Roche Management Host EULAR 2012 Investor Science Call (Transcript)

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Roche Hldg Ltd Spons (OTCQX:RHHBY) EULAR 2012 Investor Science Call June 8, 2012 11:30 AM ET


Karl Mahler - Head of Investor Relations

Karsten Jung

Paul Emery


Luisa Hector - Crédit Suisse AG, Research Division

Michael Leuchten - Barclays Capital, Research Division


Ladies and gentlemen, good morning or good afternoon. Welcome to the EULAR Roche Investor Call. I'm Goran, the conference call operator. [Operator Instructions] The conference is being recorded. [Operator Instructions] At this time, it's my pleasure to hand over to Mr. Karl Mahler. Please go ahead, sir.

Karl Mahler

Yes, thanks a lot. So good evening to all of you in Europe, and good morning or afternoon to those attending our science conference call from San Francisco and the U.S. or in other parts of the world.

I trust that you had the opportunity to download the presentation from our website. This science teleconference continues the investor science events at medical meetings that we have been organizing for the analyst and investor community in order to present key results in our late-stage pipeline in 2012. On the overview, Slide 4, you can see that this year was already quite eventful in terms of Phase III late-stage clinical use flow. Not even 1 week ago, we presented important medical data at ASCO in more than 30 oral presentations. Among them, for the first time, key data such as the pivotal Phase III data for the T-DM1 EMILIA study in patients with HER2 positive metastatic breast cancer who had previously received treatment with Herceptin and chemotherapy. The data showed an overwhelming improvement in the time these heavily pre-treated patients lived without the disease getting worse. There was also a strong trend for overall survival improvement, as well as -- however, the median was not reached yet and we have to wait for the next interim's analysis. But very strong data.

We also presented results from the so-called Avastin treatment for multiple line study that showed both improvement in progression free survival as overall survival. And another Avastin highlight was the AURELIA study. The first Phase III study of Avastin plus chemotherapy in people with platinum-resistant recurring ovarian cancer that was presented and also demonstrated an impressive improvement in progression free survival.

Today's science events from the Annual European Congress of Rheumatology, the so-called EULAR Congress in Berlin, is to share with you some very exciting new data on Actemra, studied head-to-head for the first time against another biologic, Humira. The so-called ADACTA study showed that rheumatoid arthritis patients who received all Actemra, a single agent therapy, experienced a significant greater improvement in disease activity and that the adverse event profile in the 2 treatment groups were comparable and the safety profile of Actemra in ADACTA was consistent with previous Actemra trials.

The results of this study were presented today during the late break-in session and we expect that this should help and fuel Actemra's growth in Europe as well as globally. What I've heard is that today was really all about Actemra and about the ADACTA trial.

On Slide 5, you can see that we have a broad portfolio across all development phases in inflammation autoimmune diseases with now 10 new multi entities and 7 line extensions. Beside several Actemra studies, we are broadening our portfolio to also focus on such autoimmune diseases as asthma and lupus. I want to specifically mention lebrikizumab, which just started Phase III in patients with a severe asthma and rontalizumab, which is currently in Phase II in patients with lupus, and the state of the report in the second half of this year to our site.

Turning to today's agenda on Slide #6. We will start off with a overview to the Actemra franchise done by Karsten Jung. Karsten is our Global Product Safety Head for the Immunology & Ophthalmology and the Global Strategy Head for our franchise in Immunology & Ophthalmology. This will be followed by Professor Paul Emery. Professor Emery is Director of -- in Leeds Institute of Molecular Medicines and he will first give us an overview about rheumatoid arthritis monotherapy in a real-life setting, and he will also talk about the ADACTA data which have been presented today.

This will be followed by a Q&A session, and we expect the call to last about 1 hour.

Allow me, at this point, to thank Sabine Borngräber from our team -- from our IR team, for have really great work for putting all the slides together, as well as organizing this call here.

With this one, I would like to hand over to Karsten. Karsten, please?

Karsten Jung

Thank you, Karl. Welcome to this call on Actemra, and let me start on Slide 8 to frame what we are looking for in today and what I'm going to cover in the introduction. For today's call, we're going to cover 3 focus areas for ACTEMRA's life cycle. We're going to talk a bit about Actemra in the core indication in rheumatoid arthritis, then moving on to the second packet from the top -- from the bottom to the question, how is Actemra different in RA? And last but not least, covering our plans and ideas about expanding Actemra beyond rheumatoid arthritis.

