“We don’t look at the blockbuster model at all.” The statement is somewhat surprising coming from Novartis Oncology president Herve Hoppenot. However, it succinctly lays out the division’s development model in particular, and the current thinking in fighting cancer in general.
Herve Hoppenot: “We call them minibuster, we don’t like the blockbuster. What at we are looking for is to develop drugs in a small number of patients - so by design we are trying to reduce the number of patients we’re treating - which may be opposite of what other people are thinking, and to find the patients where the benefit of the drug will be the highest. So instead of having a 20% response rate in 100 patients, I would rather treat 20 patients and have a 100% response rate because that model economically makes it faster to develop because you don’t need to do larger studies. You can do smaller studies and faster studies. You can get reimbursement quickly, because it’s better for the healthcare system to treat 20 patients instead of 100 where 80 of them will not benefit. So the healthcare system and the payers...are ready to reimburse a drug at a good price if they know that the drug is going to be effective. What they don’t like is to pay for a number of people where the drug is not going to give them a lot of benefit."
Hoppenot spoke to “Globes” at the American Society of Hematology (ASH) conference in Orlando, Florida, where Novartis officially released the results of a study comparing its successful Glivec (called Gleevec in the US, Canada, and Israel) drug to its newer Tasigna.
Both drugs treat Ph+ chronic myeloid leukemia (CML), a bone marrow and blood cancer, caused by a genetic abnormality called the Philadelphia (Ph) chromosome. The Ph chromosome produces a protein (Bcr-abl tyrosine kinase) which leads to too many white blood cells, many of which do not function normally.
CML generally progresses along three stages: the chronic phase, which is when most patients are diagnosed; to the more advanced accelerated phase and blast crisis phase.
Treatment in the advanced phases is aimed at returning the patient to the chronic phase. In the chronic phase, treatment aims to remove traces of Bcr-abl that can be found in the blood or bone marrow. Stem cell transplants can work, but are accompanied by severe side effects. So Novartis Oncology developed oral drugs that can target the protein and inhibit its activity so the production of unwanted cells stops.
The success of the treatment (response) is measured by a test called PCR. A molecular response means both bone marrow and blood show a reduction in Bcr-abl: Major molecular response is a 1,000-fold decrease in Bcr-abl, and complete molecular response means a PCR test won’t show it at all.
Novartis Oncology's Glivec was approved as a first-line treatment for adults with chronic phase Ph+ CML in 2001. The new drug was a breakthrough. While chemotherapy delivered through IV was rather indiscriminate in attacking both cancerous and healthy cells, the oral treatments targeted the cancerous protein itself. But not all patients responded to Glivec, and a newer drug, Tasigna, was developed by Novartis and approved as a second line treatment, for those who did not respond to Glivec, or became intolerant to it.
Recently, Tasigna was approved as a first line treatment in Switzerland and the US, and the study led by Dr. Timothy Hughes at the University of Adelaide, Australia - presented at the ASH conference in December has been comparing the two drugs, given to newly diagnosed CML patients. The data presented was for a median 24-month time frame.
The results have been quite convincing. Maybe most importantly, after 24 months Tasigna was more effective in preventing progression to more advanced stages (only 2 patients (out of 282) on Tasigna progressed, compared to 12 patients (out of 283) on Glivec). The data also showed that by 24 months, nearly three times more patients taking Tasigna (300 mg twice a day) reached a complete molecular response than those taking Glivec (70 on Tasigna vs. 25 on Glivec).
After 12 months of the head to head study, 44% of Tasigna patients reached a major molecular response (MMR), compared with 22% of Glivec patients. After 24 months, the difference widened - 71% of Tasigna patients reached a MMR, compared with 44% of Glivec patients.
The figures show that Tasigna has maintained its advantage over 24 months. Tasigna generally was well-tolerated and no new or unexpected side effects were observed.
Novartis executives note that with the disease remaining controlled for a very long time, some oncologists consider it a “cure”. However, patients must remain on the drug - if they stop taking it, many will relapse and the cancer will return. "Globes" asked if it’s a matter of semantics.
Globes: We have from August, when Swiss regulators approved Tasigna as first line, a quote of yours -
"Uh-oh…"
“With this approval of Tasigna as a first line treatment, we are pleased to offer newly diagnosed CML patients a new and even more effective option for delaying disease progression.” Is that the best we can do - “delay disease progression” - as opposed to calling it a cure?
