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Celgene Corporation (NASDAQ:CELG)

December 11, 2011 11:00 pm ET

Executives

Mark Alles -

Paul Richardson -

Jean-Pierre Bizzari -

Robert J. Hugin - Chairman, Chief Executive officer, President, Secretary and Chairman of Executive Committee

Antonio Palumbo -

Jacqualyn A. Fouse - Chief Financial Officer and Senior Vice President

Patrick E. Flanigan III -

Analysts

Sapna Srivastava - Goldman Sachs Group Inc., Research Division

Brian Abrahams - Wells Fargo Securities, LLC, Research Division

Michael J. Yee - RBC Capital Markets, LLC, Research Division

Rachel L. McMinn - BofA Merrill Lynch, Research Division

Subita Srimal - MP Advisors

Matthew Roden - UBS Investment Bank, Research Division

Geoffrey C Meacham - JP Morgan Chase & Co, Research Division

Ryan Martins - Lazard Capital Markets LLC, Research Division

Patrick E. Flanigan III

I'm Patrick Flanigan, and on behalf of Celgene Corporation, I'd like to welcome everyone to our investor and analyst event tonight here at ASH, both to those of you in the audience and also to those of you participating on the webcast. Before we begin today's program, I do want to acknowledge all the hard work that many people at Celgene did behind the scenes to put this event together, and especially my colleague in Investor Relations, Mary Ann Ondish.

This is a quick snapshot of today's agenda. We're very focused in today's program on the evolving landscape within multiple myeloma. Very pleased to have Dr. Antonio Palumbo come and discuss the MM-015 results and also Dr. Paul Richardson, who'll be discussing the MM-002 data with pomalidomide. And to put this into a commercial context, we have our Chief Commercial Officer, Mark Alles. Now while today's program is heavily concentrated on multiple myeloma, I do want to point out that we have a lot of exciting things going on at ASH. And Dr. Jean-Pierre Bizzari will be discussing what some of those key abstracts are, presentations that we'll be showing beyond multiple myeloma, whether it's in HL, CLL, across the portfolio of products that we have, including REVLIMID, VIDAZA and so forth.

With this agenda, we have some time set aside for Q&A. For those of you in the audience, we do ask that you go to the microphones in the middle of the aisles. For those on the webcast, there's no formal mechanism for you to ask a question. But if you e-mail either Mary Ann or myself, we'll make sure that your question makes it into the queue. Now, from a timing perspective, at about 9:00, I've been told that there will be next to us, a party, so you may hear some music for those on the webcast and for those in the auditorium. And while they are having fun over there, we'll try to have some fun here as well. But just so you know, there will be some music going on in the background.

And with that, I just want to remind everyone that during today's presentation, we are going to make some forward-looking statements regarding our development plans and regulatory timelines for REVLIMID and for pomalidomide. These statements are subject to a number of risks and uncertainties. A full description of those risks are located in our most recent SEC filing, our 10-Q filing with the SEC.

With that said, I'd like to now hand the program over to Celgene's Chairman and CEO, Bob Hugin.

Robert J. Hugin

Thank you very much, Patrick, and welcome again to everybody here in San Diego, and thanks so much for joining us, and thanks for everybody on the web for investing some of your, in many cases, late evening, to get an update on some of the important developments here at ASH.

ASH is a great event for Celgene. It's very important. It's, in many years, been transformational for our company, that data that's come out of the American Society of Hematology meeting, and in many years, it's been a very exciting time for us, sometimes a little too exciting for us. But every year, it's always been a very, very important event for Celgene, and there's no doubt this year the data presented at ASH is extremely important for Celgene in many different ways. And we've got a great, focused program here tonight, and I want to thank Jackie and Patrick for putting this together, that really will focus on the key issues that are important for the leading elements of the data being presented here at ASH.

