Mumbai: Biotech major Biocon, on July 11, said it was launching a new drug, itolizumab, approved by the Drugs Controller General of India for emergency use to treat cytokine release syndrome in moderate to severe cases of acute respiratory distress syndrome (ARDS) due to COVID-19. The drug costs about Rs 7,950 per vial and a patient needs four vials.

Itolizumab belongs to the family of monoclonal antibodies, and has thus far been used to treat psoriasis. The drug regulates or blocks the immune response in order to prevent a cytokine storm--when excessive or uncontrolled levels of cytokines (proteins important for cell signalling) are released, activating more immune cells. This results in hyperinflammation, and causes sepsis or organ failure, which can all be fatal.

We speak with Hemant Thacker, the first Mumbai doctor to carry out clinical trials with itolizumab for COVID-19 patients in early May 2020. Thacker specialises in cardiometabolic disorders as well as general medicine at Bhatia and Breach Candy Hospitals, Mumbai.

Edited excerpts:

What is the nature of the trials that you have done?

Way back in the end of April, when COVID was getting a tight grip on the city and the country, we realised that a group of drugs that belong to the monoclonal antibodies family--which means they are immuno-modulators or immuno-blockers--could be used to prevent the onset of a cytokine storm. At that time, there was only one [such drug] available--tocilizumab--and that too was in short supply. Tocilizumab had to be given twice--on days one and two. And that was about Rs 35,000 to Rs 40,000 on each day. So, we had no choice and on compassionate grounds, we tried it [itolizumab] and we found that it seemed to work--and worked quite well. And we only needed one injection as compared to two of tocilizumab.

I recruited the first patient [for a clinical trial] on compassionate grounds on May 12. The patient, on the sixth day, was requiring more and more oxygen, his respiration was getting laboured. There was a likelihood that he would go into a [cytokine] storm sooner than later. So we gave itolizumab. We give about 4-5 ampules--about 100 to 125 mg. We usually give it only once. It can be repeated after seven days. We found that this drug blocked the action of the inflammatory cytokines, which were triggered by the irritation of the virus in the body.

The virus--once it burrowed itself into the human body--set off a chain reaction, which triggered inflammation, which in turn triggered off inflammatory cytokines, some of which we call interleukins. And these cytokines pile up, till on the 6th, 7th or up to 10th day, they suddenly hit the human body, and puncture the kidney, the heart, the lungs, [and cause problems with] respiration, [or lead to] pneumonia--what we call as cytokine storm crisis.

At that stage, you either pre-empt the crisis or you block the antigens or the inflammatory markers from working in the body by blocking the receptors using monoclonal antibodies like tocilizumab. Then, no matter how high the inflammatory markers are, they do not work. So, the virus is trapped. The inflammatory markers are null and void. They punch, but they punch on a shield which prevents damage. And by that time, the virus gets tamed, the body starts responding, [and] the immune system of the body bounces back. 

So, if you are able to tide over that critical three- to five-day period, then the body has a chance to recover. Remember, this injection is only for moderate, moderately severe and severe cases, which forms about 4-5% or even less of the entire COVID patient population; 85-90% of the patients will heal on their own. Of the remaining 10-12%, most will not require these expensive immuno-modulators and injections intravenously. 

So, what do we do? We use it to reduce mortality, to prevent patients getting on to the ventilator. If they are already on a ventilator, we can get them off easier. And we are hoping that this is one modality that would form one cornerstone of the different pillars in the therapy against COVID. COVID has no magic bullet. This is not a game-changer for COVID. This is a game-changer in reducing--or trying to reduce--mortality. You cannot compare this to remdesivir or favipiravir because they are antivirals.

Do most severe cases follow the kind of progression that you just described?

They do. They come in on the fourth or the fifth day. They are given the antiviral, the antibiotics like doxycycline and azithromycin, steroids like dexamethasone and methylprednisolone, anticoagulants, and other standard of care. If the patient is seen to require more oxygen and his respiratory system is seen to deteriorate, then we preempt the [cytokine] storm and give itolizumab, and that works. I used it in about 21 patients for the study. Of these, except for one, the others did quite well.

Even back in April, you said you were confident that there were many patients who did not need hospitalisation, or critical facilities. If you were to look back over the last four months, what are the other learnings and insights that you could share with us?

The insight is that COVID still has no cure. You have to tide over; you have to bide over the COVID infection. Most of us will be quite lucky, and will fall into the 85-88% category. The remaining will fall into the next 7-8% category, who will have fever, cough, loose motions, body ache, the typical viral syndrome--they lose smell and taste. 