If you move to Slide #9, you can see how Actemra is currently doing in -- with the existing core indications. On the left-hand side, you see the sales reports. We have reported in the first quarter, CHF 184 million and the growth of about 46% versus last year same quarter. And this is driven by the known indications we have and they are mostly labeled across all countries, OPTION, TOWARD, RADIATE, AMBITION and LITHE. There are some trials and some data still missing from our core indications, but we are getting closer to fill those gaps. And I've mentioned 3 on this slide. On the right-hand side on the right-hand -- left -- right-hand side, on the bottom, you see that we have submitted for the FDA our DMARD IR filing end of the year. We have submitted patient data of 65,000 patient years equivalent to address FDA's questions, and we are expecting FDA's feedback by the second half of the year.

Another important element for Actemra's life cycle is the route of administration. Currently, Actemra is available as an IV formulation, but we are developing the subcut formulation and there are 2 critical clinical trials involved: one, SUMMACTA, Actemra given every week, which just reported positively a couple of weeks ago; and the second trial, called BREVACTA, studying Actemra in every other week dosing regimen, which we expect the data in the third quarter, allowing us to file by the end of the year for this label.

And last but not least, we are also looking for data in early RA, the study called FUNCTION, which will look into patients very early in their disease. We expect the data to read out also in the third quarter of this year.

So all in all, this is a very robust efficacy package for Actemra that will help us to forward Actemra in the RA space.

Efficacy is one element, which is important, safety is the other. If you move to Slide #3 -- Slide #10, you can see a table that supports the fact that we have a very stable safety profile over time. The data you see here are the latest data cap, which has been drawn from the Actemra clinical trials. Over 4,000 patients observed in the medium duration about 3.5 years, netting out to more than 12,000 patient-years.

And if you look in the table, you can see for the first, second, third and fourth year that through all the events of interest, serious events, serious infections, myocardial infarctions and stroke, the rate of those events stays stable over time, supporting the message that Actemra has a safety -- stable safety profile over time, thus supporting that we have a good safety profile and a good efficacy profile.

With those 2 elements, safety and efficacy, we feel confident that Actemra now has a very good, robust RA foundation, which can -- which allows us to be competitive in the market.

What makes Actemra different? Moving on to Slide #11. Let me step back one step and speak about monotherapy. You see here a very easy sketch about a patient flow in RA. From the top to the bottom, patient gets diagnosed at some point, treated by rheumatologist and most of the patients get started on a DMARD treatment in combination or a combination with a non-DMARD therapy. At some point, this treatment might not be sufficient and longer-term patients become eligible for a biologic therapy, and that's the area we are talking about, if you are talking about monotherapy, which is in this box on the bottom half of the screen. So patients can receive a biologic, either as a combination therapy, so in combination with a DMARD, or they receive a biologic therapy as a monotherapy, so in treatment without a DMARD. A patient can arrive from different reasons on a biologic monotherapy treatment. He can either be from the beginning, intolerant or doesn't take -- doesn't want to take his DMARD for the submission to its [indiscernible] is right at the beginning of a biologic treatment that he should start biologic monotherapy. He could also, over time, together with his physician, decide to discontinue his DMARD treatment due to side effects or due to other reasons. And by that, coming to a biologic monotherapy.

So there is an existing treatment paradigm out there that patients are treated on biologic therapy with a single-agent biologic only. You might ask the question, how relevant is this biologic monotherapy? If you move to Slide #12, you can see on the upper half, a sketch that gives you an impression of what we have seen from different sources. The size of the biologic monotherapy treatment is about 30%, and Emery will share more data and insight with you in his part of the presentation, but it's important to recognize that about 1 in 3 patients, currently, is treated with a single-agent biologic only. On the lower half of the slide, you see that only about half of the biologic treatments are actually indicated or have indication for biologic monotherapy. The others don't, and Orencia, on the right-hand side, you see has indications only in the U.S.