And again, it is a very important event for us. We've got new data across a wide range of Celgene products and across a wide range of indications that have the tremendous potential to make a meaningful difference in the acceleration, the advancement of our clinical programs to really support multiple regulatory filings and approvals across the globe and to have short-term, medium-term and long-term impact on our commercial activities around the globe. And with this type of clinical data coming on an annual basis for Celgene and Celgene products, it doesn't happen by accident. It is the result of more than a decade of committed, focused research and development investments. And also, it benefits greatly from the wisdom and guidance and the collaboration of thought leaders across the world, investigators, physicians, leading in the study of these diseases that we look to pursue and make a meaningful difference in the lives of patients around the world, such as Dr. Palumbo and Dr. Richardson, and our programs benefit greatly from their collaborative efforts with us.

I want to also just spend a minute or 2 before we get into the program to give you a quick update on some of the important regulatory events and progress that we're making that are very important, that will ultimately lead to making our products have the best access to patients around the world. We do want to let you know tonight that we have completed all of the 120-day questions on our application for newly diagnosed myeloma and maintenance in Europe and we're doing, finalizing the regulatory publishing to get them submitted this week. It was a big event for us, because as you heard in the last few weeks, Swissmedic also approved the REV del 5q MDS application. Now with the completion of the 120-day questions, we can move very expeditiously to also submitting the REV MDS del 5q application in Europe early into next year. And we're very much on progress to continue the geographic expansion from a regulatory perspective of REVLIMID in myeloma with the filing of our relapse or refractory myeloma application in China in the next week or so also. So very important data on the regulatory events that are going on here in the next few weeks and months, and we're advancing those programs very satisfactorily.

On the pomalidomide side, some also important update for you that -- and we're also very fortunate as well with Antonio to talk about MM-015, which is the foundation of our newly diagnosed and maintenance application in Europe. We're also very fortunate that Dr. Paul Richardson is with us, who, like Antonio, is going to have oral sessions tomorrow to speak about the data, in this case, with Dr. Richardson, as Patrick said, from our 002 trial in pomalidomide and relapse refractory myeloma. And that data continues to mature very nicely, and I think it's very important that you see that data tomorrow, because it is the backbone and the foundation for any potential we have on accelerated filings around the world. And we continue to work in the U.S. to make sure that we have the strongest data package in terms of strength of the data, the quality of the data, a full understanding of it so that we can have a filing in the U.S. as soon as possible.

But I want to let you know tonight, so we also made some very outstanding progress outside the United States. And based on negotiations and discussions with regulatory agencies in Europe, we now have a corporate objective to submit a relapsed refractory myeloma application in Europe by the end of the second quarter of this coming year, which is significantly sooner than we had originally envisioned.

And a last note on the regulatory issues before we really get into the meat of the program that you're all here for is that we have accomplished the non-small cell lung cancer filing for ABRAXANE, and we'll very quickly and hopefully, certainly, hopefully, by the end of the first quarter, we will have our European filing for that same application completed. So again, we're here to talk about clinical data, we're here to talk about ASH, and that's what we're going to do. But I did want to spend a minute or 2, giving you an update on some of the important regulatory progress that we are making. So let's get into the program, and let me introduce to you the Celgene's Head of Hematology/Oncology Clinical Development, Dr. Jean-Pierre Bizzari. Thank you.

Jean-Pierre Bizzari

So thank you very much. It's a pleasure for me to be here with you tonight and to share some of the very exciting data you will see at ASH. I mean, it's a bit frustrated because, of course, I cannot present some of the key element, but I really strongly encourage you to attend some of our key presentation on Monday and Tuesday, and you won't -- you will see, you won't be disappointed.

So I think what are the key takeaway message this year for ASH? I think for me, 5 key element. The first one, as you're going to see, we've Professor Antonio Palumbo presentation, the continuous REVLIMID, the clinical benefit in MM-015 and the fact that MPR is really becoming a standard. This, again, is, of course, pomalidomide. We are in an unmet medical need, a really prevalent [ph] patient population. And basically, you will see the broad clinical activity. The third one, of course, is the expansion of REVLIMID in del 5q. The fourth one is that after myeloma, we're moving into the lymphoma, and you will see some of the quite exciting results after rituximab. And of course we have, after myeloma, lymphoma, the next step, which is CLL, and you will see a huge program, 17 abstract presentation on CLL. We've a lot of combination. So what we're seeing is that REVLIMID is becoming the backbone of the therapy in CLL.

