Welcome to the Sanofi Conference Call on Multiple Sclerosis. I now hand you over to Mr. Sébastien Martel, Head of Investor Relations. Sir, please go ahead.
Thank you. Hello, everyone, and welcome to our IR Thematic Call on Multiple Sclerosis. This call is made to provide you with an update on Genzyme's MS portfolio and in particular, Lemtrada. Indeed, we're here in the middle of the American Academy of Neurology meeting in New Orleans. And following the release of detailed results from CARE-MS II yesterday, we believe that it was important that we provide investors and analysts with an overview of Lemtrada's profile for CARE-MS studies.
As always, we've prepared a presentation for the call, and our slides are available to download from our website. As you know, I must advise you that the information presented on this conference call contains forward-looking statements that involve known and unknown risks, uncertainties and other factors. These may cause actual results to differ materially. Please refer to our Form 20-F on file with the SEC and also, our Document de Reference for description of these factors.
With us today on the call are Bill Sibold, Senior Vice President, Head of Multiple Sclerosis. Bill actually joined Genzyme in 2011. He is responsible for Genzyme's MS franchise as the company prepares to launch 2 products. Bill knows the MS field very well having spent a number of years at Biogen Idec in various leadership positions for MS products.
And we've got Dr. Mike Panzara, Therapeutic Area Head of Multiple Sclerosis. Mike joined Genzyme in 2009. He is, first and foremost, responsible for clinical development strategy and on oversight of the alemtuzumab program. Prior to joining Genzyme, Mike was Chief Medical Officer for neurology with Biogen Idec, where he was responsible for the development of late-stage neurology products.
We're also obviously very pleased to have 2 key opinion leaders with us on the call today. Both have tremendous experience in MS and have been involved in the CARE-MS program. Dr. Alasdair Coles from the University of Cambridge in the U.K. Dr. Coles received his degrees from the University of Oxford, London and Cambridge. He is currently a university lecturer in neuroimmunology at the University of Cambridge and an honorary Consultant Neurologist at Addenbrooke's and Peterborough hospitals. Dr. Coles has researched the effects of alemtuzumab in MS since 1994 with Professor Alastair Compston.
Dr. Jeffrey Cohen at the Cleveland Clinic. Dr. Cohen has worked with the Cleveland Clinic's Mellen Center for MS Treatment and Research since 1994. Dr. Cohen's has the last clinical practice devoted primarily to the care of patients with MS and related disorders. In addition, he is Director of the Experimental Therapeutics Program and has been involved in various capacities in a large number of clinical trials developing new therapies for MS.
And last but not least, we also have the pleasure to have Dr. David Meeker, CEO of Genzyme with us on the call. With that, let me now turn the call over to Bill.
William J. Sibold
Thank you, Sébastien. Welcome, everyone, and good afternoon or good morning depending where you are. It's a pleasure to be here and very appropriate that we're having this call from AAN, which is the largest neurology meeting in the world. There are over 12,000 attendees at this meeting. And many of them have a interest in, obviously, in broad neurological conditions but MS is something which a lot of the attendees are very interested in.
So it's an exciting time for us to be having -- presenting such [indiscernible].
I'm going to cover a few things. I'll talk about the MS market, and it's a large market and how we are going to compete in that market. And really with the right products and approach, we believe that we cannot only compete but be leaders in the market. And finally, finish up with the progress that has been made and what we are looking forward to.
So the global MS market is significant and expected to grow. Based on actual reported company sales in 2011, the market was $12.5 billion, and this is expected to grow into 2016 and become an almost $18 billion market. This is driven by a couple of things, specifically the still high unmet need that exists and also, new entrants that will be coming in to the market.
MS itself is a very prevalent and serious disease. There are approximately 2.1 million patients worldwide, and it tends to be a disease that is prevalent in young women. In fact, it's about a 2:1 ratio, female to male prevalence. And as I said, it's a very significant serious diseases. The life expectancy is 5 to 10 years lower for people with MS. And the disease itself has a very profound impact on one's life, certainly affecting their family, social and professional lives.
Next slide. The market is still dominated by the ABCRE or the injectable products, and I'll go through those. Avonex, Betaseron, Rebif and Extavia are interferon, and they represent over 50% of the market as a class. When you put Copaxone in, which is the final ABCRE, it has over 30% share of the market. So it is actually a quite concentrated market with 5 products. Now all of these are injectables, and they are injected either daily or up to once per week, and all offer moderate efficacy. So this segment represents an opportunity for new and emerging therapies and really an opportunity for some fragmentation of that market to begin.
There had been a couple of late entrants to the market, being TYSABRI and Gilenya. And both Tysabri, with the well-characterized risk of PML, and Gilenya with some cardiac issues that have emerged, have really forced a discussion in the MS community about benefit risk. And despite -- and I think this really shows again the unmet need within MS, that despite the benefit risk discussion that's taking place with these products, they are becoming, on their own, very substantial products, with TYSABRI at about $1.5 billion and Gilenya approaching $500 million for the year. So as new entrants begin to enter, we think that the market will fragment some, and we think that we will be a part of that with our portfolio to capture some of the significant opportunity that we discuss.