But it is 4-5% who have a significant affliction of the respiratory tree in the form of COVID pneumonia. The more severely affected of these will require to be hospitalised. Once they are hospitalised, they have to be very closely monitored, because the time between deterioration and full-blown [cytokine] storm is very short. If it is in the hospital, you can see it coming, anticipate it, treat it, preempt it.

So would you say that in the last three months, our ability to contain or control the disease has improved--as doctors at the frontline like yourself are far more confident of controlling it than ever before?

We have more armamentarium. We have itolizumab, we have remdesivir. And all that put together has helped us to reduce the mortality--from maybe 3-4% to 2-3% now. If you can save 1-1.5 more patients for every 100, it is a lot.

How are you seeing the strain, if any, on the critical care facilities, particularly in the hospitals where you are managing COVID?

Remember that India is a country with 1.3 billion people, Mumbai is a busy city. We definitely have patients and of those patients, we have people who need ICU or critical care. So, we are always busy, and we always have our beds full. But that does not mean that we do not have place for a critical patient, or we let him go. We are not in the Italian dilemma whether to treat him or to treat her, whether to treat the 80-year-old or the 40-year-old. Fortunately, we need not have to even worry about ventilators. So that way, we are okay. 

We are learning, knowing more and more every day. We have learnt to think on our feet, to innovate. And this [using itolizumab] was an out-of-the-box thought they came up with, because this drug was available for psoriasis treatment. I have now done about 24-25 patients. Seems to be working well. Time will tell. 

For viral infections, we do not have an antiviral like a malarial drug where you take the tablet and the parasite dies. Measles, mumps, rubella, chicken pox--all these things, how are they gone? They are only gone by the vaccine. You take the chicken pox vaccine, smallpox vaccine. In our days, we all suffered from chicken pox. We did not cure it, we endured it till it burnt itself out.

I do not think that we are going to be able to tame and cure viruses. All viruses need a vaccine, and there are certain viruses that you never get a vaccine [for]. Like [for] the dengue virus and HIV, the vaccine is not successful. So, let us hope we get something [for SARS-CoV-2], or we learn to endure it by human adaptation. Either the virus will weaken, or we will strengthen.

Obviously, you are working with limited data and time with this drug. But, would you say that this drug is safe?

I have had no adverse reaction in the form of organ-threatening or life-threatening issues. In your enthusiasm, if you give this drug very rapidly in two-three hours, you can get a problem where the patient can get an allergic phenomenon with shivering, chills and other things. Now we have learnt to think, and we give it over six or seven hours, slowly. And then nothing happens. 

We have no kidney shutdown; we have had no long-term [issues]--in the sense, we only have a two-month follow up. So, time will tell us whether after six months, those that received itolizumab have any issues. But I do not think so, because it is going to burn itself out. As of now, [it is] safe.

The number of cases is obviously still increasing. While you said that you are far more confident, you have more arms in the armament, how do you see the next few months going ahead?

I want to send one message to everybody. Do not drop your guard. Do not think that we have drugs falling into the bag every day, so we are going to be safer and better. The only way you can be safer and better is if you keep wearing your mask, if you do not conglomerate, and if you have safe distance. 

Unfortunately, whether people are fed up of the lockdown, or whether people are not understanding, or they are throwing caution to the winds. You are not worried about yourself so much. You should be worried about your aged, elderly, infirm people back home. I do not see that happening. I see people on the road with gay abandon. I see people conglomerating. They are more interested in the wine shop that is closing, or the restaurant or shop that is on sale shutting down than looking after their health. 

While we at the medical end are trying, innovating, hoping, trying to polish old drugs, taking them out of the cupboard and resharpening them, we do not have a cure. These are all supportive therapies. Most of us get lucky, but to that 1-2% of people who get unlucky, God help them. So, if you do not want to be one of the 1-2% who get it, you have to prevent getting it. Once you get it, nobody can say how your body will react. It is like the lady who comes in and says, “My husband has been smoking only for 10 years and he has lung cancer; my neighbor's husband has smoked for 40 years and nothing has happened to him.” You cannot compare apples to tomatoes. You have to be careful. Corona is going to be dug deep in for the next two months--unless the hand of God intervenes or suddenly overnight we have a super vaccine, which to me is like a dream.

We welcome feedback. Please write to respond@indiaspend.org. We reserve the right to edit responses for language and grammar.

