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Drug Repurposing and its impact

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While using such repurposed drugs individually may ultimately not yield a significant clinical benefit, carefully combined cocktails could be very effective, writes Dr Balasubramanian Mahadevan, Ex-Medical Director at PD Hinduja, Saifee, Bhatia, Shushrusha &Lilavati Hospitals in Mumbai

COVID-19 has now been declared a pandemic and new treatments are urgently needed as we enter a phase beyond containment. Developing new drugs from scratch is a lengthy process, thus impractical to face the immediate global challenge. 

Drug repurposing is an emerging strategy where existing medicines, having already been tested safe in humans, are redeployed to combat difficult-to-treat diseases. 

While using such repurposed drugs individually may ultimately not yield a significant clinical benefit, carefully combined cocktails could be very effective, as was for HIV in the 1990s; 

In the absence of any vaccines to prevent COVID-19, there are many clinical trials (CT) taking place to find a treatment. These CTs are mainly focusing on either repurposing or repositioning the existing molecules. WHO has published a landscape of therapeutics which could be used for treating COVID-19, and some of them are undergoing CTs as well. Generally speaking, patents are not a concern when it comes to old molecules under CTs because these molecules are already out of patent protection.

However, a few of these molecules are still under patent protection in many countries. Two in particular – Remdesivir and Favipiravir – are under patent protection in India. The generic availability of these medicines can facilitate compassionate use and CTs in India without depending on supply from the patent holders. Therefore, the Government of India should use the compulsory license or government use license to facilitate the generic production of these medicines.

Favipiravir

Favipiravir is backed by strong clinical evidence, showing encouraging results in patients with mild to moderate Covid-19. It offers broad-spectrum RNA virus coverage with clinical improvement noted in 20-90 plus age group.

The approval of the drug was based on an interim report of phase three clinical trials. A source in the report said that Drug Controller General of India DCGI approved the drug even while the trial was ongoing as the interim results so far have been encouraging.

Last month Glenmark Pharmaceuticals had conducted phase 3 clinical trials of Favipiravir as a COVID-19 with 150 patients, enrolled from 9 leading government and private hospitals across the country.

On June 19, Glenmark Pharmaceuticals has just received the manufacturing and marketing approval from India’s drug regulator to launch the oral antiviral drug Favipiravir (FabiFlu®) for the treatment of mild to moderate COVID-19 patients in India.

This approval has been granted based on the evaluation of data and in consultation with the Subject Expert Committee, as part of the accelerated approval process, considering the emergency situation and unmet medical need of the COVID-19 outbreak.

The drug will be available for restricted emergency use in India.

Restricted use entails responsible medication use where every patient must have signed informed consent before treatment initiation.

Notably, Favipiravir is has been approved in Japan since 2014 for the treatment of novel or re-emerging influenza virus infections.

It has a unique mechanism of action as it is converted into an active phosphoribosylated form (favipiravir-RTP) in cells and recognized as a substrate by viral RNA polymerase, thereby inhibiting RNA polymerase activity. 

Last month, Glenmark had also announced that it is conducting another clinical trial to evaluate the efficacy of two antivirals Favipiravir and Umifenovir as a combination therapy in moderate hospitalized COVID-19 patients in India.

It will be available under the brand name Fabi Flu as a prescription-based medication for Rs 103 per tablet, with a recommended dose of 1,800 mg twice a day on day 1 and 800 mg twice a day up to 14th day.

The antiviral offers broad-spectrum RNA virus coverage with clinical improvement noted across age groups 20 to 90 years. Favipiravir can be used in COVID-19 patients with co-morbid conditions such as diabetes and heart disease with mild to moderate COVID 19 symptoms.

It offers a rapid reduction in viral load within 4 days and provides faster symptomatic and radiological improvement. It shortens the recovery period. Of most importance, Favipiravir has shown clinical improvement of up to 88 per cent in COVID-19 mild to moderate COVID 19 cases including those with comorbidities. Very few side effects such as rise in Uric Acid observed &alterations in liver function tests have been reported. However so far there is no documented evidence of Significant Reduction in mortality 

Remdesivir

Remdesivir, an antiviral drug first developed for treating Ebola in 2014, is one of the possible Covid-19 treatments being investigated in the WHO’s Solidarity Trial. It inhibits viral replication in the body.

Last month, the US National Institutes of Allergies and Infectious Diseases released preliminary trial results showing recovery time of COVID patients given remdesivir improved from 15 to 11 days. The Drug Controller General of India on June 1 approved a five-day regime of remdesivir. Doctors are currently prescribing it for moderately to severely ill patients.