So on the next slide, why do we think we will become leaders and can become leaders in MS. Well, there's really a few things that are driving that. First of all, Genzyme has the experience in developing innovative treatments for chronic diseases and being a patient-centric company, which is extremely important in this specialty market in the rare diseases world, that patient focus has led to a leadership position, and this will be important and will translate very well into the MS market.
We have extensive global relationships with physicians, payers and patient advocacy groups, and that's really on 2 levels. First of all, we have the strong culture of building relationships with key stakeholders that we have done on the rare diseases side. And secondly, we're assembling an experienced MS team with significant relationships that will also allow us to do that. However, with those 2 things, we also need to have the right products to be successful in this market, and we believe we have an extremely promising MS clinical development, program, and I will cover that on the next slide.
So we believe that we have a highly differentiated portfolio, with Aubagio and Lemtrada, that will serve some of the unmet needs that still exist in this marketplace. Aubagio, a once daily oral pill that appears to have interferon-like efficacy is extremely well positioned against that large injectable group that I had discussed earlier. Lemtrada, with this really unprecedented efficacy, will compete for disease-active patients. And we consider that these products are very complementary to each other. They will serve distinct parts of the market and based upon what we'd seen so far, believe that they can be very successful. Coupled with our previously mentioned approach to the market and experience, we do believe that we are extremely well positioned to compete here.
Next slide. So a lot has happened, and we have a lot to look forward to in this coming year. I'll cover first of all, Lemtrada. We have now released and presented information from both of our Phase III programs, the CARE-MS I and CARE-MS II, which was presented yesterday and you'll hear more about today. And we are on track for FDA and EMA regulatory submissions in Q2.
With Aubagio, TEMSO data has been presented, and TENERE top line results have been released. We will be reporting that in more detail a little bit later this year. We have filed in -- both with the FDA and EMA for Aubagio. And in middle of the year, we're expecting TOWER headline results to be coming.
So really, in conclusion, at Genzyme, we are very excited about our franchise. A lot of progress has been made so far. We have a lot to look forward to. And our goal is very clear. We want to become leaders in multiple sclerosis.
So with that, I will turn the call over to Mike Panzara, who is our Therapeutic Area Head of MS at Genzyme. Mike?
Thanks, Bill. Good morning, good afternoon, everyone. What I will try to do today is to provide you with a bit of background on the MS landscape and provide some context on the therapeutic approaches in MS that should help in the interpretation of the results that you will hear about today.
As the MS landscape has evolved, so too have the treatment goals. It used to be that the conversation was simply about modest effects on relapses, sometimes an effect on disability and how many injections a patient was willing to tolerate to have some hope of slowing down the inevitable progression of the disease. Happy to say that we have moved from that position, and our focus has shifted towards addressing more meaningful objectives that focus on overall patient outcomes.
First on this slide, we need -- as illustrated on this slide, we need therapies that reduce symptoms. Patients do not think in terms of percentages, they want relief from symptoms that impact their daily lives. Unfortunately, there is very little to offer them currently. Next halting or reversing the damage and visibility of this disease is a critical goal and one that is clearly not addressed. It's no longer enough to just slow worsening, patients want to get better. The unmet need for therapies to do this is quite high.
In addition, there's a need for improved disease control for patients on treatment, as the vast majority of patients continue to experience disease activity despite treatment. And there is a need for options that increase the potential for freedom from disease activity and hold promise of maximizing patient outcome.
Finally, there is a need for improved and convenient dosing options. Although there's still a lot of work to be done in these areas, we believe that the portfolio that you'll hear about today promises to make strides towards achieving this goal.
Next slide. This slide shows the data for Aubagio. As was mentioned, Aubagio is a once daily oral therapy. Based on the results of the TEMSO study shown on the left, there was about a 30% reduction in the risk of annualized relapse rate on Aubagio treatment. This was complemented with a 30% reduction in disability progression that was statistically significant in the 14 milligrams dose.
On the right-hand side of the slide, you can see the effect of Aubagio versus Rebif, that was the tendinous [ph] part of the TENERE study. In this study where the outcome was based upon treatment failure, we also captured annualized relapse rate. And as you can see there, although the study was not powered to show statistical significance, the annualized relapse rates between the groups were quite similar.
Moving on to the next slide. This slide illustrates the Lemtrada results, the top line results, which are unprecedented and have a unique dosing regimen that you'll hear much more about later in the call. On the left, you can see the reduction in annualized relapse rate from the CARE-MS I study, again, versus active comparator.
