Print BCTV: Seeing Breakthroughs Answering Questions -- Alexion, Novartis,J&J case studies from FDA's Breakthrough drug program

Seeing Breakthroughs Answering Questions

Transcript of BioCentury This Week TV Episode 145




Jay Siegel, Head of Global Regulatory Affairs, Janssen R&D

Martin Mackay, Ph.D., Executive Vice President, Global Head of R&D, Alexion

Hervé Hoppenot, President, Novartis Oncology




Asfotase Alfa, Alexion

Soliris, eculizumab, Alexion

LDK378, Novartis


Xalkori crizotinib, Pfizer

Velcade bortezomib, Janssen R&D, Johnson & Johnson

Ibrutinib, PCI-32765, Pharmacyclics

Daratumumab, Genmab/Janssen R&D, Johnson & Johnson

Janet Woodcock, Director, Center for Drug Evaluation and Research, FDA



Steve Usdin, Washington Editor




STEVE USDIN: This week, R&D leaders from three companies discuss the search for medical breakthroughs and what a government initiative could mean for children with a crippling bone disorder and patients with cancer. I'm Steve Usdin. Welcome to BioCentury This Week.


NARRATOR: Your trusted source for biotechnology information and analysis BioCentury This Week.


STEVE USDIN: It's been a long-sought goal of medical science, treatments that precisely address the root causes of disease. They're called targeted therapies. And now, the FDA is seeing a flood of them on the horizon. Last week, we heard FDA's top drug regulator, Dr. Janet Woodcock, describe how the agency's new Breakthrough Therapies program aims to get these treatments into the hands of physicians as quickly as possible.


This week, we'll see how several drugs in the FDA's program actually could be breakthroughs. We'll see how inventions from a Biotech company, Alexion Pharmaceuticals, and two pharma giants, Novartis and Johnson & Johnson promise to change cancer and a rare disease that prevents bones from forming properly.


We start with Asfotase Alfa, a drug the FDA has designated as a breakthrough for hypophosphatasia, or HPP, an ultra-rare genetic disorder. Infants with HPP have soft, demineralized bones that lead to disfigurement, organ problems, and often death. X-ray images of a baby's hand before and 24 weeks after receiving Asfotase Alfa provide a stunning glimpse of how this breakthrough candidate could transform the lives of these children.


We're joined by Dr. Martin Mackay Executive Vice President and Global Head of R&D at Alexion, the biotech company that's developing Asfotase Alfa. Dr. Mackay so we've got these X-ray images can you describe just what we're seeing there?


DR. MARTIN MACKAY: Yes, indeed. This was actually part of our Phase II study that was conducted by Dr. Michael White in patients with hypophosphatasia. The two panels here show perinatal patient. And on the left hand panel, you see the bone malformation. So basically, the baby doesn't have proper bones -- and in this case, his fingers. And then, on the right hand panel, after 24 weeks of Asfotase treatment, you see this remarkable improvement.


STEVE USDIN: So taking a step back, what is HPP? What causes it? And how common is it?


DR. MARTIN MACKAY: Well, it's a devastating disease, no question. It is ultra- rare, as you mentioned. It's an inherited disease with quite profound effects on patients. It's shown that it can happen in the perinatal stage, in infants, and juveniles, and even adults.


With the earliest stages, with the perinatal and infants, it has quite a profound effect on the patient. The radiographs show that on the fingers. But can you imagine the same for ribs? Where you see radiographs and the baby doesn't have ribs? And what that leads to in terms of bone malformation and respiratory problems? So this is why we are working on a treatment for it.


STEVE USDIN: In some of your early studies, also, you've seen babies, even, and toddlers, who couldn't walk, and who were able to walk and function as a result of receiving this therapy. It's really amazing. How was Asfotase Alfa discovered, and what's your development path going forward?


DR. MARTIN MACKAY: Yes. So we know what causes HPP. That's good news. And it's actually an enzyme that's missing from the patient. And the enzyme's called Tissue Nonspecific Alkaline Phosphotase. And what happens, because that is deficient, it causes the buildup of other chemicals in the body. And it's those other chemicals that cause the damage to bones and respiratory failure.