Mumbai: Biotech major Biocon, on July 11, said it was launching a new drug, itolizumab, approved by the Drugs Controller General of India for emergency use to treat cytokine release syndrome in moderate to severe cases of acute respiratory distress syndrome (ARDS) due to COVID-19. The drug costs about Rs 7,950 per vial and a patient needs four vials.

Itolizumab belongs to the family of monoclonal antibodies, and has thus far been used to treat psoriasis. The drug regulates or blocks the immune response in order to prevent a cytokine storm--when excessive or uncontrolled levels of cytokines (proteins important for cell signalling) are released, activating more immune cells. This results in hyperinflammation, and causes sepsis or organ failure, which can all be fatal.

We speak with Hemant Thacker, the first Mumbai doctor to carry out clinical trials with itolizumab for COVID-19 patients in early May 2020. Thacker specialises in cardiometabolic disorders as well as general medicine at Bhatia and Breach Candy Hospitals, Mumbai.

Edited excerpts:

What is the nature of the trials that you have done?

Way back in the end of April, when COVID was getting a tight grip on the city and the country, we realised that a group of drugs that belong to the monoclonal antibodies family--which means they are immuno-modulators or immuno-blockers--could be used to prevent the onset of a cytokine storm. At that time, there was only one [such drug] available--tocilizumab--and that too was in short supply. Tocilizumab had to be given twice--on days one and two. And that was about Rs 35,000 to Rs 40,000 on each day. So, we had no choice and on compassionate grounds, we tried it [itolizumab] and we found that it seemed to work--and worked quite well. And we only needed one injection as compared to two of tocilizumab.

I recruited the first patient [for a clinical trial] on compassionate grounds on May 12. The patient, on the sixth day, was requiring more and more oxygen, his respiration was getting laboured. There was a likelihood that he would go into a [cytokine] storm sooner than later. So we gave itolizumab. We give about 4-5 ampules--about 100 to 125 mg. We usually give it only once. It can be repeated after seven days. We found that this drug blocked the action of the inflammatory cytokines, which were triggered by the irritation of the virus in the body.

The virus--once it burrowed itself into the human body--set off a chain reaction, which triggered inflammation, which in turn triggered off inflammatory cytokines, some of which we call interleukins. And these cytokines pile up, till on the 6th, 7th or up to 10th day, they suddenly hit the human body, and puncture the kidney, the heart, the lungs, [and cause problems with] respiration, [or lead to] pneumonia--what we call as cytokine storm crisis.

At that stage, you either pre-empt the crisis or you block the antigens or the inflammatory markers from working in the body by blocking the receptors using monoclonal antibodies like tocilizumab. Then, no matter how high the inflammatory markers are, they do not work. So, the virus is trapped. The inflammatory markers are null and void. They punch, but they punch on a shield which prevents damage. And by that time, the virus gets tamed, the body starts responding, [and] the immune system of the body bounces back. 

So, if you are able to tide over that critical three- to five-day period, then the body has a chance to recover. Remember, this injection is only for moderate, moderately severe and severe cases, which forms about 4-5% or even less of the entire COVID patient population; 85-90% of the patients will heal on their own. Of the remaining 10-12%, most will not require these expensive immuno-modulators and injections intravenously. 

So, what do we do? We use it to reduce mortality, to prevent patients getting on to the ventilator. If they are already on a ventilator, we can get them off easier. And we are hoping that this is one modality that would form one cornerstone of the different pillars in the therapy against COVID. COVID has no magic bullet. This is not a game-changer for COVID. This is a game-changer in reducing--or trying to reduce--mortality. You cannot compare this to remdesivir or favipiravir because they are antivirals.

Do most severe cases follow the kind of progression that you just described?

They do. They come in on the fourth or the fifth day. They are given the antiviral, the antibiotics like doxycycline and azithromycin, steroids like dexamethasone and methylprednisolone, anticoagulants, and other standard of care. If the patient is seen to require more oxygen and his respiratory system is seen to deteriorate, then we preempt the [cytokine] storm and give itolizumab, and that works. I used it in about 21 patients for the study. Of these, except for one, the others did quite well.

Even back in April, you said you were confident that there were many patients who did not need hospitalisation, or critical facilities. If you were to look back over the last four months, what are the other learnings and insights that you could share with us?

The insight is that COVID still has no cure. You have to tide over; you have to bide over the COVID infection. Most of us will be quite lucky, and will fall into the 85-88% category. The remaining will fall into the next 7-8% category, who will have fever, cough, loose motions, body ache, the typical viral syndrome--they lose smell and taste. 

