convalescent Plasma and Tocilizumab) included in the one of the world’s biggest randomized trials to show a statistical decrease in the number of deaths (by up to one third) in hospitalised patients with severe respiratory complications of COVID-19. This new finding is considered a breakthrough and offers some hope as this medicine is widely available in pharmaceutical shelves worldwide. WHO emphasises that Dexamethasone should only be used for patients with severe or critical COVID-19 under close clinical supervision. It can be given orally as well as through IV. Further, the drug can be given to a coronavirus patient with comorbidities, who is in a critical condition.
The Union Health Ministry on 27 June 2020, released an updated National Clinical Management Protocol for COVID-19 cases. This includes the advice to use dexamethasone as an alternative to methylprednisolone for managing moderate to severe cases.125. Methylprednisolone: Methylprednisolone is a corticosteroidaldrug.11
Methylprednisolone, which is used in case of refractory shock or cytokine (immune cells) activation syndrome, is found to be effective in treating COVID-19. Methylprednisolone is among the drugs recommended by ICMR for COVID19 on 13 June 2020 for three days in moderate illness and five-seven days for severe illness.12
An observational research by doctors at a tertiary care hospital in Mumbai said methylprednisolone, a glucosteroid, helped them cure six out of seven serious COVID patients who had low oxygenation saturation levels — a sign of the disease’s severity — apart from several other symptoms.6. Tocilizumab (TCZ): Tocilizumab is a monoclonal antibody against interleukin-6 (IL-6).11
This drug is already approved for the treatment of rheumatoid arthritis and the cytokine release syndrome associated with the CAR-T cell treatment of cancer patients. This last condition is very similar to the pathogenesis of the cytokine storm in severe COVID-19 and justifies the experimental use of tocilizumab in the latter stage. The IL-6 blocker tocilizumab has been explored as a possible therapy for immunomodulation, to mute the so-called cytokine storm, the excessive and damaging rise in pro-inflammatory cytokines, in the final stage of severe COVID-19. Tocilizumab treatment is effective to reduce the mortality of severe COVID-19.
As per updated National Clinical Management Protocol for COVID-19, Tocilizumab (Off Label) may be considered in patients with moderate disease with progressively increasing oxygen requirements and in mechanically ventilated patients not improving despite use of steroids. Long term safety data in COVID 19 remains largely unknown. 117. Itolizumab: Itolizumab is a monoclonal antibody.
This drug is previously approved for treating psoriasis but on 11 July 2020, DCGI has approved Itolizumab for “restricted emergency use” to treat COVID-19 patients with moderate to severe acute respiratorydistress. It is for the treatment of ‘cytokine’ release syndrome in moderate to severe acute respiratory distress syndrome patients due to COVID-19.11
Although, on 27 July 2020, The National Task Force on COVID-19 has decided against including Itolizumab drug in clinical management protocols for treating the disease as there was not enough evidence currently to get the drug included in the clinical management protocols for COVID-19. Based on the media reports about the rejection of the drug, the company has now decided to share more data as “evidence”, which it has derived from off-label*use of the drug on 1,000 patients. (*Off-label means doctors have prescribed the drug after taking the consent of the patient on compassionate grounds.) 12
India’s rising COVID-19 cases need all the help they can get. In the race to treat COVID-19 pandemic, investing in repurposing drugs can result in a significant savings of cost and years earlier to the patient than traditional drug development. COVID-19 is not expected to disappear and life is unlikely to return to normal until herd immunity emerges. In the meantime, the challenge will be finding safe and effective treatments and ensuring availability on a much abbreviated timeline.
References1. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020 Feb 3 [Epub ahead of print]. doi: 10.1038/s41586- 020- 2012- 7 .2. Gallegos A. WHO Declares Public Health Emergency for Novel Coronavirus. Medscape Medical News. Available at https://www.medscape.com/viewarticle/924596. 2020 Jan 30; Accessed: March 25, 2020.3. Ramzy A, McNeil DG. W.H.O. Declares Global Emergency as Wuhan Coronavirus Spreads. The New York Times. Available at https://nyti.ms/2RER70M. 2020 Jan 30; Accessed: March 25, 2020.4. The New York Times. Coronavirus Live Updates: W.H.O. Declares Pandemic as Number of Infected Countries Grows. The New York Times. Available at https://www.nytimes.com/2020/03/11/world/coronavirus-news.html#link-682e5b06. 2020 Mar 11; Accessed: March 24, 2020.5. A.Y. Pawar, Combating Devastating COVID -19 by Drug Repurposing, International Journal of Antimicrobial Agents, https://doi.org/10.1016/j.ijantimicag.2020.1059846. Chauhan S, Comprehensive review of coronavirus disease 2019 (COVID-19), Biomedical Journal, https://doi.org/10.1016/j.bj.2020.05.0237. https://www.worldometers.info/coronavirus/country/india/8. Suranga L Senanayake. Drug repurposing strategies for COVID-19. Future Drug. Discov.9. Shahin Akhondzadeh. Avicenna Journal of Medical Biotechnology. Vol. 12, No. 2, April-June 202010. Ciliberto et al. Journal of Experimental & Clinical Cancer Research (2020) 39:86.11. R. Wu et al. An Update on Current Therapeutic Drugs Treating COVID-19. Current Pharmacology Reports12. https://www.mohfw.gov.in/pdf/UpdatedClinicalManagementProtocolforCOVID19dated03072020.pdf13. https://theprint.in/health/biocon-to-give-more-data-on-itolizumab-to-covid-task-force-after-its-rejection-for-treatment/468989/