So let me move step by step and see how much progress we've made. So the first one, of course, is REVLIMID. And what you will see is the early use of REVLIMID, of course, the smoldering. Last year, we presented some interesting data. This year, you will hear even more. The second one, of course, is the combination, because as you know, we're going to be the backbone. The second one is the continuous therapy, and Dr. Palumbo presentation is going to show you really the benefit of this combination. And also what's extremely important is the fact that we will have a long-term follow-up for the MM-009 and MM-010 in the refractory relapsed population. And of course, the safety, so again, Dr. Palumbo on the SPM analysis and the overall safety.

Let me give you 1, 2 elements. One is the efficacy, and you know what's really important for the patient is where risk reduction, the azad [ph] ratio. So if you look at the median PFS in the risk reduction, what we're seeing is that in the last 7 to 10 years, we move from 49% risk reduction with MPT up to 70%. This is Antonio presentation, MM-015, with the median PFS moving from 27 month to 31 month.

The second is the SPM. So for me, it was a very difficult year, because we had to work with the agency. The very good news is that in the relapsed refractory, the Article 20 review concluded a positive benefit risk in this approve indication. In the newly diagnosed, what we can say is 3 things: One, REVLIMID in combination with melphalan or following high-dose melphalan may be associated with an increased risk of invasive cancer. What we're seeing is that we've more look at the placebo and more analysis, we see that the difference is decreasing between the placebo and the control arm. And if you look by multivariate analysis on really the risk factors, you see that the clear one is the previous history of cancer. And you know, if you see what has been presented, for example, in the smoldering indication, it's quite obvious. But probably, one of the key analysis of this Article 20 was the fact that there's no link between the treatment duration and the risk of SPM.

The second take-home message is pomalidomide, and so basically, you will see the efficacy, the MM-002, and I think what's important with the pomalidomide dossier? I would say 4 things. One is the fact that we're dealing with a highly pre-treated patient population, median line of therapy 5. Two, we have consistency across the study and across the patient, resistant to refractory, to REV, to bortezomib, to both, to transplant over therapy. Three, the safety profile. And four, the fact that now, we're seeing a kind of combination like the PCP.

Point number 3 is the move into the MDS/AML. So the first one, of course, is the benefit-risk, and you will see some kind of analysis using the registry [ph]. We have 2 major drug in this indication, REV and VIDAZA, and the issue for us is basically to find the right therapy for the right patient, and therefore, there are a lot of presentation trying to target what's best for the patient according to the stage. We have also by design, special population, pre-transplant, post-transplant, and we are pushing very actively the development of oral AZA, because for 2 reasons; one, for convenience of the patient; and two, because you can give a continuous therapy, which is extremely important from an epigenetic standpoint.

After myeloma, the second step is lymphoma. But the first indication, basically, will be MCL but we are also very active is diffused large B-cell. And what you're going to see is probably the dream of the oncology, which is basically to get out of the cytotoxic and try to combine those 2 biological agents, and basically, you will see this rituximab resistance in B- and T-cell lymphoma, which is extremely important from a clinical standpoint. Also, the PTCL. For me, as a clinician, when you talk about PTCL and you see that these patients have a median duration of response of 17 months, 17, 1-7, is quite impressive. Of course, he is going to comment on that.

First step, myeloma; second step, lymphoma; first step, CLL. We have this year at ASH, 17 poster indication, covering the entire spectrum from the refractory, CLL 009, to the first line, CLL 008, to the maintenance, CLL 002. And so you will see today at ASH that REVLIMID is starting to be the backbone for the CLL with a lot of combination. We'll see 3 presentation, very important concept, as we've done in myeloma, the concept of consolidation and maintenance. We have a CLL 002, and of course, we have been able through the CLL 009 to clearly analyze the risk factor and the patient management at the starting dose.

