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Monday, November 23, 2020

Tocilizumab: initial excitement, disappointing trials, yet trusted by many

On October 21, the New England Journal of Medicine published a study on 243 patients that found tocilizumab was not effective in preventing death in moderately ill, hospitalised Covid-19 patients.

Written by Tabassum Barnagarwala | Mumbai | Updated: October 24, 2020 7:07:41 am
Tocilizumab, what is Tocilizumab, Tocilizumab use, Tocilizumab efficacy, Tocilizumab Covid 19, Tocilizumab for coronavirus, indian expressDoctors are divided on the efficacy of tocilizumab against Covid-19. (File photo)

A study published this week suggests that the drug tocilizumab may not prevent mortality in Covid-19 patients. It is the second such study on this drug. And tocilizumab is the second drug, after hydroxychloroquine, that had quickly earned global popularity as a Covid-19 treatment before its efficacy came under question in the wake of poor trial outcomes.

Between May and July, tocilizumab was widely used across India for moderately ill Covid-19 patients. Even today, doctors are divided on its efficacy against Covid-19.

What is tocilizumab?

It is an immunosuppressant, commonly used for rheumatoid arthritis, and marketed as Actemra by Swiss pharma company Roche. It was repurposed in January to fight severe lung infection in Covid-19 patients. Once it reached India by April-end, many Indian doctors initially reposed faith in the drug, some even calling it a “miracle drug”. At one point, demand was so high that patients had to wait for days to get a vial.

Roche supplied it to Cipla, which supplied to distributors and hospitals. Mumbai had three distributors and each witnessed a queue of 200-300 people daily to buy the drug. Then came the two study results.

What are the latest findings?

On October 21, the New England Journal of Medicine published a study on 243 patients that found tocilizumab was not effective in preventing death in moderately ill, hospitalised Covid-19 patients. At the end of 14 days, those given tocilizumab had no significant clinical improvements, except fewer serious infections, compared to those not administered the drug. While 18% of the patients in the tocilizumab group had worsening of disease against 14.9% in the placebo group, 24.6% were still on oxygen support in the tocilizumab group against 21.2% in the other group.

Tocilizumab, what is Tocilizumab, Tocilizumab use, Tocilizumab efficacy, Tocilizumab Covid 19, Tocilizumab for coronavirus, indian express Tocilizumab, also known as Atlizumab, was originally designed as an immunosuppressive drug for treating rheumatoid arthritis and systemic juvenile idiopathic arthritis, a form of arthritis prevalent among children. (Source: AP)

What were the previous findings?

On July 29, Roche published results of a phase-III trial, called Covacta, which found that tocilizumab did not meet the primary endpoint of clinical improvement or the secondary endpoint of reduction in mortality. Since then, the drug’s demand has plummeted. The trial was on severely infected Covid-19 patients with pneumonia. At the end of four weeks, it found no significant difference between outcomes in the group given tocilizumab and in the placebo group, or in the percentage of people who had died. There was, however, a faster discharge rate in patients administered tocilizumab.

On September 18, Roche published results of another phase III trial, Empacta. These results were slightly more encouraging: 44% of patients given tocilizumab are less likely to progress into ventilation requirement, but there was again no difference in mortality rates. 📣 Follow Express Explained on Telegram

To what extent is it still being used?

In a web seminar of the International Federation of Pharmaceutical Manufacturers and Associations in September, Dr Severin Schwan, Chief Executive Officer of Roche, said the company has not reduced supply of tocilizumab after the July 29 trial results. “We are using it in combination with other drugs and trial results are awaited. There is enough supply,” Dr Schwan said.

While some doctors continue to give it to patients, others have ceased to do so after the trial results. J B Mantri, Joint Commissioner in Maharashtra’s Food and Drug Administration (FDA), said demand for the drug has plummeted since August. Until July-end, 12,000 vials of tocilizumab had been consumed in Maharashtra. “After that, there is negligible demand for Covid-19 patients,” Mantri said.

Dr Gunjan Chanchalani, Head Intensivist in Mumbai’s Bhatia Hospital, said, “I have reduced use of tocilizumab. And the patient outcome has not got affected much in its absence.” Doctors also point to the cost — a 400-mg dose costs Rs 40,500, and not every patient can afford multiple doses.

And yet, one section of doctors continue to prescribe tocilizumab.

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Why are some doctors continuing with tocilizumab?

Roche has partnered with Gilead Sciences for another trial, Remdata, of tocilizumab in combination with the antiviral remdesivir, manufactured by Gilead. Although the results of the trial, which began in June with 450 patients, are not yet out, doctors are optimistic based on their anecdotal experience.

Pulmonologist Dr Jalil Parkar said remdesivir-tocilizumab combination has “turned around patients if used in the nick of time”. “One must understand that trials look for a specific outcome and select a specific pool of people. We can’t say the drug failed because the specific outcome was not achieved. I have treated more than 1,000 patients and clinical acumen has taught us better use of tocilizumab now,” he said.

In April, Dr Parkar was the first in India to use tocilizumab, on a 52-year-old Covid patient in Lilavati Hospital. Then in short supply, the drug was imported. The patient died despite plasma therapy and three doses of tocilizumab. But Parkar insists that only a delay can render the drug ineffective.

Dr Mohan Joshi, Dean of Sion Hospital, mentioned favourable outcomes in patients given tocilizumab as part of a trial study in Nair Hospital. Dr Balkrishna Adsul, Dean of Seven Hills Hospital, said he has treated 900 patients with tocilizumab. “Whatever the trial results say, if given on time this drug helps improve oxygen saturation level in 24 to 48 hours.” Dr Adsul agreed that the drug is not useful in all patients, and said he uses it in just 3-4% of hospitalised Covid-19 patients along with remdesivir. “The key is using it at the right time for the right person,” Adsul said.

What are the alternatives?

Remdesivir has not yet fallen out of favour, although results of the World Health Organization (WHO) Solidarity trial found this drug — and a few other treatments including hydroxychloroquine — were not effective in preventing mortality. On Thursday, remdesivir became the first drug to get US FDA approval for Covid-19 treatment. Until now US FDA has only given emergency-use authorisation to treatments for Covid-19. Many doctors find remdesivir effective if used early.

Plasma convalescent therapy too remains under debate. An Indian Council of Medical Research trial (PLACID) on 464 patients in 39 hospitals has found this therapy ineffective in preventing mortality. Experts have, however, questioned these results as the donors were not selected on the basis of neutralising antibodies present in their plasma.

Dr Jayanthi Shastri, Head Microbiologist in Mumbai’s Kasturba Laboratory, said ever since the test became available, they are now selecting donors based on antibody titres and history of symptoms to ensure good-quality plasma. Several hospitals also insist on testing donors before extracting their plasma to ensure the antibodies are effective.

The steroid dexamethasone and the blood thinner heparin too are being used for treatment of Covid-19.

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