"It’s a very good question. The wording reflects what we knew when we did the filing, the first application for Tasigna as first line. That was based on a 12 month analysis of the study where we compared Glivec to Tasigna. After 12 months we could observe that there was less progression with Tasigna vs. Glivec. Progression in CML means moving to an advanced phase of the disease, but there is no cure."
Hoppenot explains that an advanced stage of CML “is not good news” so “the concept of progression from chronic phase to advanced phase is really the key to understanding why it is important to treat patients with Tasigna vs. Glivec. That’s why we spoke about progression.”
Hoppenot continues, “Now today, most patients who are initiated on this product will stay on treatment, so we have not yet completely unlocked the way to cure them so that they will be able to stop completely the treatment - so they are treated chronically. Most of them will have a life expectancy which is the same as somebody who doesn't have CML, so the impact on their survival over time, for most of them, very much makes them have no perspective about life and work and everything - they are the same as everybody else; but we haven’t yet identified how we could declare them cured from their disease and stop the treatment. That is in fact one of the programs that we are beginning now to initiate.”
We were talking specifically about Tasigna, but in general, are we giving up on a cure for cancer? Are we saying that we’re not looking to cure cancer anymore, we’re looking to treat it as a chronic disease? And is that the case for all cancers, or are there some that progress so quickly that we can’t treat them chronically - it’s all or nothing?
"Today - and even before Glivec and definitely for leukemia - there are a number of cancers when you could treat patients and they would be cured the adjuvant treatment of local tumors, when you remove the tumor with surgery and you give drugs to prevent a relapse; many of the patients in breast cancer in fact are cured - but the problem is that we don’t know which ones so that sort of makes it a little complicated. But there is a chemical cure for cancer, in fact testicular cancer can be cured with Cisplatin since 25 years ago - so it’s a long time ago; metastatic cancer could be cured with drugs - that has been proven; In fact, in some forms of leukemia it has been done with chemotherapy.
"In the case of CML, what we are talking about here - we have not yet understood which patients are cured and which ones are not cured. At Novartis we are working on it in two directions. One is to do drugs, like Tasigna, that bring more patients to a level of undetectable disease - complete molecular response (CMR) - so that we cannot detect residual disease. But we know some of them are not cured because if you stop treatment a large number of them are going to relapse. So what we are doing is working on combining products for patients who have undetectable levels of abnormal cells and see if you can induce a cure for them, and then we are working in parallel with partners, with other companies, to develop tools to be more precise in detecting the remaining cells so that we can identify the patient who has no more and the one who may still have a few of them. It is an effort that we doing in cooperation with other companies who specialize in diagnostic tools, to be able to do what you are hoping for, which is what we are also hoping for - I think it would be a fantastic achievement for the industry."
Doctors relate that sometimes cancer patients come in, and later it can metastasize to other organs, like the brain was there a way to have stopped it at some point, if they’re not 100% cured, to prevent it from coming back?
"I tell you, the question you are asking is extremely profound and it is a subject of scientific debate. The question is basically: Is cancer - a metastasis, solid tumor - are the metastases happening very early because the cancer has some specific characteristic which makes it easier to disseminate in the body or, is it happening because the tumor is growing as a sort of late stage, and today there is scientific debate about that...I don’t know the answer. I think a lot of people are arguing that there are some types of cancer specifically prone to dissemination and metastasis and some others that are not.
"It is important to speak about here that the way we are thinking now in terms of research is not really on where the cancer is - is it on the breast, lung, or the colon or any place in the body - but more what are the biologic abnormalities that are specific to this tumor.
"With Bcr-abl if you have Ph positive CML then Glivec, and now Tasigna, is designed to hit the target very precisely. So the way we think is first to understand what tumor it is, and the fact that it is in the breast or the lung doesn’t make it different. Look at the abnormality in the tumor, and then develop drugs that will be specifically designed for that target - so it’s targeted therapy for cancer - as Tasigna for CML - and then develop in parallel diagnostic tools for patients who have that abnormality. That makes it a very different type of development."
Glivec wasn’t perfect - there were patients who failed on Glivec. Is Tasigna better than Glivec - and if it is, you make both - is Tasigna going to push out Glivec?