So if you see this picture, you will -- might ask yourself, well, what do physicians do when they treat monotherapy? How do they perceive that? On Slide 13, you can see a perception research that we have done late last year, asking physicians to rank and rate each biologic on the appropriateness of the treatment in monotherapy. And if you look on the graph on the right-hand side, you see that Enbrel and Humira, both the market leader in monotherapy, are recognized as being well appropriate, but Actemra has substantially grown in the perception of physicians to be highly appropriate as a treatment in monotherapy. And just to remind you, this was before the ADACTA data has been published. So this is the already existing perception for Actemra in the monotherapy treatment.

What was there before ADACTA was there? If you move to Slide #14, we actually have a growing body of evidence for Actemra in the monotherapy treatment. There are, right now, 4 big clinical trials supporting different data, supporting different treatment options for Actemra in monotherapy, from top to bottom, starting with AMBITION. The study comparing Tocilizumab Actemra versus methotrexate and showing superiority in all end points, a very important study which also led to the label. Going one line down, ACT-RAY, comparing Actemra in monotherapy with Actemra in combination therapy and asking the question, if adding methotrexate would increase efficacy and the data shows that there is a comparable efficacy between the 2 arms.

Third line, ACT-SURE, observing patients in TNF-IR setting, again, comparing Tocilizumab in combination therapy with monotherapy and showing that there is a comparable effectiveness.

And last but not least, the ADACTA trial, which we are focusing in, in a second, showing superiority of Actemra in a head-to-head trial versus adalimumab.

So this is a very robust data set that speaks to the fact Actemra, in fact, can be differentiated and have differentiated efficacy profile versus other biologic agents.

So if you look now outside of the RA treatment, we are currently looking for different indications. On Slide #15, that speak to the studies we currently are investigating and looking for different treatment where we think that patients with rare diseases can profit from a treatment with Actemra due to the different mode of action.

So the Tender study in patients with SJIA have read out, and we received label last year in the EU and U.S. for children with this rare disease, and there was no treatment before. So Actemra definitely has reached the endpoint and is now available to treat those children and help those children. CHERISH also is a trial in juvenile population, addressing pJIA, and we just have the data read out early this year and we have plan to file this year. And last but not least, we just started a Phase II trial in systemic sclerosis, where we are looking for a clinical signal, again, for a disease or rare disease where there currently is no treatment or limited treatment available.

Furthermore, we are looking for other indications and have other evaluations underway to understand more the clinical signals to inform us for upcoming clinical development plans.

I've talked about a lot about monotherapy and I've talked about a lot about how Actemra is different as monotherapy, and I'm happy to introduce now Professor Emery, who will speak to you about monotherapy and the ADACTA trial. Professor Emery.

Paul Emery

Karsten, thank you very much. So it's my pleasure to really give you a little bit of background about where monotherapy lies in the interim [ph] of rheumatoid arthritis and then talk about the ADACTA study.

The first thing to say is that for anti-TNF, there's a huge amount of evidence that this works better, these agents work better with methotrexate as both clinically and more particularly, radiologically. And so monotherapy, for the other agents, is very much seen as a second-best option.

If you ask physicians if their patients took methotrexate with TNF inhibitors, they would say nearly all of them do, but the data tell you something else. Essentially, as Karsten has alluded to, people -- our patients fail to take methotrexate for a variety of reasons. They may have a contraindication and that may be something like interstitial lung disease or liver function tests or they may actually want to get pregnant, which, in this case, methotrexate has to be stopped.

Other patients start on the combination of methotrexate and a biologic, but then stop it, and they stop it either because of the toxicity or the relative toxicity of the drug, or because they are doing very well and they don't see the need to take it. And a particular problem with methotrexate is that the side effects are immediate and the benefits are long-lasting. So if you miss a dose, you don't actually notice it, because it takes about 6 doses before a patient flares. So patients, in a way, are reinforced in not taking it by the absence of any flare.

But perhaps the biggest group of patients that aren't taking it are those who tell their doctor they are taking it and actually fail to be compliant. And these are some data here. If we concentrate on Slide 17, on the right-hand side, you can see in gray that nearly 60% of patients didn't have their methotrexate prescription filled, which means that they weren't taking the prescribed dose. And how -- just how badly they were taking, we don't know. And the blatant scale is that's in the first -- just after the first 6 months of treatment, and this is sustained even in patients who failed therapy over 2 years.

So not only are 1/3 of patients not taking it officially, but also the 2/3 that are, more than half of them are taking it in a fashion which is not appropriate or is not as prescribed.

