Drug repurposing as an alternative to costly drugs such as herceptin in breast cancer

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Published: 10 Jul 2014
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Dr Shripad Banavali - Tata Memorial Hospital, Mumbai, India

Dr Banavali talks to ecancertv at the Metronomic Chemotherapy Meeting in Milan about drug repurposing to overcome economic difficulties in global cancer care.

 

India has a unique situation because we have all the drugs available but there are many of the generic drugs available so some of those we don’t know the quality because the generic drugs are not controlled in India as compared to the FDA control in the United States. So it’s very difficult to make sure that the quality of drugs is right so that’s an additional factor that comes into play when we treat our patients in practice. That’s something unique because this is not faced by the European countries or the United States. And we have to keep in mind the drugs that we use so that we don’t give substandard drugs to the patients.

How do you decide which generic drugs are good or not?

That’s a very, very important question and it has legal implications also. So it’s very difficult for us to do studies and then say that this drug is good or bad. Basically there is no agency that tests the drugs so if a drug is available in the market the DCGI, that’s the Drug Controller General of India, if he allows a drug to be marketed the subsequent drugs do not have to be tested. So then in that situation we don’t know the quality of drugs that are available in the country and what we do is most of the time it’s a clinical experience and we try to use a general. We have various parameters through which we check the company, how much they invest in the research and development, how much they are in the market for, how long for, how much is their turnover? So depending on all this and, along with that our clinical experience, we use drugs. What is unique in Tata Memorial Hospital is that we have a drug committee which actually through all this various methods of testing, or at least getting the information of the drugs, then we actually select certain drugs and only those drugs are asked to bid for the price and according to the prices actually then they are kept. So it’s a unique situation but at Tata Memorial Hospital we actually select only a few drugs which all the clinicians are comfortable with and only those drugs are kept for sale in the hospital. The other unique part of Tata Memorial Hospital is that in India we sell drugs, actually the drugs are sold on MRP, or the maximum retail price, but the actual price of the drug may be entirely different. For example, if the MRP written on the drug is €1,000 the actual drug may be sold at €250. So many other hospitals actually they buy it for €250 but they sell it at €1,000 but at Tata Memorial we sell it at the price that we get so that the drugs are really cheap in the hospital and our patients get the whole benefit of the cost, the reduced cost that we get. That is the reason why we get… like last year we registered more than 60,000 new patients in one year. One of the reasons why people come is because the treatment is quite economical in the centre and the patients get all the benefit of whatever cost reduction that we can do in the treatment.

Can you tell us about the issues surrounding expensive targeted therapies such as Herceptin?

That is one study we published just two years back or three years back and what we analysed was out of the 440 females with HER2 new positive breast cancers who were eligible to get Herceptin, because Herceptin is standard of care for HER2 new positive breast cancers, but out of those 441 patients that we had only 8% of those got the drug, got Herceptin. Very importantly, half of those got it because they were enrolled on some trial so actually only 4% of the patients who were HER2 new positive, female breast cancer patients, got the drug. The situation has improved now because the drug prices have come down and now in the next few months we’ll start getting the generics also because they are already approved by the DCGI and hopefully in the next few months we’ll get the generics also for the drug. And when that comes the cost will further go down and hopefully more patients will get the benefit out of it. But this is true for Herceptin because it’s there in the market for some time. The newer targeted agents which are coming in the market, the cost is so exorbitant that basically very, very few of our patients really can get the benefit of any of the new not only targeted agents but even the chemotherapeutic drugs.

That is why at the Tata Memorial Hospital we are constantly looking for what we call drug repositioning or drug repurposing. That means we try to see if known drugs, for example propranolol as an anti-angiogenic agent or metformin as a biological response modifier, we have ox2 inhibitor as a biological agent and these things. So we are trying to explore all this, what we call, drug repurposing so that that will enhance the effect of our chemotherapeutic drugs that we give and bring down the cost further for the patient. So that’s one of the areas that basically my group is interested in and we are trying to… ultimately one of the main challenges that the oncological community is facing now is not only finding cures for cancer but also how to decrease the cost of cancer and how to make cancer treatment more affordable to the patients.

