Chandigarh: On July 6, 2021, the World Health Organization (WHO) approved two rheumatoid arthritis drugs, tocilizumab and sarilumab, to treat Covid-19. "These are the first drugs found to be effective against COVID-19 since corticosteroids were recommended by WHO in September 2020," the WHO said in a press release.

Tocilizumab has been part of India's guidelines since June 2020, as an investigational therapy for Covid-19. In May 2021, the Indian government also approved two new Covid-19 treatments for emergency use: a monoclonal antibodies cocktail, also approved by the US drug regulator and recommended by the European Medicines Agency (EMA); and 2-deoxy-D-glucose (2-DG), a drug only been approved by India.

Current Indian guidelines updated on May 27, 2021 recommend only paracetamol for fever for mildly ill patients, plus a few medicines to treat symptoms, such as inhalational budesonide for cough. Steroids can be used for hospitalised moderately severe and critically ill patients, whose oxygen levels fall below 92. Remdesivir is recommended, as an experimental drug, in select moderate and severe patients within 10 days of onset of the disease.

The new drugs are the first to show potential since corticosteroids started to be used for Covid-19 treatment. In addition to vaccination and precautions such as mask-wearing and physical distancing, medical treatments for Covid-19 are key to fighting the pandemic.

We examine how these drugs work and the evidence of their effectiveness in treating Covid-19.

Tocilizumab and sarilumab

Sold under the brand name Actemra by the Swiss pharmaceutical company Roche, tocilizumab belongs to a class of drugs known as interleukin-6 (IL-6) blockers. It is an immunosuppressant primarily used to treat rheumatoid arthritis, and has been repurposed to fight lung infection in Covid-19 patients. It is imported and distributed by Cipla in India and a 400 mg vial was available online for Rs 32,480 as of July 21, 2021.

Like tocilizumab, sarilumab is an IL-6 blocker, originally developed to treat rheumatoid arthritis. It is sold under the brand name Kevzara by Regeneron Pharmaceuticals.

How do these work?

Both medicines work by blocking IL-6, a cytokine, or small protein, that helps control the body's immune system. In severe cases of Covid-19, the virus causes an immune system malfunction known as a 'cytokine storm'. The body releases IL-6 cytokines in excess, causing inflammation within the body. These patients find it difficult to breathe, despite being given oxygen. Tocilizumab and sarilumab block IL-6 and prevent further deterioration.

Scientific evidence

On July 6, 2021, the WHO included IL-6 receptor blockers--tocilizumab and sarilumab--in its list of lifesaving medicines to treat severely or critically ill Covid-19 patients. The WHO recommended these drugs based on a meta-analysis of 27 clinical trials conducted on 10,000 patients across 28 countries.

The drug reduced the odds of death by 13% in severely or critically ill patients, as compared to standard care, the evidence shows. "The odds of mechanical ventilation among severe and critical patients are reduced by 28%, compared with standard care," the WHO recommendation says.

"I treat this recommendation with guarded optimism," said S.P. Kalantri, director and professor of medicine at the Mahatma Gandhi Institute of Medical Sciences in Maharashtra. "The trials have not had a long time of follow-up, they could have missed capturing adverse events like bacterial or fungal infections. These trials were mostly conducted in high income countries and the drug is also expensive," he said.

Tocilizumab should only be used for patients who are rapidly worsening and it should be administered within 24 hours of admission to moderate to critical patients, said Gunjan Chanchalani, a critical care physician at the Cumballa Hill Hospital in Mumbai. But the medicine is a "double-edged sword", Chanchalani cautioned. If given to patients whose immune system defences are low, it could increase their susceptibility to bacterial and fungal infections by further lowering their immunity. The Indian guidelines recommend tocilizumab only in critically ill patients who do not improve even after 24-48 hours of being administered steroids.

REGEN-COV2 Monoclonal Antibody Cocktail

On May 5, 2021, India's Central Drugs Standard Control Organisation (CDSCO) authorised Roche's antibody cocktail, REGEN-COV2, for emergency use.