So there were some early studies done with a notion of replacement -- just give the patient Alkaline Phosphotase. But unfortunately, that didn't work very well. Our scientists, on the other hand, engineered Alkaline Phosphotase. And what they added to the enzyme was another part of the molecule, which allowed the molecule to get to the place where it needs to be and to deliver it to the bones. And it was that time, as shown in those radiographs, where we saw the remarkable benefits.


STEVE USDIN: So this is an ultra-rare disease. There's probably 2,000 or 3,000 children a year born in the United States with this condition. How many patients have you studied now, and how many more do you think that you'll have to study before you can get approval for it?


DR. MARTIN MACKAY: Yep, so a couple of points. We don't actually know the total number of patients. We know it's ultrarare. But one of the things that you notice is, when you come along with a treatment, and an effective treatment, a treatment that really transforms the lives of patients, you understand the disease better.


But there's no question it's small numbers of patients. That's the area that we work in. We have treated over 50 patients with Asfotase Alfa. And we do see profound effects in those patients. The response rates have been terrific, to date.


In terms of what the development path is, we continue with our studies. And one of the things I'm sure we'll discuss is this breakthrough designation and what that means?


STEVE USDIN: Yeah, so what does it mean?


DR. MARTIN MACKAY: You know it's relatively early to say. We were given this designation just a couple of weeks ago. A, we're absolutely thrilled by it because it plays into the area that we work in Alexion -- you know, ultra rare devastating disease.


What we expect it will mean is a very good discussion with the FDA, and a continual discussion as we go through the development path. That's going to be very important to us in terms of the development pathway for Asfotase Alfa. So we really welcome this.


STEVE USDIN: So very quickly, also, this is another issue, which is a kind of controversy about some of these drugs for ultra-rare conditions, which is the pricing and access. Your other drug that you've already got approved, Soliris, costs more than $400,000 a year. Do you expect that Asfotase Alfa will have similar pricing? And how do you ensure that people who don't have insurance, or can't afford it, can access them?


DR. MARTIN MACKAY: So in terms of Asfotase Alfa, it's really too early to think about pricing. I mean, we are just absolutely devoted to developing this medicine and getting it to the patients that it needs. But you raise an interesting point about Soliris, or eculizumab. We've been successful now talking to over 50 countries, both public and nonpublic payers, to make sure that eculizumab -- Soliris -- gets to the patients that need it.


STEVE USDIN: So Dr. Mackay, Soliris is expected to generate about $1.5 billion in revenues for Alexion this year. The pricing is north of $400,000 per patient. You're working on four or five other ultra-rare diseases, and there are hundreds, maybe, thousands of them. Is it going to be sustainable, do you think, for the healthcare system to have those kinds of pricing for all of these, if we're lucky enough to find therapies for them?


DR. MARTIN MACKAY: Yeah, the way I look at this is, the diseases that we work in are devastating. If you think about patient where the prognosis is so poor in so many cases, that whole aspect of access is very important to us. What's equally important to us, though, is how good our medicine is.


And I like to look at it this way as, how bad and how good? How bad is a disease? And for us to work in it, it has to be devastating. And how good is our medicine? We're not looking for incremental benefits here. We're looking for a profound difference in the patient's lives. You caught a glimpse of that with the radiographs. So you put that together, it's really important, as companies, that we work in this space and get those medicines to the patients that need them.


STEVE USDIN: Another thing I'm wondering about -- for Soliris, for example, one of the things that's interesting, when it's for an ultra-rare condition, but, actually, it's for now, what? Two ultra-rare conditions. And you're looking at other ones. It's a drug that affects the complement system, sort of the flip side of the inflammatory system. Couldn't a drug like that, either that drug, or one that would be similar to that, have much broader applications? Can you learn things from these ultra-rare conditions that could be applied to more broad conditions?