So if we could go to the Slide 18, please. This is a slide which most physicians will tell you was not true because they would say most of their patients were on it, but sad to say, it's something different. You can see throughout the world, around 1/3 of patients on registries are not taking methotrexate officially. Let us say the -- of the 16% or 6% that are taking it officially, many are not taking it correctly. So monotherapy is a very big issue. It's a sizable -- perhaps even as much as half of the population are not taking methotrexate as described and we don't really know the consequences of it. What we do know is for TNF inhibitors, it results in a considerably less efficacy.

Next slide, please, which is Slide 19. This gives you some of the reasons why methotrexate may not be taken. You can see that there's an adverse events of 73% -- any adverse event, 73% and officially, patients stopped at about 10%. It's probably a little higher than that in truth. And the things they stopped for is gastrointestinal, liver function, epilepsy [ph], for females alopecia is a very big issue. And I think it's underestimate because it's so hard to categorize it with the CNS effect. Many patients find they feel very under the weather for 24 or 48 hours afterwards. I have many patients who take methotrexate over the weekend so they don't miss work because they don't feel well enough for the 24 hours afterwards to go to work.

So there is an issue. And there hasn't as yet been an adequate substitute for methotrexate, which actually have the same efficacy or better toxicity profile.

Next slide, please, 19. So it's on that background that we have the ADACTA study, which is a head-to-head study, a double-blind stress study, which actually compares adalimumab, which is commonly used as a monotherapy, at its standard dose with tocilizumab, at its standard dose. And we have the next slide, which show this plan, which is just -- sorry, just to get back to the last slide which shows the authors and others involved in this study, which was presented today as a late-breaking [ph] abstract.

And we're looking at the 24-week data in this particular presentation. So you see that 326 patients surrounded by its one-to-one, double-blind, randomized control, so placebo is subcutaneous, with doses about 8 milligrams to kilogram IV and there was placebo IV with adalimumab 40 milligrams subcutaneously.

If patients were not improving and they didn't have a 20% improvement, for ethical reasons, they were allowed to escape week 16, which we'll discuss exactly what that involves and it actually went over to adalimumab placebo injections. And the actual endpoint is at week 24, with an 8-week safety follow-up.

The primary endpoint was the delta for DAS, Disease Activity Score, 28, which is the standard measure or composite measure of activity for rheumatoid arthritis.

Slide 23. So this is -- these are the patients that got into the study. They had to have RA of greater than 6 months. The key point is they previously had methotrexate and rising tolerance or it was felt the continued treatment was considered inappropriate. So these were on methotrexate, had it stopped, went into the study.

They've had no prior treatment for biologic. They were biologic naive. So this was their first biologic, so you would expect them to respond quite well to a biologic agent. And all DMARDs were withdrawn at least 2 weeks prior to baseline and they actually had to have active disease, a standard measure of high disease activity, which is a DAS 28 score greater than 5.1.

Slide 24, please. And as mentioned, the primary endpoint is the delta DAS 28 from baselines week 24. A number of key standard exploratory endpoints we use, DAS remission, which is a score less than 2.6 and DAS low disease activity, less than 3.2. The ACR, American College of Rheumatology, improvement criteria of ACR 20% improvement, 50%, 70%, which are composite measures of improvement. We have to actually have certain requirements of 20% improvement or 50% so on the ACR EULAR Boolean remission. And of course, safety was studied with adverse events and laboratory parameters. And a post-hoc analysis was undertaken with the Clinical Disease Activity Index, this is an alternate index, which actually does not include the acute phase response. And the reason for that is that interleukin-6, which is blocked by Tocilizumab and anti-interleukin-6 receptor antibody can have a direct effect on the liver in the reduction of acute phase responses, and this is to ensure that these are genuine effect on the disease activity itself.

So next slide. We have here the -- a schema of the patient disposition. 326 patients answered, equal randomization. And if you looked in the green slide, you'll see how many have completed, 77% for adalimumab, 81% for tocilizumab. That in itself is what we consider a very important endpoint.

There were fewer withdrawals on the tocilizumab, 15% versus 17%, and a fewer number went to the escape, 4% versus 6%. So bottom line here is a high completion rate for tocilizumab and adalimumab at around 80%.