But it is 4-5% who have a significant affliction of the respiratory tree in the form of COVID pneumonia. The more severely affected of these will require to be hospitalised. Once they are hospitalised, they have to be very closely monitored, because the time between deterioration and full-blown [cytokine] storm is very short. If it is in the hospital, you can see it coming, anticipate it, treat it, preempt it.

So would you say that in the last three months, our ability to contain or control the disease has improved--as doctors at the frontline like yourself are far more confident of controlling it than ever before?

We have more armamentarium. We have itolizumab, we have remdesivir. And all that put together has helped us to reduce the mortality--from maybe 3-4% to 2-3% now. If you can save 1-1.5 more patients for every 100, it is a lot.

How are you seeing the strain, if any, on the critical care facilities, particularly in the hospitals where you are managing COVID?

Remember that India is a country with 1.3 billion people, Mumbai is a busy city. We definitely have patients and of those patients, we have people who need ICU or critical care. So, we are always busy, and we always have our beds full. But that does not mean that we do not have place for a critical patient, or we let him go. We are not in the Italian dilemma whether to treat him or to treat her, whether to treat the 80-year-old or the 40-year-old. Fortunately, we need not have to even worry about ventilators. So that way, we are okay. 

We are learning, knowing more and more every day. We have learnt to think on our feet, to innovate. And this [using itolizumab] was an out-of-the-box thought they came up with, because this drug was available for psoriasis treatment. I have now done about 24-25 patients. Seems to be working well. Time will tell. 

For viral infections, we do not have an antiviral like a malarial drug where you take the tablet and the parasite dies. Measles, mumps, rubella, chicken pox--all these things, how are they gone? They are only gone by the vaccine. You take the chicken pox vaccine, smallpox vaccine. In our days, we all suffered from chicken pox. We did not cure it, we endured it till it burnt itself out.

I do not think that we are going to be able to tame and cure viruses. All viruses need a vaccine, and there are certain viruses that you never get a vaccine [for]. Like [for] the dengue virus and HIV, the vaccine is not successful. So, let us hope we get something [for SARS-CoV-2], or we learn to endure it by human adaptation. Either the virus will weaken, or we will strengthen.

Obviously, you are working with limited data and time with this drug. But, would you say that this drug is safe?

I have had no adverse reaction in the form of organ-threatening or life-threatening issues. In your enthusiasm, if you give this drug very rapidly in two-three hours, you can get a problem where the patient can get an allergic phenomenon with shivering, chills and other things. Now we have learnt to think, and we give it over six or seven hours, slowly. And then nothing happens. 

We have no kidney shutdown; we have had no long-term [issues]--in the sense, we only have a two-month follow up. So, time will tell us whether after six months, those that received itolizumab have any issues. But I do not think so, because it is going to burn itself out. As of now, [it is] safe.

The number of cases is obviously still increasing. While you said that you are far more confident, you have more arms in the armament, how do you see the next few months going ahead?

I want to send one message to everybody. Do not drop your guard. Do not think that we have drugs falling into the bag every day, so we are going to be safer and better. The only way you can be safer and better is if you keep wearing your mask, if you do not conglomerate, and if you have safe distance. 

Unfortunately, whether people are fed up of the lockdown, or whether people are not understanding, or they are throwing caution to the winds. You are not worried about yourself so much. You should be worried about your aged, elderly, infirm people back home. I do not see that happening. I see people on the road with gay abandon. I see people conglomerating. They are more interested in the wine shop that is closing, or the restaurant or shop that is on sale shutting down than looking after their health. 

While we at the medical end are trying, innovating, hoping, trying to polish old drugs, taking them out of the cupboard and resharpening them, we do not have a cure. These are all supportive therapies. Most of us get lucky, but to that 1-2% of people who get unlucky, God help them. So, if you do not want to be one of the 1-2% who get it, you have to prevent getting it. Once you get it, nobody can say how your body will react. It is like the lady who comes in and says, “My husband has been smoking only for 10 years and he has lung cancer; my neighbor's husband has smoked for 40 years and nothing has happened to him.” You cannot compare apples to tomatoes. You have to be careful. Corona is going to be dug deep in for the next two months--unless the hand of God intervenes or suddenly overnight we have a super vaccine, which to me is like a dream.

We welcome feedback. Please write to respond@indiaspend.org. We reserve the right to edit responses for language and grammar.



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