And on the right, you can see the results -- the annualized relapse rate from the CARE-MS II study, with a 50% reduction in the annualized relapse rate, again, versus Rebif, an active comparator. You'll hear much more about these results, specifically the CARE-MS II study where we not only had substantial effects on slowing of accumulation of disability but quite exciting observation that a significant number of patients had sustained improvements on therapy.
Next slide. Finally, it's very easy to get lost in essentially what's is an alphabet soup of MS outcomes across clinical trials, and it's very easy to get confused as we try to sort out what was actually evaluated in clinical studies. This slide attempts to do this versus for sustained accumulation of disability, which is perhaps the most confusing aspect of these trials.
First, across the x axis on the bottom, you can see the way progression is typically measured in these studies. One can select 3 months sustained accumulation of disability or 6 months sustained accumulation of disability. In other words, this disability as measured by EDSS worsened by 1 point or more and whether that worsening sustained for either 3 or 6 months. In general, the 6 months sustained endpoint is a bit higher hurdle, more specific and more predictive of permanent accumulation of disability.
The y axis focuses on whether studies have been done versus a placebo, which is typical, or whether studies were done versus active comparator. Again, with those studies versus active comparator, this sets an even higher hurdle for efficacy in a pivotal study.
The bottom left corner of the grid indicates the minimum goals targeted when designing an MS trial, 3 months sustained accumulation of disability versus placebo. Finally, the placement of the products on the grid indicates what endpoints were assessed in the pivotal trials and whether the endpoint was achieved for the products indicated.
As one can see, Lemtrada stands alone, setting the 6-month sustained accumulation disability endpoint and all trials' the primary endpoint, which each study conducted over at least 2 years versus active comparator. When one adds to this observation that nearly 1/3 of patients with pre-existing disability experienced sustained improvements in their disabilities course, alemtuzumab stands alone in a unique position in this landscape.
And with that, I am going to pass the call over to Dr. Alasdair Coles who's going to take us through some of the interesting mechanisms of action that we have learned about Lemtrada. Dr. Coles?
Thank you very much, and it's good to speak to all of you. Before you hear the exciting clinical data from my colleague Jeff Cohen, we thought it would be interesting for you to hear just how it is that we think alemtuzumab works.
On your first slide, you'll see that alemtuzumab is a monoclonal antibody and that it is infused. But the key thing is to note how infrequently we infuse it. So the initial treatment is 5 daily infusions over 5 consecutive days, and then, patients receive no further treatment until month 12, when they have 3 consecutive days of infusions, and there is no further treatment.
Second thing to note on this slide is that the drug does not hang around for very long. It's in and out in a matter of a few days. So just how does it work? Well, on your next slide, you'll see that the targets of alemtuzumab is one component only of the immune system, that is the lymphocytes. And these are depleted rapidly, and then they reconstitute. Cells of the innate immune system are left entirely intact, which may explain why we see so few opportunistic infections even around the time of alemtuzumab infusion.
So what do we think is the actual therapeutic mechanism following alemtuzumab? Well, what show it's not depletion of lymphocytes. We don't characterize these as an immunosuppressive treatment, rather it is the effects on the immune repertoire as a lymphocyte reconstitutes. Two things happen. Firstly, the repopulated lymphocyte system becomes enriched for regulatory cells and for memory cells, suggesting that the lymphocyte environment is now tolerogenic and that it retains memory for past infections and indeed even vaccinations.
Secondly, and quite surprisingly, the lymphocytes that repopulate after alemtuzumab treatment, seem to secrete neurotrophins. That is to say, factors which, in the laboratory at least, promote oligodendrocyte and neuronal growth and survival. And it may just be this latter effect that contributes to the unprecedented improvement in disability that we see in our patients.
And all of these effects are durable. So in our cohort in Cambridge, we see this same immune consequences in rich regulatory cells and rich memory cells and neurotrophin production many years after alemtuzumab treatment. So we now characterize alemtuzumab as a potent immunomodulatory therapy.
So with that, I'll hand over to my colleague, Jeff Cohen, to talk you through some of the clinical data
So thank you, Alasdair. Good morning, good afternoon, everybody. I'm very pleased to speak to you today and to summarize the very exciting results from the Lemtrada Phase III program. So on this table, you'll see a summary of the 2 Phase III studies, which Alasdair and I presented yesterday at the American Academy of Neurology meeting. There are several important points I want to make from this table.
So first of all, this was a sizable Phase III program, enrolling over 1,400 patients. The second point that I want to make is that both Phase III studies were 2 years. So this is important because not only did it allow us to examine relapses, which is one very important aspect of multiple sclerosis, but also allowed us to definitively assess the benefit of Lemtrada on other very key aspects of multiple sclerosis: disability, as you heard Mike tell you earlier, not only MRI lesion activity but also brain atrophy. So in other words, by extending the studies for 2 years, we were able to look at 2 very important indications of preservation of brain tissue.