As we know, basically in the next few years 70-80%, at least 70% of the patients with cancer will be in the low and middle income countries. So we have to start thinking about it because until now we always thought that cancer is a disease of the developed countries and it’s not important in low and middle income countries where infection and all the other communicable diseases are more common. But that is no longer an issue now because it’s not really that the incidence of cancer is increasing, it’s increasing but that’s not the only reason. The main reason is the population in these countries is growing and the population in the developed countries is either stable or coming down. So because of that in the next few years, that is by 2030, more than 70% of the patients with cancer will be in the low and middle income countries. Unless we tackle this problem it will be very, very difficult for the patients there to take an anti-cancer treatment.

What about the use of metronomics in India?

Actually metronomic is a concept which came from the West. We were doing it, actually, in India; many of us were doing it out of necessity. That means we were giving our patients this low dose in the palliative setting, just to give them oral low dose therapies just to palliate them. But now with the scientific research behind it and the scientific concepts that are coming out in metronomic therapies it is now becoming more and more acceptable, not only to the oncologists but also to the patients because metronomic therapy is a unique way of giving treatment because what happens is when you give your maximum tolerated dose based therapies, which are so-called standard of care, that means they give the highest dose of the drug and then give the next dose after two or three weeks by when the counts recover, by that we’re also causing damage to the tumour microenvironment and this itself can cause a lot of resistance. That is maybe one of the reasons why, unlike in paediatric cancers which are highly curable with this type of therapy, respiratory cancers are a more homogeneous population so they respond well to these empiric types of therapies. But in adult cancers it’s a more heterogeneous group of cancer cells so even in one patient, in a patient, for example, of breast cancer, there is so much heterogeneity that if you give only this high dose MTD based therapies in no time or in a short time you can develop secondary resistance and then basically they won’t respond to any treatment. So the concept here is that you use your standard MTD based therapies up front, decrease the tumour load and once you’ve decreased the tumour load maintain that or you start using the metronomic therapies that basically you don’t allow. Because some types of tumours are [??] and don’t allow the tumour to repopulate back and hopefully you may not cure the patient but, like diabetes or hypertension, you give the drug continuously, you keep it under control and the patients do well. Most of the patients with diabetes or cancer don’t die of their disease but die because of age-related problems. So in the same way cancer, change it from an acute disease to a more chronic disease and let the patient live with these low dose drugs. So many of these are tolerated very well by the patients and basically you have good quality of life and maybe a better outcome also. So that’s a concept which we are trying to explore now.

What about your treatment regime for sarcomas?

It’s a very unique regimen because there’s a drug called Tamoxifen which is an anti-oestrogen. It’s a hormonal drug which was used mainly in patients with breast cancer but we know that Tamoxifen has a lot of other biological properties, especially in the higher dose it’s an anti-angiogenic, it decreases the TGF-beta so it causes other changes also. This concept came because initially we used to use this drug, when I was trained you used to use this drug for patients with brain tumours. We were using anywhere from 40-160mg/m2 and the patients used to tolerate it well. So we thought with an anti-angiogenic why not use it in sarcoma because at that time we had no treatment for patients who relapsed with the disease and the overall outcome was very, very poor, basically it was in months. So we started using this combination of Tamoxifen with etoposide and cyclophosphamide. All these three are oral drugs, very cheap in India. The monthly cost of the drugs would be around $20-$25 and with that we got excellent results and now actually when we analysed the data full time actually we saw that the median survival is in years, as compared to months with the other therapy. The next plan is we use this combination maybe as maintenance therapies in patients with metastatic disease who do very poorly with so-called standard of care. So it’s a very unique combination and has given us excellent results, especially in Ewings and in other sarcomas. So we’ll explore it further in the coming months.

Do you think developed countries with funding issues will follow suit?

