Bangla Sunday, July 12, 2020

COVID-19 drugs from India, Pakistan, Bangladesh: Remdesivir, camostat, avipiravir, HQC and others

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An arsenal of existing antivirals are being brought to bear against SARS-CoV-2. Most of them are manufactured in South Asia — primarily India, Pakistan and Bangladesh.

It has emerged that COVID-19 is not an "atypical pneumonia" (lung disease). As it is, there's no therapy approved for SARS-CoV-2, the virus that causes COVID-19. The prestigious medical journal The Lancet has pointed out, that the spectrum of disease kicked off by COVID0-19 is “broad”.

“Among hospitalised patients with COVID-19, pneumonia, sepsis, respiratory failure, and acute respiratory distress syndrome (ARDS) are frequently encountered complications,” it reported.

Moreover, it states: “Activation of coagulation pathways during the immune response to infection results in overproduction of proinflammatory cytokines leading to multiorgan injury.”

At least four peer-reviewed research in the US, the UK, and China provides the clearest evidence yet of this COVID-19-is-not-just-an-atypical-pneumonia thesis, with one pointing to "coagulation abnormalities and thrombosis in patients with COVID-19.”

No vaccines yet

The SARS-CoV-2 virus first emerged in late 2019 in China, and the disease it cased was declared a “pandemic” by World Health Organisation on March 11, 2020. On June 7, 2020, there were 6.891 million cases confirmed worldwide with almost 400,000 deaths, or a case-fatality of 5.6%.That rate is still bound to go down, as more tests are conducted. Theres the medical community gets a better grip on the virus.

Thousands of infections are still being recorded every day. Recovery rates are high, and case fatality rates as low as <1% in many countries.

A key factor that appear to be helpful in reducing viral loads: antivirals repurposed for COVID-19. There are also new therapies that helps cure COVID-19 patients, such as the revolutionary stem cell therapy invented by a medical team in Abu Dhabi.

Repurposed drugs

With the repurposed drugs, medical experts explain that the current standard of care is “supportive”.

Vaccine is still months away: In a best-case scenario, the earliest COVID-19 vaccine candidate is expected to pass crucial Phase-3 human trials around October.

Following are the leading arsenal of antivirals being used to treat COVID-19:

  1. Camostat Mesilate

Manufacturers: Ono Pharmaceutical (Japan), Sun Pharmaceutical Industries Ltd (India)

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Camostat Mesilate (CM) is a serine protease inhibitor. Under the trade name Foipan and FOY-305, Camostat is manufactured by Ono Pharmaceutical and is approved in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis.

Studies show that Camostat Mesilate works by blocking SARS virus’ entry mechanism into human cells. SARS-CoV-2 exploits the cell entry receptor protein angiotensin converting enzyme II (ACE-2) to access and infect human cells.

CM utilises research on severe acute respiratory syndrome coronavirus (SARS-CoV) and the closely related SARS-CoV-2 cell entry mechanism. It has been demonstrated that SARS-CoV-2 cellular entry can be blocked by camostat mesilate.

In mice, CM dosed at concentrations similar to the clinically achievable concentration in humans reduced mortality following SARS-CoV infection from 100% to 30-35%.

On May 22, 2020, India’s Sun Pharmaceutical Industries Ltd, said that it received Indian regulatory approval to start clinical trials of pancreatitis drug nafamostat mesilate in COVID-19 patients.

While CM remains clinically unproven, past laboratory and animal tests against SARS-CoV-1 showed it has antiviral functions, and it can be safely administered in high enough doses to match the concentrations that were effective in the lab.

The University of Tokyo had announced plans for a trial of nafamostat and camostat mesilate, a related drug, starting as early as April 2020.

An article in Antimicrobial Agents and Chemotherapy, states that while suitability of CM for treatment of COVID-19 is currently being evaluated in a clinical trial, it is unclear whether compound concentrations can be attained in the lung that are sufficient to suppress viral spread.

A study published in the scientific journal Cell in March found that camostat blocks an enzyme essential for the entry of the coronavirus into the lungs, drawing researchers' interest.

One of them was Dr. Joseph Vinetz, a professor at the Yale School of Medicine, who is ready to launch a clinical trial of camostat.

Ono launched camostat as a treatment for chronic pancreatitis in 1985 and post-operative reflux esophagitis in 1994. The company is now supplying the drug for COVID-19 studies in Japan and overseas, according to spokesman Yukio Tani.

  1. Favipiravir / Avigan / Avifavir

Manufacturers: Japan, China, India, Russia

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Favipiravir is an anti-influenza medication. It has been repurposed to fight COVID-19. Preliminary trials are said to have shown that Avifavir could shorten recovery times for patients with the coronavirus.

Originally sold in Japan under the brand name Avigan, Favipiravir was developed by Japan’s Fujifilm Pharmaceuticals and approved in 2014 as an antiviral medication to treat influenza.

A pyrazinecarboxamide derivative, Favipiravir and is also being studied to treat a number of other viral infections.

Favipiravir works by blocking the ability of a virus to replicate inside a cell.

Some doctors began trying Favipiravir to treat coronavirus patients early on, reasoning that its anti-viral properties would be applicable.