Third, the 2 studies enrolled somewhat different patient populations. So both enrolled patients with early active multiple sclerosis, the sort of patient that we would be concerned or at risk for future disability. But beyond that, there were differences in the patients enrolled. So the CARE-MS I study enrolled patients who were naive to treatment. In other words, they had not received prior multiple sclerosis therapy. In those patients, Lemtrada was tested as their first therapy. So this is one potential group in which this drug might be used.
The CARE-MS II study enrolled patients who had been previously treated with standard MS therapies, interferon or glatiramer acetate, Copaxone, but who had continued disease activity while on those therapies. That, unfortunately, is a very common circumstance of when we're treating multiple sclerosis. We need a therapy that we can utilize when those therapies are inadequately effective. So that's the second setting in which Lemtrada might be used.
Finally, both studies, as did the Phase II study, compared Lemtrada to Rebif, one of the currently approved standard therapies for multiple sclerosis. So there's a very important point I want to make about this overall program, which is that we set a very high hurdle when testing Lemtrada. And we did that, first of all, by comparing it against an active drug, a drug that itself is effective against relapses, disability and MRI.
And secondly, as you heard earlier, when we were testing its effect on disability, we required that change in disability had to be maintained for 6 months. The reason why that's important is because we now know that disability that last for 6 months is likely to be permanent.
So next slide. So this shows one of the key results from the CARE-MS I study, the study that involved treatment-naïve patients, showing a very robust prominent effect on relapses that, over the course of the 2-year study, were reduced by 55% in the patients treated with Lemtrada as compared to those treated with interferon. If you look on the left-hand side of the slide, you see that this benefit developed early. It was seen in the first year in the study, and it was also durable. It was maintained in the second year of the study.
Next slide, please. Another way of looking at relapses is to look at the time at which the patient experiences their first relapse. And as you see, the benefit on relapses occurred very early. These 2 curves separate -- have started separating already by 3 months. What we also see from this figure is that the proportion of patients who experienced no relapses was increased from 59% in the interferon group to 78% in the Lemtrada group. So that's very important because patients are not so much interested in a relative decrease in relapses. They’re interested in having no disease activity.
Next slide, please. So this graph shows the relapse results from the CARE-MS II study, showing, again, a very consistent, very prominent benefit on relapses. In this case, on the right-hand side of the slide, a 49% reduction in relapses over the 2 years of the study comparing the Lemtrada patients versus the interferon patients. And then, again, as you see, the benefit was seen early. It was present already in the first year of the study and was maintained in the second year of the study.
Next slide, please. So patients are interested in lessening their number of relapses, but what they're really concerned about is preventing them from becoming disabled. And so this figure shows a very important result from the CARE-MS II study. So this shows time to development of sustained accumulation of disability, as we've said now several times, setting a very high hurdle for that definition. And showing that the proportion of patients that develop disability was reduced from 20% in the interferon group to 12.7% in the Lemtrada group. So this is a very key result, showing lessening of disability as compared to a drug that itself lessens the risk of disability.
Next slide, please. So not only are patients interested in not becoming disabled, but they, in fact, ask us in the office, "When I am going to get better?" So this figure, again, shows what we think is a very important, very interesting result. So this shows the average of level of disability in the 2 patient groups in the CARE-MS II study over the course of the study, measured by the EDSS scale. So this is a very standard way of measuring disability by neurologists.
It's based on the neurologic exam. 0 is normal. 10 would be the most severe score. So an increased score represents worsening. And so what this shows is that the interferon patients on average got worse over the course of the study, Their EDSS increased on average by 0.2 steps. Whereas, on average, in fact, the Lemtrada patients improved over the course of the study by 0.17 points. And so by the end of the study, the difference between these 2 curves was statistically significant. It represents a net benefit of 0.41 EDSS steps, which would be noticeable on an exam.
Next slide, please. So in summary, for the efficacy results, there was a very consistent substantial benefit on relapses, one of the primary -- co-primary endpoints in both studies. It appeared early and was maintained over the course of this study. The CARE-MS II study also showed significant benefit on the other co-primary endpoint, sustained accumulation of disability. There was a trend on that same endpoint in the CARE-MS I study. However, it was not significant, and we think that's because a relatively low proportion -- an unexpectedly low proportion of patients in the interferon arm experienced disability progression, which made it much more difficult to show an advantage.
Importantly, patients treated with Lemtrada in the CARE-MS II study were more than 2x more likely to experience improvement in disability, not only decrease risk of worsening but increased likelihood of improvement. And the benefit -- the statistically significant benefits on both of those co-primary endpoints were supported by a wide range of other assessments. Although not shown here, a very important one was benefit on brain atrophy, which we think is a very strong indicator of preservation of brain tissue, our ultimate goal in treating multiple sclerosis.
So that's one -- so the next slide. So that's one side of the story. The other side of the story, of course, is what are the potential risks of treatment with Lemtrada. So the adverse events in the 2 Phase III studies are summarized in this table. First of all, overall Lemtrada was well tolerated. And the adverse event profile is very predictable. It's been very consistent over the course of the Phase II and the Phase III program.