“Yes. The history is the following. Glivec was discovered, and it was a breakthrough at the time, as a way to target Bcr-abl. When it was discovered Novartis started immediately to start designing - it was really designer chemistry - molecules that would have better affinity for the target so that we would be dealing with cases of mutation, cases of resistance to Glivec. So that was the history: Even before Glivec became a big product, the chemists and researchers were really interested in improving over Glivec.”
Hoppenot explains that the safety profile of Tasigna is at least as good, if not better with regard to some side effects, than Glivec and that is very important because “if patients are treated for a number of years you cannot have a drug that has these wide side effects, because then they will not take it and they will relapse.”
Hoppenot says that Novartis has observed already in the US where the drug was approved for first line more than half a year ago that “in fact a large number of people are choosing to start with Tasigna from the beginning instead of Glivec - so there will be a replacement.”
So the patients are going straight to Tasigna?
"Yes."
Is the rate of incidence for CML in Israel in line with global rates?
"For CML we have observed very small differences from country to county, in fact the incidence of CML has been fairly consistent around the world, so it’s the same thing - it is not a very population-specific type of disease."
You started at Novartis in 2003, after Glivec had been discovered, but before Tasigna. How did Tasigna come about - and what was your role?
"There was a lot of work on Tasigna. I joined Novartis for two reasons. One is the quality of the team and the integrated worldwide positioning. We are, and we were at the time, the only one - many people have tried to copy us but they have a lot of trouble doing that, which is interesting, but anyway - we have this system worldwide where we have oncology teams dedicated to cancer working with us in the countries, in the region, at the global level, from research, translation of medicine, development, and all the commercialization and access for the product, so all of that is integrated with people who have this view that is very close from the research to the patients.
"The second thing was the quality of pipeline. Because Novartis was in front of everybody in this field of rare disease and targeted therapies that are very specific for a small group of patients and are providing a very large benefit. To me, it’s the best model to accommodate the economic need of the company - an economically viable model, but also to be economically viable for the healthcare system in the country - and to have both at the same time by selecting patients and working on a small number of patients.
"I joined in 2003. At the time Tasigna was not called Tasigna, it was a product we had somewhere in our chemistry department. We did the first in man, the first experiment in patients, and then we moved it extremely rapidly, by giving the resources that you need to do it, to be second line, and then moving to first line by making the decision to go head to head to Glivec. It was not an obvious decision at the time…"
Because you were going against your own drug…
"Yes, and there was a perception that Glivec is so good that going against it is a little odd. So it was not obvious, but... we have shown at Novartis in many cases that when we have a drug in a given disease, we have a sort of special knowledge of the disease, of the chemistry around it, and then we are probably more able than anybody else to provide a drug even better than what we have.
"That’s what we have done with Zometa and Aredia, we have done it with long acting Sandostatin…and it’s not by chance, it’s because we had these people around the world, partnerships with academic centers, and the ability to improve on our own product."
You mentioned a small number, that’s something else that seems unusual. There are reportedly about 24,800 CML patients in the US, which seems to be a really small number to be developing drugs for?
"Oh, sounds big to me. We are developing drugs for diseases that have incidence and prevalence that are far less than that. A good example is gist (gastrointestinal stromal tumors), in fact another indication for Glivec. It’s a disease that is very rare, and was even more rare before there was a drug for it, because now patients are living longer, but where we found out that the drug was active…we developed it…and today around 20-25% of sales of Glivec worldwide come from that indication gist.
"So it’s a substantial economic benefit to the company. It’s a very large benefit to the healthcare system because now there is a drug for these patients. And in terms of development, we are not shy to develop drugs for rare diseases, in fact we like it."
That sounds unusual. You would think that if you’re going to invest all that time and energy you want a blockbuster drug, that’s going to be offered to tens of thousands, millions, or hundreds of thousands of patients and you’re saying that you’re developing for a few thousand patients, and you’re putting in the time and energy, and you’re not even doing it just to be “good”, you’re doing it because you think you can make money from it.
"That’s what I’m saying. The economic model we have is based on the idea that we need to have sustainability over a long period of time. So from our standpoint we don’t look at the blockbuster model at all…the model economically - it’s a strategic model for us, it’s not just because, you know, we don’t find large populations that we go to a small population. In fact, we want to go to the population where it will help. If it’s a bigger small population, so be it, fine, but we are literally trying to select the patient group that will be treated with our product to find the one that will have the largest possible benefit so its molecular diagnostics, working on identifying sub-groups of patients.