So this is our hematology pipeline. I'm going to comment very briefly on the key element of it. Very important is the MM-020 study comparing ALDI [ph] to MPT. You know that the accrual was finished at the end of 2009, and basically, you're going to hear in 2012 the analysis based upon the number of event. MDS 004 and 005, moving extremely rapidly. The sprint, which is MCL study, is going to be completed and next year filing. MC 002, the same study in Europe. Diffused large B-cell for next indication using a bio-marker strategy, follicular lymphoma, the study performed with GELA about to start, and of course, as I mentioned, the CLL-002 and 008. Pomalidomide, the MM-002 study presented by Paul tomorrow and the MM-003 for Phase III study in Europe accruing extremely well, myelofibrosis and VIDAZA.

So if you look at this hematological pipeline, it's quite impressive. But I think what has been really key in 2011 this year is the fact that our reserves from [indiscernible] San Diego team have been really able to put 3 INDs, 3 INDs this year with Array, CC-115 and CC-122, and we've done a lot of collaboration, Acceleron, Agios, Array, GlobeImmune, Quanticel, and at the end of the day, this is a unique opportunity for us to move things forward.

So if you look at the program milestone, as I said, next year, basically, pomalidomide, the MM-003, European Phase III study, pomalidomide myelofibrosis; MM-20, the interim analysis based upon the number of event; MCL 001, with the SPA after Velcade; the oral AZA program, which has been validated by the regulatory authorities; and the diffused large B-cell strategy based upon a biomarker strategy. In 2013, 2014, the CLL program. We have a CLL 008, first-line versus Chlorambucil; the MDS 005 with interim analysis; and of course, the MM-020 results. And 2015, the cooperative with GELA, with REMARC study, maintenance diffused large B-cell; the REVLIMID maintenance CLL-002, and the relevant study on follicular lymphoma.

So that was my last slide. I'm not going to introduce -- I don't need to introduce Antonio Palumbo, who's going to give you an update on the MM-015. Thank you.

Antonio Palumbo

Thank you very much for the very nice introduction indeed. And I will present some of the data that has been, to some extent, already present at previous year. And let me introduce with the concept that I think is important beside the MPR-R and lenalidomide maintenance.

Today, with this study, along with the study coming after autologous transplant, there is a major change in the treatment paradigm of myeloma. What is becoming clear is that the use of a maintenance in the myeloma setting is probably representing 70% of the total efficacy of a given treatment. Why this? Because generally speaking, in myeloma, you always have a residual disease. So it doesn't matter which is your induction regimen, you end up with some residual disease. The residual disease needs some sort of continuous treatment, and the use of this continuous treatment, we will show, but it's not only with this drug, even several other drug, is changing and is increasing at least of around 10 to 15 months of the remission duration.

The other concept I would like to leave -- give you is, and this is coming from Europe, and Europe is much more clear. This I think probably will come worthwhile and the issue is, one question is, are we improving overall survival? The answer in myeloma is definitely yes. You will see our survival curve, the median of our survival of myeloma patient was 3 years. We are talking about 5 years for the elderly; 7, 8 for the younger patient. But more important than that, what is important to consider in terms of both of quality of life and then cost efficacy, that we will less and less be available to keep treating third, fourth, fifth, sixth relapse for many reasons. First, more that this disease is advanced, more the disease becomes resistant. More the disease is resistant, more the risk of co-morbidities in patient care, inability becomes essential. So what is will become, again, a change in the treatment of cancer more than myeloma, if you want? That will be very important to prolong as much as possible, the remission of the early phases of diseases, and eventually, start to be palliative, early on that we are used to do today. And this is another concept to remember, if you want to consider the use of maintenance. It's very important to prolong as much as possible the remission duration after induction, because beside the cost of the drug, the low risk of co-morbidities gives a saving for the healthcare assistance, while if you need inpatient care for toxicity, deaths is increasing very much the cost of the healthcare assistance. But of course also, it's a matter of quality of life. And also the ability to live without the need of a third person that must take care of you, and that's another major issue. Because to be autonomous, to be able to live in your own house without need of being in a hospital, in a special structure, this is another major issue in terms of healthcare costs.