I am going to go into some of these in more detail on other slides. But a couple of points to make from this table. First of all, infections were somewhat increased with Lemtrada. This would not be unexpected with a very potent immunomodulatory therapy. However, as you heard from Alasdair, for the most part, these were routine infections, and we think that although Lemtrada has very prominent immunomodulatory effects, key aspects of the immune system are preserved, allowing patients to fight infections.
Secondly, there were 3 deaths in the Phase III program, 2 of these were from motor vehicle accidents and the third death was from aspiration in a patient who had severe disabilities from a brainstem relapse having occurred 1 year previously. And then, finally, both therapies, in general, were well tolerated. But in fact, more patients treated with interferon in these studies discontinued treatment or discontinued from the study as a result of side effects.
Next slide, please. So one well recognized side effect of Lemtrada are side effects associated with infusion. This is due to the lysis of immune cells after administration of the drugs. It's been seen since the beginning of the testing of Lemtrada. The mechanisms for these are well understood. The infusion-associated reactions are generally mild in severity and can be controlled by premedication with antihistamines, acetaminophen and corticosteroids.
Secondly, infections were common in both groups. They were predominantly mild to moderate in severity. There were some serious infections. But as you heard, they were, for the most part, with routine infectious agents. There were no suggestion of unusual infections. There was no PML seen with Lemtrada.
And then, from the beginning of the testing of Lemtrada, it's been recognized that it can lead to a development of autoimmune phenomenon, most commonly thyroid disorders and among the thyroid disorders, most commonly Graves' disease of the thyroid. In some patients, that evolved into hypothyroidism or low thyroid function. With a comprehensive testing program and anticipation of this potential side effect, thyroid disorders can be very readily treated with either medications to treat the symptoms of hyperthyroidism or when needed, medications to decrease thyroid function and when thyroid function is low, thyroid hormones to replace it. And that's a very standard very straightforward medical management approach.
The other principal autoimmune disorder that's been seen is immune thrombocytopenia or immune attack on platelets, cells within the blood that are involved in blood clotting. So the main complication of that, that can at times occur, would be bleeding. Again, with routine blood testing, blood counts, this can be detected early, leading to the ability to readily treat with standard therapies, corticosteroids and/or immune -- IV immunoglobulin. In this program, most patients responded very readily to that straightforward approach. One patient had a relapse and underwent splenectomy as a second line therapy in the abstention.
So in summary, this Phase III program has supported experience with Lemtrada showing a very prominent, very robust efficacy on a wide range of very important aspects of the MS disease process. It does have some potential side effects, but with comprehensive monitoring these can be detected early and treated with, for the most part, conventional therapies.
So I'll now turn over the podium to Dr. Panzara. Thank you.
Thanks, Jeff. And just to summarize, I think that you can hear that we feel that we have a real transformative approach to treating this disease.
First of all, we have unprecedented, say, efficacy results, and I think that is both in terms of the program itself, setting high hurdles, all studies versus an active comparator, but also in terms of the results themselves, namely a reduction in EDSS scores as described, supported by more than twofold increase in sustained reductions in disability in people who have pre-existing disability.
This efficacy was apparent across multiple endpoints. We have a consistent manageable safety profile. Given the years of experience, we now feel we have a good understanding of that profile. And as such, the monitoring program proves successful as you heard a detection of these adverse events.
This leads to what we believe is a favorable benefit risk, all in the context of convenient dosing, and as such, we believe Lemtrada has great potential in treating this what can be devastating disease.
So with that, I'm going to hand it back to Sébastien for the Q&A. Sébastien?
Thanks a lot, Mike. So we're now ready to open the call for questions. [Operator Instructions] So operator, we're actually ready to take the first question.
[Operator Instructions] The first question is from Richard Parkes from Deutsche Bank.
Richard J. Parkes - Deutsche Bank AG, Research Division
It's Richard Parkes from Deutsche Bank. I'll just start off with a couple for Dr. Cohen, and then I'll drop back in the queue. First of all, I wondered if you could talk about the practicalities of the monitoring requirements during the clinical trials and what's likely to be required in the real world, particularly kind of how often patients have to present for blood tests, et cetera. And then, the second part, a component that is the rates of thyroid abnormalities and ITP. If I remember correctly, it seemed to be a little bit lower than in the Phase II study. I'm just wondering if there were any patients that received treatments, such as steroids or immunoglobulin, or have those interruptions for suspected abnormalities but didn't actually go on to develop thyroid disease or ITP and therefore count in that kind of incidence rate.
