Covid-19: Cytokine Storm and Itolizumab’s Hurried Breakthrough Affair in India

Is cytokine storm misleading in Covid-19 and should immunomodulator drugs be used as therapies?

Although the SARS-CoV-2 virus primarily affects the respiratory system, lungs, it also affects the brain, kidney, and heart in severe cases of COVID-19. According to WHO, about 20 percent of the infected individuals show moderate-to-severe symptoms and require hospitalisation. In the first week post diagnosis, some patients develop mild-to-moderate symptoms like fever, dry cough, fatigue, sore throat, reduced or normal leukocyte count, and increased creatinine kinase levels. In moderate-to-severe cases, when viral pneumonia sets in, patients have shortness of breath because of reduced levels of oxygen. In severe cases, the condition of patients deteriorates further. This stage is characterised by severe acute respiratory distress syndrome (ARDS), where oxygen levels drop and make it difficult for the patient to breathe–the patient is put on a ventilator.

How does body respond to Virus

Typically, when a virus enters our body, a group of cells–called the Antigen-Presenting Cells (APCs)–ingest it, break it into small chunks of protein and present these chunks on their surface. Only when these chunks of protein are presented do the immune cells (called T cells) specifically identify them as invaders and elicit responses from more cells and destroy the virus. This is a policing action, where the APCs point-out the infected cells and the T-cells come and kill them, clearing the virus from the body.

Cytokines–small proteins released by an activated T cell–communicate the message to other immune cells to bring about a response to the virus. CD6 (a protein present on the surface of T cells) interacts with activated leukocyte cell adhesion molecule (ALCAM)–a molecule present on the APC. This interaction releases tremendous amounts of cytokines like IL-6, which activate other immune cells and causes an excessive immune response–cytokine storm.This is good for destroying the enemy virus in the body but causes collateral damage, mostly this cytokine storm is something that the body can’t control.

Such an exaggerated response of the immune system damages the lungs instead of protecting them. During the recent Covid-19 pandemic, experts have suggested that many COVID-19 deaths have occurred because of cytokine storm. Some studies have particularly correlated increased levels of IL-6 in blood with respiratory failure, ARDS and organ damage, suggesting that IL-6 is an important cytokine that should be blocked to prevent the adverse effects in COVID-19.

Immunomodulators to treat cytokine storm

Since little is known about SARS-CoV-2 virus and Covid-19 many drugs were used to give relief to the patients. Treatment in India was focusing on hydroxycholoroquine, remdesivir, favipiravir, dexamethasone, methylprednisolone, low molecular weight heparin, azithromycin, ivermectin and convalescent plasma. These drugs and biologics were approved by the Covid-19 task force and Drug Controller General of India (DGCI), for treating Covid-19.

One way of tackling the cytokine storm was to use a monoclonal antibody to block IL-6 receptors, which are present on immune cells, onto which IL-6 bind and activate other immune cells. The other way was to use a humanised anti-CD6 IgG1 monoclonal antibody, which binds to CD6 and blocks it from interacting with ALCAM.

While Tocilizumab–a drug used off-label for COVID-19 treatment in India–follows the former mode of action, Itolizumab–a repurposed drug, recently approved for use by the DCGI–follows the latter.

Itolizumab story

Biocon’s ALZUMAb, also known as Itolizumab, is being used for seven years now to treat psoriasis and is now repurposed to treat COVID patients. Recently, Biocon announced the drug’s efficacy and called it a breakthrough drug in the treatment of Covid-19.

The company received the DCGI approval to market Itolizumab  (ALZUMAb) Injection 25mg/5mL solution for emergency use in India for the treatment of cytokine release syndrome in moderate to severe  ARDS patients due to COVID-19.

The company also announced that it had concluded phase II clinical trial for COVID treatment with Itolizumab. “The data is compelling, and I am confident that this ‘first-in-class’ biologic will save lives and help reduce the mortality rate in our country,” Kiran Mazumdar Shaw, Executive Chairperson, Biocon announced.

Many experts supported Biocon’s claims. “In our hospital, we have tried Itolizumab in many COVID-19 patients with moderate-to-severe ARDS and found significant improvement in clinical, radiological and inflammatory markers after administering Itolizumab. These outcomes were quite evident with one dose of Itolizumab when administered before the ‘cytokine storm’ set in. Most of the patients have well tolerated the drug. Given the growing surge of COVID-19 cases, I would recommend use of Itolizumab in moderate-to-severe complications in COVID-19,” Dr Mohan Joshi, Dean of BYL Nair Hospital, Mumbai, one of the clinical trial sites said.

However, this did not go down well with the scientific community and patients rights’ groups. The study design has drawn flak from experts. “As a phase 2/3 [randomized controlled trial], this trial is seriously deficient in its design. Its defects–particularly the extremely small sample size–largely invalidate the claims made in the press release from Biocon, that ‘primary endpoints for reduction in mortality rate were met’ or that ‘the data is compelling’,” Jammi Nagaraj Rao, a public health physician and epidemiologist in the UK, wrote in an article in The Wire Science.