Yes. Like we discussed, not only when we present this data and we always tell that this will be important for developing countries, many of my colleagues from developed countries ask why would this not be useful in developed countries because price is an important factor also in developed countries. The only thing is that we have to do all this thing in a scientific way, like the data which we have now is hypothesis generating data, it’s what we can call pilot data. So we have done something, it has given us a response but now the second step would be to do scientific studies with both the laboratory as well as especially randomised trials where you use standard of care in one arm and metronomic therapy in the other and see whether it really makes a difference. In this respect, actually, we have started the first randomised trial in patients with head and neck cancer because head and neck cancer is one of the commonest cancers in our country. Many people don’t smoke but they chew tobacco and because of that there’s a lot of oral cancer in our country. Many of these patients are from poor economic backgrounds, they come with advanced disease, and not only do less patients but also new patients who come with advanced disease, nearly 60% of them get the disease recurrences and it’s very difficult to treat. So because of that we’ve started using oral simple doses and basically, uh, based oral protocol in the neoadjuvant setting and then continued it in the perioperative setting and as maintenance. Those who took at least three months of this drug, more than 90% of them were doing well. So seeing these responses actually now we have started a randomised trial where we will be giving this. We have started giving this therapy to one arm and the other arm gets the standard of care and hopefully this is going to be a 400 patient trial, actually large trial, with a good power of telling us whether it is really useful. In the coming years it will tell us whether this treatment really makes a difference as we have seen in the pilot data.

So that’s one thing. The other area where we are interested is in the triple negative breast cancer but again we were using this metronomic maintenance after the standard therapies and all of our patients who had advanced disease, locally advanced disease, not the metastatic one but the locally advanced non-metastatic triple negative breast cancer, many of them are doing well. So because of that we hope that we can use this because up till now for triple negative breast cancer there was no maintenance therapy. Like in ER/PR positive we give the hormonal therapy Tamoxifen or letrozole, some type of maintenance is given; for HER2 new positive breast cancers we give them Herceptin but for these patients there was no therapy and I think this has made a difference. This maintenance therapy has made a much important difference in the outcome of these patients and we hope to start again this as a randomised trial in the hospital in the coming few months or years.

What about Glivec?

Glivec is a very, very important story but Glivec is now, because of the generic Glivec, the generic people formed the case. We, as you know, it went even in the international forum but it’s important. We always say in our country that all the new drugs, we need new drugs, we need new effective drugs but at the same time we need new effective cost-effective drugs also. So in that respect actually we always feel that we talk with the company people, when we talk with the pharma, that you have to keep your drug, you have to make profit otherwise we will be interested in taking out new molecules. But if the pricing of the drug should be GDP based, basically - a drug which costs $10,000 in the USA cannot be sold at $10,000 in India. For example, the average salary of an Indian will be in terms of basically a few hundred dollars as compared to thousands of dollars in the USA. So you have to make sure that the drug is sold according to the GDP of that country otherwise we’ll lose effective drugs. There are hundreds of other drugs available which really may not make a big difference but Glivec or imatinib was one drug which really, really made a difference. And we will see, we will read in the journals, when we go to meetings we will see that Glivec or imatinib is an excellent drug for chronic myeloid leukaemia but we couldn’t give that to our patients. Our patients would read it on the net and they will demand and we will say we cannot give it because the cost of the drug was exorbitant and we couldn’t give it to this thing. But with the generics the cost came down. At the same time the Max Foundation also started a Glivec programme through which hundreds and thousands of patients are getting a free drug now. All this has helped to improve the outcome and now chronic myeloid leukaemia no longer is a challenging disease because most of the patients do well if they take the proper drugs. I think it has set quite a good example where if the community and the pharma come together I think we can do something good for our patients. So the pharma also with the NGOs, with the Foundation actually really tried to give many of the patients free drugs. So I think we need some type of joint action because it has to be public-private partnership and especially for effective drugs. There are non-effective drugs, we are not worried, you can wait, but for the effective drugs there needs to be some way because it’s like there’s water in front of you and you cannot drink it, it’s not ethically right. For us it was very, very difficult to treat our patients having the knowledge that there’s something effective available and we couldn’t give it. But the pharma also needs a profit but it has to be in such a way that both benefit out of it.