So in terms of your first question, of course, the specific monitoring program will need to be discussed with regulatory when this drug is submitted. But in the clinical trials, the monitoring program largely comprised monthly complete blood counts. So that's not -- particularly, onerous patients can go to a lab and have that done. A very important additional aspect was education of patients and the clinicians to the potential symptoms of thyroid disease, the potential symptoms of immune thrombocytopenia, so that if they developed those, the patients notify their physician early. In terms of the rate of thyroid disease and ITP, I would say that overall, my sense is that the rate went fairly consistent. One would expect some variability from study to study. The important point was that as we've learned to anticipate these side effects and have been testing for them preemptively, they are detected that at an early stage, which facilitates treatment with routine approaches and leading to a good response in most cases.
Alasdair Coles here. Just to follow that up, let me remind you the Phase II trial lasted 3 years, and the Phase III trials are ongoing for 2 years. We would anticipate a few more people getting thyroid disease beyond the end of the formal 2-year period on this Phase III trials, and I would anticipate personally that we see rates approaching 30% for all of these trials of autoimmune and thyroid disease in the alemtuzumab arms.
The next question is from Peter Verdult from Morgan Stanley.
Peter Verdult - Morgan Stanley, Research Division
Peter Verdult here from Morgan Stanley. Two questions. Just firstly for Dr. Coles and Cohen, I mean, given the developing competitive landscape, especially with respect to old therapies, I wonder if you could comment on if Lemtrada was approved and you have full access to the drug, what percent of your MS patients would you -- your current MS patients would you consider eligible for treatment with Lemtrada? And then, secondly, I mean, the feedback we've had from U.S. and European docs on Lemtrada I would just characterize as cautiously optimistic, and it's clear as well that market expectations are below the $3.5 billion Genzyme claimed to be the peak sales of this drug at the time of Sanofi's initial bid. So in terms of you being AAN and as not, could you maybe just comment on some of the biggest pushbacks you're getting from your peers with respect to Lemtrada and the care data beyond efficacy, say for your dosing schedule and maybe how you respond to them?
Peter, Alasdair Coles here. I know that financier so I can't answer your second question. So speaking personally, I think the person who I would want to treat with alemtuzumab is someone who wants and needs high efficacy. And the pushback, as you call it, from people here at the AAN, is that they are impressed, very impressed with the efficacy of alemtuzumab. But the second condition that I would ask for, for patients who I wanted to treat is someone who understood the issues around the safety profile and was prepared to commit, not for weeks or months, but for several years of monitoring and attendance at my clinic. And I just can't put a percentage on that. I know you like it, but I'm not going to do it.
Peter Verdult - Morgan Stanley, Research Division
How about percentage range?
So I would -- this is Dr. Cohen. I would just say a couple of other remarks, which is one is that, and I alluded to this in my remarks, is that a very common scenario that I encounter in the clinic, in fact something I encounter everyday, is a patient who has committed to disease therapy with one of the injectables but who is continuing to have relapses or active MRI lesions. In fact, the majority of patients have ongoing disease activity on those drugs. So that, as shown in CARE-MS II, is the population that is benefited very well by this drug. So I can't give you a precise percentage, but I can tell you that, that's a very common scenario. In addition, there are some patients who very early on in their disease even before they started therapy we're already worried about. We know that they're destined most likely to do poorly because they've had frequent relapses that are severe, that they recovered from incompletely or their MRI looks scary. And so those -- that's an additional population that we might consider using this drug in. Finally, I think one thing that you have to take into account is that, in general, neurologists are very cautious. And when they hear about potential side effects, they get nervous about that. But then, over time, they become more comfortable with them. And we're -- in the field, we're starting now to think much more about risk-benefit balance rather than just focusing on one aspect or the other.
Next question is from Mark Dainty from Citi.
Mark Dainty - Citigroup Inc, Research Division
Two quick questions. Just for the disability score change, I'm looking at 0.24 from a basis sort of around 2.7. Perhaps the clinicians could just put some context in that sort of how meaningful that is, because it seems to me the EDSS score goes up in 0.5. And so perhaps you could just give it some thoughts as to how much that really means to a patient? And then, a quick clarification. Did you see any Goodpasture's disease in any of the Phase III studies?
So in terms of your first question, so the average change in EDSS was small. So one -- but one can interpret that as whether it's clinically meaningful or not because that's the average overall of the patients. Some patients had no change. Other patients had a much more dramatic change. Much more -- an analysis that's much more indicative of clinically meaningful change in disability was so-called time-to-sustain reduction of disability, which required patients to improve by 1 point, and that had to be maintained for 6 months in patients that already had some measurable disability. I didn't show that analysis this morning, but I did show it yesterday, and that also showed a very convincing advantage of Lemtrada over Rebif in terms of increasing the proportion of patients that improved. That amount of change on EDSS would be noticeable to a patient and to their physician and would be considered clinically meaningful. In terms of your other question, there were no cases of Goodpasture's in, at least, the CARE-MS II study and none in CARE-MS I either.
The next question is from some from Vincent Meunier from Exane BNP Paribas.