Having said that, going back to the data, this is what I would like -- I wanted to leave you, and you can see here the major treatment for elderly. You can see that the progression 3 for both MPTs ranging between 20, 24 months with advanced, updated results, the PFS is usually around 21 months for both MPT and MPV. The addition of a maintenance is increasing of 10 months. In other studies, goes up even up to 35 months. So this is the major issue in terms of -- and the major advance in terms of efficacy for the use of a maintenance approach.

Now go back to the data of 15. This is the design of the study, you probably know very well. Three arms: an induction with the 3-drug MPR, followed by lenalidomide until progression, arm A; arm B, 9 courses of MPR without maintenance; arm C, MP alone. These are the patient characteristics, so the median age is 70. 76% of patients were between 65 and 75, something I like to highlight always, because the results of these studies should be weight, with the fact that by chance, we had a very high portion of patient with poor prognosis. Usually, the highest stage 3, is usually 25%, 30%. Here, we are going up to 50%. So we have around a 15%, 20% more high-risk patient than normal, and this should be considered when you judge the data, because these patients have a significant higher risk of poor prognosis.

These are the data, and this is the main data coming from this study. And I would like you to get concentrated on those curve, because this is telling exactly what happening in myeloma. You can see here, up to the first 9 months of treatment, that is exactly the treatment of induction, curves are, to some extent, superimposed. The moment that you stop treatment, the curves drops. The moment after induction, you just give maintenance, things completely change the outcome. So here, you can see the difference is mainly and is coming from the use of a maintenance approach. And this is not only true in this setting, it's also true in other setting, in other trials, with other compounds. This is the overall survival. At present, the overall survival is similar in the different groups. But again, remember that here is projected that 3 years, around 70%, 75%, usually the median was 50%. So we have here, at least, 25%, 30% increase in overall survival, although you do not see a difference among the different arms.

What about SPM? Well, SPM has been a major concern, and SPM, to make it here a long story, try to make it as easy as possible. With a combination of melphalan and lenalidomide, the risk of SPM is increasing 2x in comparison to bortezomib, for example. If you use lenalidomide without melphalan, with dexamethasone or cyclophosphamide, the risk of SPM is basically the same than bortezomib. And if you want to make a comparison without the risk, the risk of the dying for infection during an induction chemotherapy is 3x more than the risk of having a second primary malignancy. So to put everything in perspective, melphalan plus LAN is increasing the risk of SPM. LAN without melphalan is not increasing the risk of SPM, and if the risk of dying of infection is higher than the risk of second primary malignancy.

Another issue and has been the beginning of concern, why MPR alone was not superior to MP. And this is a story that is not only true for MPR, it's actually true for many other combinations. Elderly patient, they are not all the same. A 67-old person is not the same that an 85, but unfortunately, we give the same dose to both people. And the major issue here is not that MPR is not effective. The major issue here, as you can see here, that in patient over the age of 75, the discontinuation rate increases, but what is even more important to highlight, that the cumulative dose intensitive, so your wish of giving the drug is 88% in 65-75, but drops down to 50% over the age of 75. So which is the issue here, it's the usual issue for elderly. You are giving a treatment, you are giving too much. If you have too much discontinuation, your cumulative dose goes down, you don't give what you want to give, you give 50% less, and of course, you don't see the efficacy. This is a story that has been true for MPT, for VISTA, twice weekly versus once weekly. We have some preliminary data using a different approach, and a lower intensity of melphalan significantly lowered the discontinuation of -- the discontinuation rate in the frail population. So I think from this setting, the future will be to make a fine-tuning of the doses we use and to make a fine-tuning and a lower dose intensity for the frail patient condition.