"And Novartis has shown it - we have developed drugs for neuroendocrine brain tumors - we have today Sandostatin there, we developed Exjade for patients with iron overload, iron accumulation…we are developing many of our pipeline products in very niche indications."
Hoppenot mentions another study that was presented at ASH, of Panobinostat (LBH), in a group of patients with refractory Hodgkin’s disease. “It’s very rare, so we don’t even speak about these kinds of 25,000 patients, it’s a very small number of patients; but the benefit - they have no other treatment today. Many of them are relatively young, many people with Hodgkin's disease are below 30 years old, and we will have a drug that will help them. So we are really looking at medical need, targeted therapies, small number of patients, large benefit, and that’s an economic model that we believe would be sustainable over time. It’s not obvious, many people are questioning that, but I think it is very true.”
Israel has a big biotech industry. Looking through some of the stories we’ve written about in “Globes”, there actually are a lot of companies working on cancer treatments. Anything that sticks out in your mind? Any specific technology?
"We are looking at partnerships with other companies all the time, and we do partnerships, you can look at the track record of Novartis with many different companies. We try to do it at the early stage at the time of the technology when the technology is bringing a breakthrough. We have no specific country we want to partner with. It’s really a global effort and I have no specific name about Israel."
Hoppenot continues, "Our survival as a company in our field - oncology and hematology - is based on our ability to develop new breakthroughs. It's not about me-too. It not about doing drugs that already exist next door, I mean that does not work. It's another business, in fact, that we are doing elsewhere at Novartis, but our business, the one we are managing in the oncology business unit, is based on bringing new products that will help patients who don’t have treatments that work today - and there are a lot of them, cancer is not a disease that is very well treated today. We have a lot of growth potential."
Looking at some of the Israeli companies specifically…a lot of companies are working on cancer diagnostics, biomarkers, trying to find “before” it happens. Is that something that at Novartis Oncology you think about as well?
"Absolutely. It’s not really about “before” - we do some of that too. I think what we are more interested in is literally to be able to characterize the tumor, because the past history, the past hundred years in most cases people were treated based on where the tumor is breast vs. lung, etc.
"What we are doing today and literally it has changed the entire development model - is not where, it’s what.
"Is this tumor a tumor that has a mutation of the PI3 pathways, of the ALK mutation in lung cancer, or abnormalities in the pathways? That could apply to different types of cancer - maybe 30% of patients with breast cancer have the PI3 kinase abnormality, 5% of lung cancer, and 10% of colon cancer, and that will become a target for us, saying the PI3 kinase abnormality is what we are treating, and it will apply to different kinds. Therefore, we need the tools to sequence the tumor, to identify the mutation, and all this molecular diagnostic effort is something that is fundamental. We have a division at Novartis that is specialized in molecular diagnostics and they are partnering with companies all over the world, to find the best technology to be able to do that. It's really important because it is a separate business - it could become a business by itself. It’s also what will help us design the best possible drugs for a specific group of patients."
Do we know today what causes cancer - can we say X causes cancer, Y does not? Is it a function of the Western lifestyle, the modern lifestyle?
"We know there are some chemical things that can generate cancer, we know with asbestos for a certain type of mesothelioma…I don’t think the science is there today, to really go to the roots of each of the cancer that we are observing. We know some of them are fueled by certain things like estrogens or other types of molecules that we have in the body naturally, and then there are others where we don’t know exactly the cause and the root. That’s an answer that we don’t have, that I don’t have, and that I don’t think anybody has. Where we are making progress is finding out what is making this cancer grow and become a life threatening disease."
Do you think we’ll be able to cure, get a real treatment - to the level where it’s not noticeable, in our lifetime, across the board, for cancer?
"Some cancers have been transformed by treatment. Tasigna and CML it has changed the life of patients with CML completely, they are back to normal life. There are some other examples - Cisplatin for testicular cancer 20 years ago was a cure for testicular cancer - it still is, it’s still used today, so they are small examples or rather, big examples in small populations of that.
"I think we will see a replication of these groups of patients who have been well identified where we have good treatment.
I don’t think there will be a universal cure for cancer, I hope for that, but I don’t think…It’s a complex disease, we can see the complexity now, the more we look the more complex it becomes."
The Globes reporter was hosted by Novartis Oncology at the ASH conference in Orlando, Florida in December.
Published by Globes [online], Israel business news - www.globes-online.com - on January 16, 2011
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