Vincent Meunier - Exane BNP Paribas, Research Division
I have 2 questions. The first one is on the EDSS. There is no significant difference on disability EDSS-based endpoints in CARE-MS I, and you say this is due to unexpected lower rates of sustained disability in the comparator group. So is there any reason to explain this? Is there any bias in the study to explain that? And what's your view on -- what is the conclusion in terms of clinics? The second question is the pricing of the drug. Assuming it's used in leukemia at a higher dose, if we just take the same dose and we consider the yearly treatments for MS, the pricing should be very low, so we can assume there will be a repricing of the product. And can you please give us any information on that?
Alasdair Coles here. Just to answer your first question, you're absolutely correct. So 8% of alemtuzumab patients hit the disability endpoint in CARE-MS I and 11% of the Rebif patients hit that endpoint. And that was not a statistically different. So 2 comments on that. Firstly, that the trial was designed and the numbers chosen on the expectation that 20% of Rebif patients would hit the disability endpoint. So it turns out that we selected a trial population who accumulated unexpectedly low rates of disability, and I think that's because we deliberately selected such early patients. But the consequence of that, because they were not hitting the disability endpoints on Rebif as frequently as we anticipated was that the trial was underpowered in the end to pick up a treatment difference with this particular endpoint. But can I remind you for the MSFC, which is another measure of permanent neurological impairment, there was a clear treatment effect showing superiority of alemtuzumab over Rebif. The pricing question, Bill.
William J. Sibold
This is Bill. I'll take the pricing question. So first of all, our primary goal is to ensure appropriate use of the drug, and we're developing plans on how to bring Lemtrada forward for MS, as well as plans to how Campath -- mass Campath will be made available in the future. And our commitment is to ensure that patients who need Campath will receive it. As far as pricing, the only comment that I'll make is that you've heard the very dramatic results that have been presented here. And we believe fundamentally that Lemtrada pricing should be based upon the benefit that it's bringing to patients.
Vincent Meunier - Exane BNP Paribas, Research Division
Okay. So maybe if [indiscernible] repricing and then, for the use in leukemia for Campath, it will be a conventional delivery?
William J. Sibold
Now, look I think at this point, as I said, we're in the planning process and we will make available information as we move forward.
The next question is from Richard Vosser from JPMorgan.
Richard Vosser - JP Morgan Chase & Co, Research Division
It's Richard Vosser from JPMorgan. First question just on the retention of patients. I think you mentioned it was a very high. I think you presented about 95%. I wondered if you could give us some ideas why you think it was so high and perhaps contrast that with BG-12 where the retention of patients was, I think, in the 70% range presented yesterday. And then the second question just on the issue of retreatment. I think you, at the start, mentioned that clearly only 2 potential doses, one at the beginning and one at month 12. But I just wanted your thoughts on when and if you would think of retreating patients. I think it was mentioned yesterday at the AAN that you had retreated some patients from the Phase II, and just what your experience was there would be very useful.
So, I'll take -- this is Jeff Cohen. I'll take the first question. So retention in a study is a very important parameter because if a sizable number of patients either discontinued treatment or discontinued the study, it may make it difficult to interpret the results. So we were very pleased that retention in the Phase III studies was quite good. There are, in general, 2 reasons why patients drop out of a study: one is side effects. And as we said, even though are some potential side effects of Lemtrada, in general, it's very well tolerated. Most patients have very few side effects. So that, in part, accounts for why retention particularly in that arm was very good. As you noted, retention in the interferon arm was not as good. And there are very common side effects with interferon. Second -- the second reason why patients discontinue with study is because they perceive that they're having continued disease activity or worsening. And so again, that's speaks to the very prominent efficacy of this drug that patients felt they were doing well, so they continued in the study. I'll let Alasdair comment on retreatment. He's the world's expert in that.
So just some pointers here, really. Firstly, you should know that all of the patients in this Phase III program and all the previous patients in the Phase II trial are offered the opportunity to take part in an extension study that we should be able to answer your question more formally in a few years time. But you will see from our publication in neurology earlier this year that at 5 years -- following up the Phase II trial, at 5 years without any further dosing with alemtuzumab, we still see clear efficacy, which remains superior to Rebif. So 2 cycles offers long-lasting efficacy. And my personal cohort in Cambridge where we followed 87 patients like this since 1999, we have retreated either when a patient has had a relapse or when they have a new lesion on an MRI scan. And in that entire cohort, since then to now, which we've retreated 2 people 5 times and no more than that. Quite a number of our patients have still just had 2 cycles of alemtuzumab. So my personal prediction going forward is that this is not a drug people will be having on an annual basis by any means. So they'll be having far less frequently than that.
The next question is from Philippe Lanone from Natixis.