So we have the demographic and baseline characteristics. Here, they are nothing too surprising. The average age was -- for rheumatoid have the normal 4:1 ratio of female to male which you see in studies. The duration, which is important in determining responses, was around 6 years. In fact, notably, tocilizumab have 1 year longer disease duration, which would act against the outcome -- the longer duration, less well you tend to respond and they'd had the adalimumab [ph]. The DAS 28 you see minimum was 5.1, and it's quite common to have a DAS 28, therefore, much higher and 6.8 is -- got comparable sort of studies. Tender joint counts of 16, around; swollen joints around 12. CDAI, start was 40, around 40. ESR was considerably elevated, between 45 and 50, as well as CRP. And the HAQ which is a measure of functioning, you see at 1.7 and 1.6, which is very characteristic for these studies.

Slide 27, please. This is the primary endpoint and it is dramatic. If we look at the difference, it's minus 1.5, and you can see for yourself the P value with 30 in front of the 1. So a highly significant primary endpoint was met.

Slide 27 -- 28. And this is showing the primary endpoint over time. And you can see that by week 8, there's a considerable separation between the 2 arms, tocilizumab, being the bottom arm, is reducing the DAS to a greater degree than adalimumab. And you might suspect that, that difference is going to get an even better judging by the curves and the lines that curves.

Next slide, please. This actually looks at the secondary endpoints of patients in DAS 28 remission or low disease activity. And if you look at the remissions, first of all, you can see DAS remission occurs in almost 4x as many patients, which really is a remarkable separation. And low disease activity is more than doubled in the group, 50% of patients on this monotherapy going into low disease activity or better within the first 6 months.

Slide 30, please. ACR improvement criteria. Improved or significantly better in the tocilizumab group, with 65% getting a response of ACR 20, 47% at ACR 50 and 32% ACR 70. These are very good clinical response rates, compatible with -- as you might expect, with the improvements in DAS.

Slide 31, please. This is a post-hoc analysis of CDAI, which is the Disease Activity Index, which essentially has removed the impact of the acute phase response. And the remission, there's a doubling of the remission rate, which is significant, 9.3% versus 17%. And when you look at the combined remission and low disease activity, it's 30% versus 19% in that score [ph]. So it isn't just the acute phase response that's driving the differences between these 2 drugs.

Next, please. Now on Slide 32, now this is looking at the swollen joint count, confirming what we had seen in the previous slide that it isn't just the acute phase, but the patients and the joints themselves are improving and the separation, which again, is going out in its max [ph] by the end of the 6 months. Slide 33, please.

So we go now to the safety and the adverse events. This is very much in line with what we'd expect of biologics. Those patients with at least one adverse event is around 80%, but serious adverse events occurred in around 10%. One -- of the patients with infection, 42% and 48%. But once we look at of course all the serious adverse events of infections and they are just equal at 5% each.

Now there were 2 deaths, and these are both in the tocilizumab arm, so I'm going to help you through these 2 deaths.

Slide 34. One appeared to be a drug overdose with marijuana, benzodiazepines and methadone in the urine. The patient was not known to be a drug user until this time point so would've been excluded from the study had it been known. And that was drug unrelated. The other was a sudden death of a 56-year-old male on study day 93 and was labeled possibly related to study drug. This patient had considerable comorbidities: there's interstitial lung disease, peripheral vascular disease and actually had a stent and hypertension, was overweight with a BMI of 28 and had been a 30-year smoker.

It's unknown what this patient died of and there was no autopsy, so we won't know any further about that. But clearly have major comorbidity.

Next slide. The effect of blocking interleukin-6 on the liver synthesis is now extremely well known. It's been discussed at great length. Essentially, what you see is the return, in a way, of the lipids to what they would've been if you didn't have information, and so you'll have a rise in the LDL-cholesterol ratio. This is more dramatic with IL-6, which switches off the LP [ph] and inflammation more dramatically. And this is entirely in line, you see it goes up initially, then it stabilizes and there is a -- and it's, well-- it is a well-known difference between TNF and IL-6 blockades in this respect.

Next. Slide 36 is looking at liver function test abnormalities. We don't really consider taking much more than 2.5 as being particularly significant. So if you're looking, you're really looking at the 2.5 to 5 upper limit normal, and you see that occurs in about 5% in the tocilizumab versus 2% or 1.9% in the adalimumab, again, completely is a matter of what was known. And of course, a part of this is the withdrawal effect of IL-6 on that is pacified. At the very severe end, there's a small number in both groups for which we're seeing no difference, obviously.