This is the response rate, major difference in terms of response rate, you can see here, VGPR of 35% versus 10%. To give you an idea in terms of CR, it's 15% of CR and MPR versus 3% in MP. So you have 5x more CR. The speed of response is much faster with the three-drug combination. So the three-drug combination is needed for 2 reasons. First, you increase the rate of response, you increase the profound site of the reduction, but also, you increase the response that becomes faster. This is the subgroup, basically, is the same story. What I would highlight here, that in the group of 65-75, you start to see a difference between MPR alone versus MP, and this is demonstrating that the 3 drug are effective but are effective in the younger, fit patient. They are less effective in the frail patient over the age of 75. On usual, as usual, as seen before, the maintenance is completely changing the slope of the curve. Maintenance is effective in -- and this is different from MPR. MPR is effective in 65-75, it's less effective over the age of 75. Maintenance is effective in younger patient, 65-75, but equally effective in patient over the age of 75.

I would like to highlight this, there is a 70% reduced risk of progression, this is unprecedented in the conventional treatment of myeloma patient. The survival in the group 65-75, we are starting to see a different. The result ratio is 0.70, although the P is not statistically different, but we start to see a diverging of the curve. My personal comment is that when you have such a major difference in terms of progression for your survival [ph], before or later, the difference in overall survival will be apparent. Because when you start to have a reduced risk of progression of 50%, 70%, this will translate in an advantage in overall survival. Of course, we need a longer follow-up, because now the survival of elderly patient is certainly between the 4 and 5 years.

Conclusion. The conclusion is that MPR-R is the new standard of treatment; that this combination is highly active, especially in the group of 65-75 years of age; and we need the fine-tuning to adopt the doses we use in this trial for patient over the age of 75. But what is even more important is to say that continuous lenalidomide therapy achieved unprecedent in PFS with a median PFS of 31 months. But as I was saying before, what is really changing the treatment paradigm of myeloma is that maintenance is needed and will be needed in all patient after induction independently from the drug they are using.

Of course, many thanks to Celgene, who sponsor and was a great help to us in doing this trial, and, of course, all the patients and nurses and physicians.

So after that, I believe I have to leave the word to my colleague, Paul Richardson, that is here.

Paul Richardson

Great. Thank you very much, Antonio. And I think I've got to switch this on. Yes, that's lovely. Well, good evening, ladies and gentlemen. It's a pleasure to be here. It's been an absolutely ferociously busy ASH. I'm very grateful for members of the Celgene team getting me here on time. It's something of a record, actually, I have to tell you.

But anyway, on that note, it's really my pleasure to talk to you about what I think is, for me, anyway, one of the most exciting trials that I've been part of in quite a while. And that's our randomized open-label phase I/II study of pomalidomide, both alone and in combination with dexamethasone at a low dose in patients who meet or require or have an exquisite unmet medical need. In other words, they are specifically relapsed and refractory but resistant on to lenalidomide and Bortezomib or both. We'll be presenting this meeting -- this final results of this trial tomorrow afternoon, and I'd encourage you all to come, because, obviously, what I'm going to share with you tonight I'm going to add to tomorrow.

These are my disclosures. And by way of background, I think most of you are very familiar with pomalidomide. It's a fascinating molecule. And that what it would combines at a bi-chemical level, if you will, is the best of lenalidomide and the best of thalidomide. And by that, I mean it contains both the carbonyl and the amino group that is specific to both other separate molecules.

And very interestingly, in that context, it's shown some remarkable activity very consistently in all the early phase trials that have been done. I should tell you that preclinically, it's actually the most potent IMiD, and that was identified some years ago, in fact. That observation preclinically has translated clinically, some very important work, and I especially want to acknowledge, actually, Dr. Stephen Sky [ph] and Matt Strictly [ph] in Britain, who were the first to do the Phase I work with it. And on that basis, then, Martha Lacy and her team at the Mayo have really built on that to show that when you combine it with dexamethasone, as we would expect, based not only on the clinical observations that we see with lenalidomide and thalidomide, but also on the preclinical synergy that we see, this is quite striking. That actually, when you put this drug with low-dose dexamethasone, there was a synergistic effect. And what was really important is that the Phase I trial in Britain had built a dose-in schedule that needed further definition. And similarly, indeed, in Martha's work, too, it was very clear that in the truly relapsed and refractory population, we needed to define exactly what was the MTD. And it was really with that as a background that we did our Phase I trial looking at the dose escalation of 2, 3, 4 and 5-milligrams.