DR. MARTIN MACKAY: That's certainly possible. That's not what we do. We are very much focused on the ultra-rare diseases and the two that you mentioned, for eculizumab -- Soliris -- PNH, and Atypical HUS. And they fit into this very well. They are ultra-orphan. They're devastating for patients.


The really good news is eculizumab makes a profound difference to those patients. We have real expertise. Our scientists at Alexion know complement very well. And that's why we look for other ultra-orphan diseases where complement plays a role. And as you mentioned, we've got a number of programs earlier in development.


STEVE USDIN: What's it what's the difference in developing a drug for an ultra-orphan disease compared to developing one for a more common disease?


DR. MARTIN MACKAY: Well, I think this goes right across whether it's a small, it's ultra-orphan, that we work in, or larger, it's really understanding the path of physiology of disease.


STEVE USDIN: Thanks. In a moment, we'll hear about a potential breakthrough treatment for lung cancer. First, here's a snapshot of the growing cohort of therapies in the FDA's breakthrough drug program.


NARRATOR: You're watching BioCentury This Week.




STEVE USDIN: Most of FDA's breakthrough candidates are very precisely targeted. Novartis' LDK 378 is a good example. And early studies have produced dramatic results for patients with lung cancer tumors that are driven by a specific gene mutation. To discuss LDK 378 and the development of breakthrough targeted cancer drugs, we're joined by Hervé Hoppenot, President of Novartis Oncology. Mr. Hoppenot, maybe the best way to start is by talking about this gene mutation. What is it, and how does it allow you to segment out certain lung-cancer patients for this kind of treatment?


HERVÉ HOPPENOT: The history of the LDK development is very symbolic of what we have been trying to do at Novartis. In fact, since the Gleevec story, 15 years ago at most. And the LDK story started 10 years ago, when ALK was identified.


And a little bit later, in a group of patients with lymphoma. And a little bit later, it was also found in patients with non-small cell lung cancer. And 10 years ago, on 2003, 2004, a program was started to target that new oncogenic target that was just identified.


And through these six or seven years of finding, identifying, standardizing, the best drug, LDK came out at the end of the process as the best potential candidate. And we started clinical studies in 2011. So there's a group of patients with non-small cell lung cancer, between 3% and 8%, who have this abnormal gene, and where we know this drug could be of great benefit.


STEVE USDIN: So what were the kind of results you've got that led you to apply and led FDA to grant breakthrough designation with LDK 378?


HERVÉ HOPPENOT: Yeah, what makes it really symbolic of modern oncology development is that we are able to start the first studies, the first in man in patients who have the abnormality that we are targeting.


STEVE USDIN: So you knew that it was likely to work in them?


HERVÉ HOPPENOT: We hoped it is working. But what's more interesting is that we are able, first, to do the study in patients who could benefit from the treatment, which is obviously one of the big advantages. And from the development standpoint, we do the dose escalation, and we have, in fact, a proof of concept all in the same study.


And that's what happened with LDK. It's not always the case. In that case, it was successful. We were able to expand the study. Now we have around 114 patients that have been included. And we were able to see around 400 milligram dose so somewhere halfway in the dose escalation, that we had very dramatic responses already.


So then we continued to adjust the dose and to find what's best dose that we can use for this product. And now we are around 750 milligram. And we know it's a dose that will be very effective for this patient with that very specific translocation that we discussed.


STEVE USDIN: So you've gotten this breakthrough designation. What does that mean? What is going to change as a result of that? What's going to happen that wouldn't have happened without breakthrough designation?


HERVÉ HOPPENOT: It's difficult to know because we are in the middle of learning how this process is working. The accelerated review process did exist already for a number of years. We had a number of our own products that went through it and could lead to, relatively, a very rapid approval in the US. What we hope will come out of the breakthrough designation is the ability to have a dialogue with the FDA, to be able to align with them prior to the filing on what they really need to be able to review the file and give us approval.