Next. So in conclusion, the efficacy of tocilizumab monotherapy was superior to adalimumab monotherapy in reducing signs and symptoms of RA. In terms of safety, the adverse event profile was comparable between the 2 arms. The safety observed in the tocilizumab arm of the study is consistent with the known safety profile of tocilizumab. And there are no new or unexpected adverse events observed.

So with that, I'll show you the investigators on Slide 38. I'm very happy to help with any questions you might want to ask. Thank you.

Karsten Jung

Thank you, Professor Emery. And [indiscernible] Slide 41. Let me just summarize what we just heard and then we can move into the Q&A session. So we've seen that Actemra has now built a solid foundation of clinical data in RA and we are closing kind of the last biggest gaps. And with the ADACTA trial, Actemra also has now a very strong data set to inform treatment decision in RA in monotherapy. And -- but that's not the last to come, there is a continuous news flow come in over the next 1.5 years. And you can see in the table below, that we are expecting some news around subcut, so the ADACTA [ph] trial will read out NT filing. We'll have them in 2012. We expect the RA -- early RA trial, and we expect feedback from the FDA later this year. And in 2013, we expect the first readout for systemic sclerosis.

Karl Mahler

So thanks a lot, Karsten, and thanks a lot, Professor Emery, for the excellent presentations and the overview on Actemra and the ADACTA study. And with this one, operator, I would like to open the Q&A session.

Question-and-Answer Session


[Operator Instructions] The first question is from Mrs. Luisa Hector from Credit Suisse.

Luisa Hector - Crédit Suisse AG, Research Division

I've got a couple. So just looking at the Humira label, it does seem to suggest that if it's used as a monotherapy, then it should be dosed every week rather than every 2 weeks, which suggests that it was underdosed in the ADACTA study. But are you saying that given the sort of real life situation that many doctors don't realize the methotrexate is not being used, the compliance is poor, that actually the study still stands up because it's more of the real-life experience? So that's the first question. And then the second question -- yes, sorry?

Karl Mahler

Would you like us to deal with that first? Because it is quite an important one.

Karsten Jung

Yes, please, if you would like to give an answer so we can stay online.

Paul Emery

The first thing to say is that the vast majority of people taking monotherapy Humira are taking the standard dose that was compared here, is probably, on estimate, over 80%. But if you're actually going to talk about Humira or adalimumab at weekly dose, you're talking about a drug that's costing EUR 25,000. So no one, certainly where there's state reimbursement, no one is allowed to do this because there are so many alternatives. If you're going to have a drug that's twice as expensive as another drug, with no evidence the higher dose is more effective, then that really isn't an acceptable proposal in the health economy. So first of all, it is what is used. Secondly, if we were to use it, it would be quite uneconomical.

Karl Mahler

Lisa, you had another question?

Luisa Hector - Crédit Suisse AG, Research Division

Yes, the second question is to both Karsten and Professor Emery, please. I just want to understand your view of what the greatest hurdle is for Actemra being used more as a front-line therapy or as a monotherapy. I don't know whether this ADACTA study is sort of aiming for both, but what would you see as the greatest hurdle for the drug being used in this setting?

Karsten Jung

Let me just take this first and then I hand over to Professor Emery for -- if he wants to add his view. But there are a couple of layers you need to look at. And definitely, ADACTA gives physicians a clear efficacy decision point to decide now between adalimumab and Actemra and we hope, certainly, that they use both data to make their treatment decision. But this definitely should move Actemra forward in line for therapy and the treatment in monotherapy. The second hurdle that might occur and people have had is the convenience question. So the IV formulation, which is the one we actually use in ADACTA, but with the upcoming subcut formulation, that definitely will also go away. But in every discussion we had, it was obvious key that efficacy is the first decision point with physicians I know and we certainly think that ADACTA will address this efficacy question very clearly. Paul?