REGEN-COV2 is a combination of monoclonal antibodies casirivimab and imdevimab, which are administered together for treating mild to moderate Covid-19 patients. A pack of REGEN-COV2 contains one vial of casirivimab (1,200 mg) and one vial of imdevimab (1,200 mg) and is priced at Rs 1.19 lakh. One pack can be used for two patients, thus the cost per patient is Rs 59,750.

How does it work?

Monoclonal antibodies are artificial antibodies that mimic the activity of our immune system. Casirivimab and imdevimab are specifically directed against the spike protein of SARS-CoV-2, the Covid-19 virus, and are designed to block the virus' attachment and entry into human cells, a press release by the company says.

Scientific evidence

In November 2020, the US Food and Drug Administration (FDA) issued an emergency use authorisation (EUA) for casirivimab and imdevimab to be administered together for those at high risk for progressing to severe Covid-19 and/or hospitalisation. The approval was based on the results of clinical trials done in the US in 799 non-hospitalised patients with mild to moderate COVID-19 symptoms. In patients at high risk of disease progression, 3% on casirivimab and imdevimab were hospitalised or had to visit the emergency room, compared to 9% of patients on a placebo, according to the US FDA.

There are data to show the treatment's effectiveness but "you have to administer it within 72 hours of symptom onset preferably, and no later than seven days", said Chanchalani. However, "it should not be used in patients who are already showing signs of worsening," she added.

In India, Mumbai's municipal corporation introduced monoclonal antibody therapy to 212 patients with mild to moderate Covid-19 at Seven Hills Hospital, as per an article in The Indian Express. The treatment has been giving positive results, according to the article.

2-deoxy-D-glucose (2DG)

The Drug Controller General of India (DCGI) approved 2-DG for emergency use as an adjunct treatment (in addition to a primary treatment), in May 2021. The drug was developed by India's Institute of Nuclear Medicine and Allied Sciences (INMAS), part of the Defence Research and Development Organisation (DRDO), in collaboration with Hyderabad-based pharmaceutical company Dr Reddy's Laboratories. Each sachet (one dose) of the drug costs Rs 990.

How does it work?

The virus depends upon glycolysis (breakdown of glucose) for energy. By accumulating in virus-infected cells, the drug hinders the process of glycolysis and prevents the growth of the virus.

Scientific evidence

Dr Reddy's Laboratories and the DRDO carried out a clinical trial of 220 patients at 27 Covid-19 hospitals across 10 states between December 2020 and March 2021, according to a government press release from May 8, 2021. A significantly higher proportion of patients improved "symptomatically" and "became free from supplemental oxygen dependence (42% vs 31%)" by the third day, in comparison to standard care, the press release said.

The DGCI has approved the drug for patients with moderate to severe Covid-19. However, health experts raise questions about its efficacy. "The trial has excluded people with any kind of comorbidities and patients who have the risk of worsening," said Chanchalani. The trial included mostly patients with mild Covid-19, most of whom would have improved anyway, she added. The drug is not approved by the WHO or any other international regulatory body.

Why is this important?

Since the beginning of the pandemic, scientists have researched, and doctors have used, a variety of treatments for Covid-19, including steroids, anti-malarial drugs, anti-parasitic drugs, plasma and anti-virals. But, in many cases, drugs, such as hydroxychloroquine (HCQ), an anti-malarial drug, were being used in India despite little evidence that it helped.

In the case of HCQ, the health ministry's guidelines from April 28, 2021 recommended HCQ as a prophylaxis (preventive) for caregivers and contacts of Covid-19 patients. This was after the fact that, in July 2020, the WHO discontinued HCQ from its solidarity trial as it had no impact on mortality due to Covid-19.

The Indian government has been slow to update its treatment guidelines for Covid-19, with plasma therapy recommended from June 27, 2020, despite studies that it did not help Covid-19 patients. It was finally removed from the guidelines on May 17, 2021. HCQ was part of the guidelines until April 2021 and ivermectin, an anti-parasitic, until May 2021.

Like India, the EMA and US FDA have also authorised remdesivir for Covid-19 treatment. But the WHO had, in November 2020, issued a conditional recommendation against the use of remdesivir in hospitalised patients, regardless of disease severity, "as there is currently no evidence that remdesivir improves survival and other outcomes in these patients".

(Anoo Bhuyan contributed to this story.)

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