You know, the old process, even through the accelerated review process, is a process where we accumulate all the data, we go to the FDA, they review it, and they tell us good or bad. In that case, we have a period of time between now and filing where we can meet with them, we can align on what they need, and I think it can be been very beneficial, specifically for products that go very quickly through the development process, because a number of questions are not really clinical questions. A number of questions are about chemistry, stability, industrialization that needs to be done very quickly and where I think it's very beneficial to have a dialogue with FDA and to be able to calibrate with them what would be required so that they can give us a good outcome to the finding.


STEVE USDIN: And so, very briefly, also about the results that you've gotten from it -- this is the second, actually, ALK inhibitor for non-small cell lung cancer. The other one is Xalkori from Pfizer. What's the difference between LDK 378, based on your early results, and the first one that was approved for this same subpopulation?


HERVÉ HOPPENOT: So we know the targeting is different. So that sort of the pre-clinical profile of the two drugs is very different. We don't know the clinical difference head-to-head. But what we know is that the first activity that was seen was in patients who were previously exposed to Crizotinib and we're progressing, and then were responding, again, to LDK. So it was effective in patients --


STEVE USDIN: Who failed the other ALK inhibitor. Well, thank you. The roster of breakthrough drugs is dominated by cancer therapies. Johnson & Johnson's received four breakthrough designations for cancer drugs. We'll talk about them in a moment.




NARRATOR: Now, back to BioCentury This Week.


STEVE USDIN: Johnson & Johnson's been awarded four breakthrough designations for cancer drugs. Three are for a single molecule, which Johnson & Johnson's developing for B-cell cancers in partnership with a biotech company, Pharmacyclics. J&J also received breakthrough designation on the basis of dramatic data in treating multiple myeloma.


I'm pleased to be joined today by Dr. Jay Siegel head of global regulatory affairs for Janssen R&D, part of J&J. Dr. Siegel worked for 20 years at the FDA center for biologics, including seven years as head of its Office of therapeutics research and review. Dr. Siegel, let's start with the first breakthrough designation for Ibrutinib Can you tell me, what was the basis for the FDA giving you that designation? What could it mean for patients if it gets approved?


DR. JAY SIEGEL: Right, so the first the designation for Ibrutinib it was in mantle cell lymphoma, which is a particularly difficult to treat type of non-Hodgkin's lymphoma -- as you said, a cancer of a type of lymphocyte, the B lymphocytes that circulate in the bloodstream.


This particular disease is problematic because it is both relatively aggressive among lymphomas, and, unlike some other aggressive lymphomas, it's particularly resistant to therapy. So once the disease relapses, or fails to respond to the first treatment, there are not many options available. One approved drug, bortezomib, or Velcade, that we're involved in developing, other drugs that are experimental.


But pretty much, they cause responses that are rather short lived and occur in a minority of patients. In the earliest studies in this population with Ibrutinib, we saw remarkable, unparalleled types of results, with approximately 70%, almost 70%, of patients responding -- with over 20% having complete response, having evidence of their disease disappear compared to say single digit type responses with other drugs.


STEVE USDIN: And you've got some other indications but they're also similarly, for Ibrutinib, they're in B-cell cancers. There's another drug that you've received breakthrough designation for that's for multiple myeloma. Can you tell us about that one?


DR. JAY SIEGEL: Yes that's Daratumumab. It's a monoclonal antibody. It's also a partnership with Genmab, although it's a licensing arrangement. And we're responsible for the development.


And it's earlier in development. But even in its first clinical trials, in patients in multiple myeloma, we treated highly refractory patients. These are people who have failed three lines of therapy, or have failed to respond to the two most critically invaluably important types of drugs for this disease. And in those patients, their typical life expectancy is significantly under a year.


And we found, even in the first -- just treated about 30 patients -- and only 12 at doses high enough where we would expect to see any sort of activity of the drug and are extremely pleased with the types of responses we saw. Of those 12, about five or so having very good responses, in terms of the abnormal proteins in their serum, even larger numbers having very good responses in terms of the growth of the tumor cells in their bone marrow.


STEVE USDIN: So can you talk a little bit about what breakthrough status, breakthrough designation, might mean for either one of these drugs. What might happen that wouldn't have happened without breakthrough status?