Initial results suggested the drug could help shorten recovery time for patients.

On May 30, 2020 (Saturday) Russia’s Ministry of Health approved Avifavir for emergency use to treat COVID-19, after "encouraging" results from clinical trials of the drug (generic version: Favipiravir) in several countries, including China and Japan. It is Russia’s first COVID-19 drug.

Earlier, on May 22, Indian pharmaceutical Strides Pharma Science has received regulatory approval to start clinical trials of antiviral drug Favipiravir.

Earlier this month, Glenmark Pharmaceuticals became the first pharma company in India to get the nod to conduct trials on the drug. The results of this study are expected by July or August.

  1. Remdesivir

Manufacturers: Gilead Sciences (US); Mylan (India), Cipla, (India) Hetero Labs (India) and Jubilant Life Sciences (India) India, as well as Ferozsons Laboratories in Pakistan; Beximco Pharmaceuticals (Bangladesh)

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Remdesivir is an experimental, broad spectrum antiviral made by US pharmaceutical Gilead Sciences first developed to treat Ebola, a viral hemorrhagic fever. It showed early promise in a primate study in 2016 and was later rolled out for a major trial in the Democratic Republic of Congo, where it was compared against three other medicines.

On April 30, remdesivir has been shown to speed up recovery times for patients with COVID-19 by 31 per cent following a major US-led trial (a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults). It thus became the first US drug with proven benefit against the disease.

On June 2, the broad-spectrum Remdesivir was approved in India for 'restricted emergency use’ in India. India’s top drug controller the Central Drug Control Standard Organisation (CDCSO) has given permission to Gilead Sciences for authorisation of its anti-viral drug Remdesivir "only for restricted emergency use" on hospitalised COVID19 patients, according to a senior government official.

Remdesivir would be available in form of an injection and will only be sold on retail by the prescription of a doctor for hospital use.

CDCSO after consultation with an expert committee has granted the Remdesivir drug only to be given in emergencies in laboratory-confirmed COVID-19 patients in India.

US Food and Drug Administration (FDA) has also issued an emergency use authorisation for Remdesivir for COVID-19 in adults and children hospitalised with severe disease.

Bangladesh’s Beximco Pharmaceuticals was the first company in the world to introduce a generic of the drug, under the brand name Bemsivir.

In May, Gilead also announced that it has signed non-exclusive, licensing agreement with five generic manufacturers to expand access to its experimental antiviral drug remdesivir for COVID-19 patients.

The licensees include Mylan, Cipla, Hetero Labs and Jubilant Life Sciences in India, as well as Ferozsons Laboratories in Pakistan. The companies will be able to manufacture and distribute remdesivir in 127 countries.

  1. Gabexate mesylate and nafamostat mesylate

Manufacturer: Italy, Japan, India

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Gabexate mesylate is a factor X inhibitor and serine protease inhibitor. A study published in Antimicrobial Agents and Chemotherapy, tested gabexate mesylate (FOY) and nafamostat mesylate (NM) (brand: Futhan) along with camostat mesylate (CM) for inhibition of SARS-CoV-2 infection of lung cells.

All these compounds are approved for human use in Japan. It inhibits TMPRSS2-dependent host cell entry of MERS-CoV.

A comparison of the antiviral activities of the three compounds revealed that none interfered with cell viability or with host cell entry mediated by the glycoproteins of vesicular stomatitis virus or Machupo virus (negative controls).

Gabexate mesylate slightly inhibited SARS-CoV-2 S-driven host cell entry, while camostat mesylate robustly suppressed entry.

Notably, nafamostat mesylate, which is FDA approved for indications unrelated to coronavirus infection, inhibited SARS-CoV-2 S-mediated entry, according to the study.

Nafamostat has been identified as a potential candidate for COVID-19 patients by scientists at University of Tokyo and Leibniz Institute for Primate Research, Germany, the company said in a statement.

  1. Hydroxychloroquine

Manufacturer:  Zydus Cadila and Ipca Laboratories in India; Sanofi (Plaquenil) in Europe

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Hydroxychloroquine (HCQ) is an anti-malarial drug being repurposed for the treatment of COVID-19. In March, the US Food and Drug Administration (FDA) issued an emergency-use authorisation (EUA), allowing health care providers to use the medicine for illness.

It was followed by an announcement by The National Institute of Health (NIH) that it has started clinical trial to test the effectiveness of HCQ. The NIH, a part of the US Department of Health and Human Services, is America's medical research agency.

An article published on pre-print service medRxiv on March 20, 2020, evaluated the role of Hydroxychloroquine on respiratory viral loads. The study results were "preliminary", based in an open-label non-randomised clinical trial. The researchers claimed that chloroquine and hydroxychloroquine “have been found to be efficient on COVID-19, and reported to be efficient in Chinese patients infected by this virus.”

Twenty cases were treated in this study and showed a significant reduction of the viral carriage at Day 6, compared to controls, and much lower than reported average carrying duration of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.

The study concluded that hydroxychloroquine is significantly associated with "viral load reductio"  or "disappearance" in patients with COVID-19 and its effect is reinforced by azithromycin.

India manufactures 70% of the world's supply of hydroxychloroquine — Zydus and Ipca Labs being the two biggest players.