Bengaluru: On July 11, Biocon Limited announced that the Drugs Controller General of India approved its drug Itolizumab “for emergency use in India for the treatment of cytokine release syndrome (CRS) in moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19.
Since then, the company has been on the receiving end of severe backlash from the scientific community and the doctors alike for the small sample size and the Itolizumab for COVID-19 trial methodology. Experts criticised Biocon for touting Itolizumab as ‘breakthrough drug’ for treatment of Covid-19 patients because the sample size used for the trial was small (30), and more evidence was required to prove the efficacy of the drug in reducing mortality. What was more questionable was the way DCGI waived Phase 3 trial in Itolizumab for COVID-19. Biocon said that the DCGI waived the need to conduct Phase 3 clinical trials (usually large-scale multi-centre trials), and allowed the company to post marketing surveillance, or Phase 4, data. This further cast doubts on the way the DCGI approval was given.
Two days after the initial announcement, Kiran Mazumdar-Shaw, Executive Chairperson, Biocon, conducted a press conference to clarify these doubts. In a series of press interviews and television appearance she emphasized on Itolizumab’s unique mechanism of action and its ability to bring down mortality in moderate to severe ARDS patients due to COVID-19.
“As Itolizumab has been approved in India and given that we are in the middle of a medical emergency, we went ahead with a pivotal clinical trial involving a cohort of 30 patients. The two-arm, randomized study met both the primary and secondary endpoints, with the Itolizumab arm demonstrating statistically significant advantage over the control arm, culminating in the drug’s approval for restricted emergency use by the DCGI,” she said.
She also pointed towards a similar study done in Cuba.” These results are in line with findings from a similar clinical trial in Cuba, where 76 COVID-19 patients were treated with Itolizumab. At the end of the trial, 79% of severely ill patients were discharged from the ICU after 14 days of treatment, while moderately ill patients showed a reduction in the rate of disease progression,” Mazumdar-Shaw said.
Itolizumab Covid-19 Trial
A multi-centric, open label, two-arm randomized pivotal clinical trial was conducted in 30 eligible patients at four hospitals across Mumbai and New Delhi. Twenty patients were randomized to receive Itolizumab plus best supportive care, while 10 patients received best supportive care alone in the control arm. The primary endpoint was mortality at the end of one month.
At the end of the treatment period, Itolizumab demonstrated statistically significant advantage over the control arm in one-month mortality rate. All 20 patients on drug arm who were administered Itolizumab recovered fully and were discharged from hospital. Whereas three out of ten patients in the control arm with best standard of care died. Key efficacy parameters of lung function such as PaO2 and SpO2 (oxygen saturation) improvement without increasing FiO2 (oxygen flow) also showed statistically significant advantage for the Itolizumab arm over the control arm. All patients on the Itolizumab arm were weaned off oxygen by Day 30, and none needed ventilator support unlike the control arm.
Key secondary endpoints of clinical markers of inflammation such as IL-6, TNF-α, serum ferritin, d-dimer, LDH and CRP showed clinically significant suppression post Itolizumab dosing and correlated well with clinical improvement in symptoms and chest X-ray images. Itolizumab was overall well tolerated and found to be safe with infusion reactions manageable with slowing infusion rate.
Biocon in a press release said that Itolizumab when administered to patients with moderate to severe ARDS due to COVID-19 effectively controlled hyper-activation of the immune system in response to the SARS-CoV-2 virus and prevented morbidity and mortality related to the ‘cytokine storm’. Older patients and those with co-morbidities like diabetes and hypertension, who were treated with Itolizumab, recovered well.
On July, 14 a rebuttal came from Dr Balram Bhargava, director general, ICMR, during a health ministry briefing. 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. “We know that in severe COVID-19 patients, there is a problem of a cytokine storm. Cytokines are released, and they are responsible for a storm that ultimately leads to serious conditions. There are two drugs that are thought to be preventing the cytokine storm, Itolizumab and Tocilizumab. Neither of them have yet demonstrated mortality reduction by any trial. Trials are wanting, and are happening in different parts of the world to look at whether there is mortality reduction with these two drugs,” Bhargava said on Tuesday.
When questioned regarding the same Mazumdar-Shaw tweeted saying, “His statement is right as he is saying to establish this you need larger data sets to corroborate these findings and we will do it through India Ph4 n US clinical trials.”