Remdesivir  shortened the time to recovery in adult patients who were hospitalized with COVID-19 pneumonia, improved Oxygenation and reduced ventilatory requirements.

The side effects reported in patients who received remdesivir included constipation, hypoalbuminemia, hypokalemia, anaemia, thrombocytopenia, and elevated bilirubin.

Other drugs such as Lopinavir–ritonavir arbidol, chloroquine, interferons, immunoglobulins, and the plasma of patients who have recovered from COVID-19 infection have also been tried with varying degrees of success.

The WHO had launched the “Solidarity” international trial to evaluate the four most promising therapies for the management of COVID-19 compared to the standard of care. 

The various drugs included in this trial are remdesivir, chloroquine or hydroxychloroquine, lopinavir–ritonavir, and interferon-β-1a. As of April 21, 2020, over 100 countries were participating in the trial.

Tocilizumab

Tocilizumab, a monoclonal antibody against the interleukin (IL)-6 receptor, is used as an immunosuppressive agent. According to a case series from China, significant lung damage is caused by the triggered immune response and cytokine release, and IL-6 appears to play a major role in the cytokine storm.

  In a small series published by Xu et al., it was observed that by day 5, 75% of the patients had a reduction in the oxygen intake and C-reactive protein levels and improved lung opacities on the CT thorax. No significantly elevated levels of transaminase, neutropenia, or infection were noted. 

Tocilizumab improved the clinical outcomes in critically ill patients and, thus, helped to reduce the mortality. It was also effective against the cytokine storm and, therefore, benefitted patients with COVID-19
Toclizumab has also been successful in treating patients with severe COVID-19 in civic hospitals in Mumbai.

 Several randomized trials are underway for this drug (tocilizumab dosed at 4–8 mg/kg intravenously or 400 mg with a single dose not exceeding 800 mg) in China.

Based on the demonstration of pulmonary microthrombi in critically ill patients who succumbed to COVID-19, it was proposed to consider anticoagulants in the management of the disease. Coagulopathy, a feature observed in COVID-19, is associated with high mortality.

 Mortality in patients with severe COVID-19 reduced with the use of heparin.

 It is recommended that all patients should receive thromboprophylaxis, unless contraindicated, preferably with low-molecular-weight heparin.

Convalescent plasma

Convalescent plasma or passive immunotherapy has been tried when no specific drugs or vaccines are available for infectious diseases. Its use has also been suggested by the WHO under the Blood Regulators Network for any emerging epidemic where treatment is not yet developed. 

It has been found to benefit critically ill patients during the MERS and SARS outbreaks. Duan et al. reported the safety of a single dose of 200 mL of convalescent plasma obtained from persons who had recently recovered from COVID and had neutralizing antibody titers over 1:640, in ten patients with severe COVID-19. 

The clinical outcomes of the patients improved, and 70% of the patients had a clearance of the viremia. 

A case series by Shen et al. demonstrated that convalescent plasma improved the clinical status of five critically ill patients with COVID-19. Ye et al. also reported that the transfusion of convalescent plasma led to resolution of the ground-glass opacities (GGOs) and consolidation in five out of six patients and virus clearing in two out of six patients.

 A Phase II, open-label, randomised controlled trial (NCT04374487) has been approved by the Indian Council of Medical Research (ICMR)to assess the efficacy and safety of convalescent plasma in patients with COVID-19. 

As the safety profile of convalescent plasma of patients recovered from COVID-19 is not much of a concern, the Phase I portion of the trial has been skipped. In addition, it is not necessary for a donor to test negative for COVID-19; however, resolution of symptoms for at least 2 weeks before the donation is essential.

Many Patients in India have benefited from Plasma Therapy.

Remedisvir has achieved better results in moderate to severe cases and Hospitalized patients. The absorption and bioavailability of the drug is better as it is used Intra-venously. 

Favipiravir is used mainly in mild to Moderate cases and since it is available in Oral Form could be given at home.

The number  of tablets is more and is available only as 100 mg form. Compliance could be an issue that needs to be strictly monitored 

References

  1. https://english.jagran.com/lifestyle/coronavirus-cure-dgci-approves-glenmark-to-manufacture-favipiravir-for-covid19-treatment-heres-all-you-need-to-know-10013086
  2. https://indianexpress.com/article/explained/the-drugs-india-is-fighting-covid-with-6449377/
  3. http://www.crstonline.com/article.asp?issn=2590-3233;year=2020;volume=3;issue=2;spage=233;epage=243;aulast=Qayyumi
  4. Publication–COVID 19—The New Age Pandemic–M.Balasubramanian—Chapter 6–Remdesivir- The Most Promising Covid-19 Drug–pages—31–34

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