DR. JAY SIEGEL: Sure. Well, breakthrough is, of course, an early program. So the answers to that remain not yet fully defined. But Ibrutinib, especially in its first indication, a mantle-cell lymphoma, was one of the first breakthrough designations. And we've had meetings with the agency, the FDA.


And I must say that our teams have been just extremely pleased with how the FDA has worked with us on this product. They've literally not only brought together people from all disciplines, ranging from clinicians to plant inspectors, to try to get a coordinated approach to look at every aspect of this product, every issue that we face, and see how they can help us address those issues. Not only have they brought those together, but they've even identified, prospectively issues.


So rather than not only just responding very well to our questions, they say, look, here's something that's going to be a concern. Let's think together how we can get the type of information we need to accelerate this. So it's become a really active partnership that is identifying problems in advance. The agency is really marshaling its resources to enable this drug, should it prove to be as helpful as its current promise suggests it will be, will enable it to get to patients as quickly as possible.


STEVE USDIN: And that's something that doesn't routinely happen when you're submitting a normal application, you don't know exactly what FDA wants, you do your best to figure it out, you submit the data, and then you see what happens, right?


DR. JAY SIEGEL: I think that's right. Now, the agency does have other programs, in the past, for promising cancer drugs and for promising other drugs -- AIDS -- and in other areas. And there are opportunities that can accelerate those products. But the new breakthrough designation is one that's really focusing on a smaller number of products and really bringing a broad variety of types of resources together to solve these problems.


STEVE USDIN: We'll continue our conversation about breakthrough drugs with Dr. Jay Siegel in just a moment.


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STEVE USDIN: We're talking with Jay Siegel, a former senior FDA official, about developing breakthrough drugs. Dr. Siegel, there's going to be two criticisms, I think, of the breakthrough program. One is, people are going to be concerned the drugs are going to get out there that haven't been fully tested, that might be dangerous. And the other is going to be that FDA is collaborating too closely with companies, that they're too cozy with companies.


What would be your response to both of those criticisms?


DR. JAY SIEGEL: Well, with regard to the first, understanding the safety of a drug is a continuum, a continuous process. There's never for any drug, at any one point in time, where you know everything you could possibly know about the safety of the drug. So even after drugs are marketed, all drugs, we continue to do surveillance.


The point, then, of breakthrough product, if it truly has the profound and important benefits to patients who have very serious diseases, not only could you potentially tolerate more safety concerns, but you could tolerate more uncertainty about safety. It may not be so important to know precisely the incidence of something like, say, skin rash or headache if the drug is going to prolong life.


So this will enable those products that truly have that type of benefit to get to the market while we continue to learn about them. As to the agency working with industry, and I've been on both sides of the coin, the agency and the industry, each of course, have their own perspectives. And the agency is a regulatory body. It must regulate industry. But ultimately, it's a public health agency, and its goal and mission is to advance the health of the public and to protect the health of the public. And it's quite appropriate for a regulatory body to help industry understand how to bring forth important new therapies as quickly and safely as possible.


STEVE USDIN: So very quickly, also, when we're talking about these therapies, both of these therapies, they're going to help some patients. They're going to help some patients a lot. But it's not likely that they're going to be the cure. How do we get from these kinds of breakthroughs to cures?


Well, the development of therapies for cancer is a complex process and takes some time. Typically, as with these drugs, the first studies we're going to do are in patients who have few other alternatives, very advanced in refractory disease. When we see good activity and we prove the drugs to be effective for those patients, then we can start looking at them in more combinations earlier in the disease instead of currently approved therapies. And that sort of approach may lead to more and more benefits and hopefully, at the end of the research process, toward increased cure rates.


STEVE USDIN: Well, thanks. That's this week's show. I'd like to thank my guests, Martin Mackay, Hervé Hoppenot and Jay Siegel. And remember to share your thoughts about today's show on Twitter. Join the conversation using the hashtag #BioCenturyTV. I'm Steve Usdin. Thanks for watching.