Recently, India’s Central Drugs Standard Control Organization (CDSCO) approved Itolizumab for patients infected with COVID-19. Moreover, Tocilizumab’s use for COVID-19 is accepted off-label by the Indian regulator. Associated as costly and not easily procured drugs, the State of Assam in India is the first such state in that nation to procure Itolizumab just days after its approval. Hospital providers are administering aggressive treatments to keep patients from progressing into severe and critical states in a bid to reduce deaths. Certain more critical circles within India are concerned about how Itolizumab was rushed through to approval by regulators and the drug’s sponsor called Biocon Limited of Bangladesh. Balram Bhargava, the Director-General of the Indian Council of Medical Research (ICMR), frets there’s a lack of sufficient evidence from the clinical trials that these drugs reduce the death rate in COVID-19 patients. In the meantime, demand for Tocilizumab soars despite the lack of comprehensive evidence that it treats COVID-19. The TrialSite has raised the cautionary point about whether IL-6 inhibitors are the right path to treat COVID-19 based on unfolding clinical research evidence.
What are these Drugs?
Tocilizumab (Actemra) is an immunosuppressive drug mainly used for rheumatoid arthritis treatments (RA) and systemic juvenile idiopathic arthritis. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases. Actemra is produced by Roche.
Itolizumab (trade name Alzumab) is a humanized IgG1 monoclonal antibody developed by India-based Biocon and the Center for Molecular Immunology (CIM) in Havana, Cuba.
Clinical Trials and COVID-19
Questions about powerful IL-6 immunosuppressive abound as the data points for success vary depending on the point of view, the study, and observation. The TrialSite reported that a class of IL-6 called Sarilumab (Kevzara) failed to meet primary or secondary endpoints during a U.S. Phase 3 clinical trial in COVID-19 patients requiring mechanical ventilation. Serious adverse events were worse in the sarilumab group. Hence industry sponsors Regeneron and Sanofi halted the trial that received public funds.
India recently approved the use of Tocilizumab for certain COVID-19 cases, and it would appear demand for the drug is quite robust. As will be shown below, there are absolutely no legitimate clinical trials pointing to clear evidence that Tocilizumab is safe and effective for addressing at least certain COVID-19 cases. Despite that, due to a number of unfolding dynamics, the drug has become approved for just that—COVID-19. And in the process, demand has skyrocketed so much that black markets have formed, and the Indian middle to upper class must shell out a lot of money for that part of the world to access the drug.
Actemra (Tocilizumab) failed in an Italian study as well, but there are at least 43 ongoing COVID-19 trials testing this drug. The Italian study found no benefit for the use of Actemra after completion of the study involving 126 patients.
Although smaller off-label cases (e.g., real-world) revealed some promise as Paolo Ascierto, an Italian doctor, reported that Tocilizumab appeared to show effectivity in three severe COVID-19 cases in early March. Those results led to patient improvement, and the Italian Pharmacological Agency (AIFA) expanded testing to five other hospitals. This led to Roche expanding studies there.
In association with a donation of the drug to China during the pandemic, Roche acknowledged that there is no evidence as to the drug’s efficacy to help COVID-19 patients.
In Australia, the drug is considered an off-label treatment for COVID-19 patients associated with acute respiratory distress syndrome (ARDS). Because the immunosuppressive is associated with benefits to cytokine storm treatment caused by a specific cancer treatment, the cytokine storm is associated with mortality in severe to critical COVID-19 cases. But holding this up as evidence for an effective treatment against COVID-19 is a stretch considering the side effects, etc.
Indian Approvals & Acceptance of both Tocilizumab and Itolizumab for COVID-19
As reported in Guwahati Plus, Balram Bhargava, the Director-General of the Indian Council of Medical Research (ICMR), has concerns with the approval of these drugs. He suggests that a lack of sufficient evidence from clinical trials fails to show that they reduce mortality in COVID-19 patients.
Real Concerns about Agenda: Does Political Economy Trump Science?
For example, critics in India are concerned about the approval of Itolizumab. They suspect something is terribly wrong with the process, and perhaps other political and economic forces are at work superseding scientific and medical certainty. Why are they so concerned? They will tell you first and foremost for the research that has occurred there has been far too small of a sample size. They will note the sponsors were allowed to rush the drug to market, actually bypassing the critical Phase 3 pivotal clinical trial. Moreover, they show how claims were made in the press before the data was peer-reviewed and published. Of course, the argument on the other side is that there is a pandemic, and lives must be saved.
Costly and Hard to Access
Moreover, critics contend that in addition to a lack of good evidence, these are expensive and hard to procure drugs in a nation of 1.35 billion with some accounts, literally over 50% of the population still living in poverty. A staggering number of economically struggling people, even the more politically correct government numbers of around 20%, would leave 270 million in poverty. Few could access this drug which will cost about 40,000 rupees for a full treatment. Moreover, drug suppliers, the Indian press reports, have only been able to secure 100 vials of Itolizumab.
Demand for Tocilizumab (Actemra) Soars Despite Lack of Clinical Evidence
There is no real evidence, based on randomized controlled trials, that Roche’s Actemra (Tocilizumab) helps reduce COVID-19 death rates. However, because of some early activity in China indicating the IL-6 could be effective, India picked up on that information, and the drug was placed on the health ministry’s clinical guidelines for COVID-19—again with no real evidence. Consequently, doctors started using it off label as the drug is approved for rheumatoid arthritis. That usage constrained supply of the product. Roche, in the meantime, due to a series of events, saw demand for its product grow as a “treatment for COVID-19.” By 2019, Actemra sales grew at a healthy pace, leading to $2.42 billion, making it sixth among Roche’s top-selling products. Undoubtedly, those numbers are growing with COVID-19.
Evidencing such demand, the Municipal Corporation of Greater Mumbai, according to the Economic Times, will procure 20,000 doses of Tocilizumab in the hopes of addressing a growing COVID-19 death rate despite the lack of clinical trials evidence. According to the local press, the negotiations with Roche involve a price range of a 200 mg vial for 15,000 Rs ($200.20) to 400 mg vial for 30,000 Rs ($400.39).
Founded in 1978, Biocon is an Indian biopharmaceutical company based in Bangalore, India. Founded by Kiran Mazumdar-Shaw, the company produces generic active pharmaceutical ingredients (APIs) marketed in over 120 countries worldwide. They maintain a number of subsidiaries from biotech to a contract research organization (CRO) called Syngene International Limited.
Call to Action: The TrialSite continues to monitor and track how various nations are considering various drugs being used to treat COVID-19. If you have any research requests, send them to us.