Paul Emery

Well, I think the first thing to say is that this coming in against drugs we should have 10-years' license and you're not immediately going to change things. And the licensing authorities initially didn't rush to make it the first-line option, but it's important that probably the most influential one, NICE, is now changed that opinion. So that's relatively recent, we haven't seen the impact of that. So that's for patients taking methotrexate. The patients who can't take methotrexate, we haven't had very good monotherapy gauge to be honest. And no one really knows what goes on with the monotherapy population. For example, in the U.K., if you use monotherapy, often the payers stipulate particular reasons and they're very strict about ensuring response. I think this is going to change the monotherapy horizon almost completely, because this really has for the first time shown very great differences in monotherapy. We've always known that monotherapy TNF was inferior to the combination of methotrexate, so it's been the second-best option, which we haven't really talked about very much. This now tells us that we have a monotherapy option, which is equivalent to the combinational option and I think will make a terrific difference. Patients don't like taking methotrexate, and we've spent our time educating them that they have to. But that will change, certainly, I think.

Luisa Hector - Crédit Suisse AG, Research Division

I don't know whether Karsten can tell us whether what proportion of Actemra is used as monotherapy at the moment? Do you have a sense if any of it is monotherapy?

[p id="E04" name="Karsten Jung" type="E" />

Oh, that depends vastly from country to country, but let me give you a kind of an overall feeling. Right now the Actemra market share is somewhere in the single digits and that doesn't differentiate a lot between monotherapy and combination therapy, although mono is a bit higher. But if you look at -- the market share of Humira was the market leader that's certainly to your question, and there's certainly room to grow for Actemra in the monotherapy environment.

Paul Emery

You just have to think that 1/3 of the cost of the biologics is on monotherapy, nearly the size of that market.

Karl Mahler

Thank you, Luisa. Next question, please.


The next question is from Mr. Michael Leuchten from Barclays Capital.

Michael Leuchten - Barclays Capital, Research Division

Two questions for me. One, I guess going back to the monotherapy feasibility slide that you showed for Actemra, where you asked physicians to rank how to use or what drug to use in monotherapy, I guess another way to look at that is whether people are confident using these drugs in combination with methotrexate because of adverse events. So is there an aspect here that physicians are currently shying away from being more aggressive with Actemra in combination therapy? And how do you think, if that's the case, can that change going forward? And then secondly, can you say -- just can you explain to me how the escape therapy was treated statistically in the trial? What happened to those patients? Were they censored by the time -- in week 16 or how did you treat those?

Karsten Jung

Okay. Let me take the first question on the physician's perception first, and then we have our current assigned leader ex-sub Nikki [ph] here in the room, who can speak to your second question. So the first question, speaking to if there is anything that physicians shy away from combination therapy, there is nothing we see so far in any market. And just consider that the market share for Actemra is almost the same in both monotherapy and combination therapy. And the vast data set we have on Actemra is on combination therapy, which led to the indications and to the approvals in the different marketplaces. So I don't know if you want to add something to that, Professor Emery?

Paul Emery

Well, the slide here isn't "would you prefer monotherapy in these drugs?" It's about the appropriateness, which is really asking about the strength of the evidence of its efficacy. And it is and it has been a fact from the beginning with IL-6, uniquely blocking -- IL-6 blockade, uniquely seems to not require the presence of methotrexate to operate optimally. And that -- so I think that message has got across and you will see 2/3 of people feel that monotherapy is appropriate and not a second-best option, which they obviously feel for some of the other agents.

Karsten Jung

And just to -- to state or figure this obviously appropriateness what is considered to be an early indicator of behavior over time, so obviously this, with ADACTA, together, will hopefully change treatment decisions in monotherapy over time. So to the second question, Nikki?

Unknown Executive

So to answer your question as to how the escape patients were handled specifically, in the primary endpoint, the escape patients were handled as withdrawal patients, so they were not in the analysis. But we did a robustness analysis in which we put back the data, so put those patients back into the analysis so we included their data. And we have the identical results for our endpoint of changing that from baseline to week 24.

Karl Mahler

Are there further questions, operator?


[Operator Instructions] Ladies and gentlemen, there are no more questions at this time.

Karl Mahler

Yes, thanks a lot. So I just wanted to thank Professor Emery and also Karsten and the rest of the team for their help and support of making this call as it was. Thanks a lot. Thank you, all, for your interest in Roche and I wish everybody a nice weekend. Bye-bye.

Karsten Jung

Bye-bye. Thank you.

Paul Emery

Bye-bye. Thanks.

Karl Mahler

Bye. Thanks a lot.

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