Clinicians were not entirely convinced of Itolizumab’s effect on reducing death in Covid-19 patients, even though they talked about the usefulness of immunomodulatory agents in treating COVID patients experiencing cytokine storm. “We cannot play safe, at this time, as it is difficult to find a new drug in such a short time. Many have tried to re-purpose existing drugs, and studies from across the world have shown promise with Tocilizumab in treating cytokine storm in COVID patients,” Dr Rajesh Gupta, Additional Director of Pulmonology and Critical Care, Fortis Hospital, Noida, said. But he was wary of DCGI’s approval of Itolizumab based on evidence from the phase 2 trial with small sample size. He also added that many rheumatologists [he had spoken to] were not convinced about the safety of the drug in psoriasis patients as well, and has his ‘fingers crossed on the drug’s effect on COVID patients.’

Biocon’s announcement led to intense debate on Itolizumab’s life-saving capabilities in Covid-19 patients and the supposed clinical trial evidence. A day after Biocon’s announcement Dr Balram Bhargava, Director-General, Indian Council of Medical Research (ICMR) said that there was no evidence yet that Itolizumab can reduce mortality in COVID-19 patients. Shooting down Biocon’s claim that Itolizumab brings down mortality, the apex research body said that more data was needed to establish efficacy in preventing deaths in Covid-19. Biocon conducted a virtual expert panel debate to clarify its claims.

Itolizumab: Developments in Cuba and USA

Cuba is another country that has experimented with Itolizumab, besides an interferon that Cuba developed for treatment of Covid-19 patients. According to a report in Reuters the Health Authorities in Cuba said that Cuba’s experimental treatments have helped it achieve an overall COVID-19 death rate of 4.2%, compared with the regional and global averages of 5.9% and 6.6%, respectively.

This was used as supporting evidence to substantiate the Itolizumab claims. However, as reported by a news site OnCuba there has not been a controlled trial to test Itolizumab in Covid-19. Tania Crombet, Director, Clinical Research, Center for Molecular Immunology (CIM) was quoted as saying, “In Cuba, we deliberately didn’t want to do a controlled trial in which there were patients without access to one of the two medications.” The experts believe that patient selection is key to Itolizumab’s success in treating Covid-19 patients. The data generated thus far are preliminary and more data should be collected and studied thoroughly Dr Crombet said. She added that they would later make a comparison of current patients, in retrospect, with those who did not receive these medications before the approval of regulatory authorities to introduce the drug.

The anti-CD6 monoclonal antibody could curb cytokine storm by modulating the immune response. Researchers have tested this for conditions where the immune response of the patient is to be suppressed such as, rheumatoid arthritis, acute graft-versus-host disease and psoriasis. However, there are some concerns about its safety in these conditions as well. Also, the researchers and clinicians await a clearer picture, not only about the efficacy of anti-CD6 monoclonal antibody in treating COVID-19 patients, but also about cytokine storm in COVID-19 ARDS.

Interestingly, Equillium Inc. (US partner of Biocon) is planning a global randomised controlled trial of Itolizumab in COVID-19 patients. The company has said that it will file a US investigational new drug application (IND) for the same.

In the meantime, the Indian task-force that recommends and sets standard treatment regimen for Covid-19, has dropped Itolizumab from clinical management protocols due to lack of evidence, but will look at the drug once more data emerges.

Biocon has said that the company will provide large real world data to enable the committee to reconsider its decision on inclusion of itolizumab in the protocol. The company also said that it has planned for a 200 patient pan-India phase 4 trial to be conducted across 10-15 hospitals to create a larger body of evidence for efficacy of itolizumab in COVID-19 complications.

The burning question remains

Should cytokine storm in Covid-19 be give so much importance? Pratik Sinha, Division of Pulmonary, Department of Medicine, Critical Care, Allergy and Sleep Medicine; University of California, San Francisco and colleagues clarify this in a recently published article.

In an editorial opinion, published in the Journal of American Medical Association Internal Medicine, the authors compared the IL-6 levels in COVID-19 and other ARDS and found them to be much higher in the latter. “Incorporating a poorly defined pathophysiological entity lacking a firm biological diagnosis may only further increase uncertainty about how best to manage this heterogeneous population of patients,” the authors wrote. They concluded by saying that until new data establish otherwise, the linkage of cytokine storm to COVID-19 may be nothing more than a tempest in a teapot.

At a time when the total reported Covid-19 cases in the world have crossed 16 million and deaths approach 6.5 lakh people worldwide, the need for effective drugs or vaccines has never been more pressing. India, with close to a 1.4 million cases and 32 thousand deaths, has the third highest number of total reported Covid-19 cases. But can the situation be an excuse for an unjustified, risky shortcut and profiteering? Only time will tell how we control this unprecedented pandemic, until then, we will have to rely on the existing options and physicians’ conscience.

Edited by M Neelam Kachhap