Philippe Lanone - Natixis Bleichroeder LLC, Research Division
Yes, we were –- we’re interested about your reduction of disability figures that you gave into CARE-MS II especially. I wonder how that could be included in the labeling because TYSABRI and Gilenya do not have that indication. Could we dream of having that as an indication? Or it would require some more studies? And also, what about the 3 deaths? That they were in the studies at the time they fell off their bicycle, but people in the placebo group have bicycles too. So could it raise an eyebrow at the FDA? Or can you rule that fully out? And lastly, maybe the direct competitor for Lemtrada could be more from ocrelizumab from Roche because this will be also once a year injectable, and what we have seen from the Phase II is that the efficacy could be a bit superior to Lemtrada. So have you looked in these results and can you comment on that?
So this Mike Panzara. I'm going to take the first question. Regarding the reduction of disability and labeling, really can't speculate on what our label is going to look like. All I can say is that all of these data will be included in the packages that we sent to regulators around the world and will be highlighted in the submission. Second of all, I will just take the ocrelizumab question, and then I'm going to pass over to Jeff and Alasdair about the accidents. Regarding ocrelizumab, again, that is very early days of that study. I think that to make a comparison between 3 Phase III studies and a Phase II, I think is premature.
So this is Jeff. In terms of the deaths, I would be shocked if those deaths were of concern to regulators. They did not appear to be related to treatment.
Alasdair Coles. Just to point out it would be -- I think we can only address this issue when ocrelizumab is compared against an active comparator. It's a big mistake just to translate one figure from one trial across to another. You have to take note of what the comparator is, and a placebo is not the same as Rebif.
Philippe Lanone - Natixis Bleichroeder LLC, Research Division
Yes, but there was -- in the study there was an interferon calibrator so we can infer some information.
Sure, at very small figures. And not sufficient to stack up against the numbers and the duration of treatment that we have here.
Let me just make one -- just a point about that design. So including an active comparator a so-called tracker arm, it's open label with the small sample size. It's not the same thing as designing a trial from the beginning against an active comparator as was done in this Phase III program. And just to reiterate, you have to be very careful comparing relative benefits against the placebo against relative benefits against an active effective drug.
The next question is from Michael Leuchten from Barclays.
Michael Leuchten - Barclays Capital, Research Division
Two questions, please. One, going back to the EDSS improvement, is there any data that would show us what percent of patients were EDSS of maybe 4 or worse that actually went to 3 or better? Secondly, on the autoimmune side effect issue, is there any diagnostic approach that you're taking to screen for the patients at the highest risk of maybe developing it? And maybe a tricky third, in terms of the dose, what were your discussions with the regulators on picking the dose? And what do they want you to show with the 12 milligrams?
Okay, this is Mike Panzara again. Regarding the various milestones and thresholds of EDSS scores, there is a wealth of data included across this program, and all of these information will come at major scientific meetings, publications, et cetera. So that will all come in the future. Regarding the autoimmune risk, very active area of interest, obviously. This is something that we want to study, something we're working with Dr. Coles and others. Internally, a lot of efforts to help us assess risk, and that's -- again, one of these things is very active area of interest. And finally, regarding dose. As was described yesterday, there were 2 doses in the CARE-MS II study, 12 milligrams and then, exploratory 24-milligram dose. I'm not going to comment on any interaction certainly with regulators about anything on this. But I can say that when you look, the primary efficacy analysis in all of our studies has been 12 milligrams versus Rebif.
The final question is from Himam Bobber [ph] from Cowen and Co.
Actually a couple of my questions are already asked. But I think one other question that I had is if you could talk a little bit about the reversibility of the adverse events. So for example, ITP at an any case is worst and not reversible, if you could talk a little about that, that would be great.
So in terms of the ITP, at least in the Care-MS II study, which I presented yesterday, so there were over all 7 cases. One important point is that 4 of them were picked up on routine blood testing even before the patients had symptoms. The other 3 cases were detected when the patient reported symptoms. Secondly, of those 7, one patient improved spontaneously without treatment. The other 6 improved with standard therapies, corticosteroids and IVIG. One of those patients then went on to have a relapse somewhat later and had underwent of splenectomy, which is sometimes used as the second line of treatment. So overall, the patients responded very readily and are in prolonged remissions.
Alasdair Coles here. So we've published this in the Journal of Blood,, and we have more patients from our Cambridge experience. And our hematology colleagues say that they regard the ITP that we induced, as it were, as being a very treatable. We tend to get them earlier than wild type ITP off the streets, and they respond normally to the standard regimens, and we've seen no lasting query [ph].
Well, at this point, we would actually like to first thank Dr. Coles and Dr. Cohen for being with us today in this very interesting conference call. Just before closing the call, we would like to remind participants that our next conference call is on Friday for the Q1 2012 results announcement. This will be at 3:00 p.m. Paris time. And at this point, I would simply like to, on behalf of Sanofi and Genzyme's management, thank you for your participation, and wish you all a good day. Bye now.
Ladies and gentlemen, this now conclude our conference call. Thank you, all, very much for attending.
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