What we also built was a 3-week on, one-week off schedule. Now we've obviously learned this from lenalidomide, but we felt strongly based upon the observations made by Steve Sky [ph] and Matt Strictly [ph] when myelosuppression had been observed that, in fact, this syncopated or this interrupted dose in schedule would actually be appropriate. So 3 weeks on, one week off, that was our hypothesis. And by the same token, we wanted in this exquisitely vulnerable population, relapsed and refractory, to define an optimal dose and schedule.

So I want to talk to you a little bit about the Phase I, obviously, and then we're going to spend a little bit more time at the end of my presentation this evening talking to you about the Phase II randomized. But I do want to emphasize to you that the full results will be presented tomorrow afternoon.

One note about the Phase II randomized. We sought in this Phase II randomized trial, having defined a dose-in schedule in the Phase I combination approach to better understand the independent contribution of pomalidomide as a monotherapy, but most importantly, at the same time, understand the synergy with low-dose dexamethasone. To that end, we had one arm assigned to monotherapy, but at progression, the addition of low-dose dexamethasone was required and the other arm just began with pom, low-dose dex from the get-go.

So in terms of eligibility criteria, I do want to spend a bit of time on this, because it's important in this busy field of relapsed and refractory disease to understand exactly how we define this. Patients had to have measurable levels of M protein, obviously; they had to have 2 or more prior therapies by definition to meet the key category that they had to not only be relapsed, but they had to progress on or within 60 days of last treatments to be truly relapsed and refractory. The other key constituent of this trial was that we define patients by virtue of being lenalidomide and bortezomib, either or both refractory. And to do that, we set a high standard. Patients had to have actually have 2 or more cycles of lenalidomide or 2 or more cycles of bortezomib to meet this criteria. That's important, because, obviously, if a patient gets 1/2 a cycle of bortezomib and progresses, can one really argue that that's refractoriness? Similarly, for lenalidomide, would that be the same? So I think this rigor to entry criteria was very important.

Now in terms of endpoints. The primary was progression-free survival. This is the Phase II piece, we're going to touch on the Phase I in a minute. And our secondary endpoints, we had to look at response using a synthesis of modified EBMT in uniform to look at duration of response, overall survival, and, of course, evaluate safety.

I want to spend a little bit of time on the Phase I, because I think it's very informative. This, obviously, was a classical Phase I in which we dose-escalated from 2 to 3 to 4 to 5. As you can see here, 100% of the patients had, had prior lenalidomide and bortezomib. All of them had, had prior dexamethasone. A very important point to make is all the patients were not only refractory to just one line of dexamethasone but to multiple lines of dexamethasone. So any argument that there was dex sensitivity in this group of patients is clearly not correct. What's also important is that they had, had prior thalidomide and also stem cell transplant. But very interestingly, in this Phase I population, we show you how many patients had also had prior carfilzomib. And of course, the double-refractory group, the particularly poor-prognosis group, also constituted [ph], or, rather, were part of a large part of this trial.

Now what did we see? I think these are quite interesting data. What they show in the Phase I was that we're able to not only establish the 4-milligram dose was the MTD, we were excited to see the quality of responses improving with dose. We made the descriptive observation that at 4 or 5 milligrams basically not only with the higher response rates, but, interestingly, they remained longer on treatment compared with those who received lower doses. Now this was descriptive because the numbers were small, but what's really interesting is there's a very nice paper tomorrow that you should see, presented by Xavier Leleu [ph], which is a randomized Phase II, showing that actually, the 4-milligrams, 3 weeks on, one week off is in fact superior to the continuous dosing developed by Martha, primarily because the one week off allows a superior tolerability profile. Not only that, there is actually a longer duration of response. So this initial Phase I observation has actually been validated by Xavier's work.

Now what about our own randomized Phase II? Well, as you know, there were 221 patients enrolled, 108 assigned to pom alone initially, and 113 to pom and low-dose dexamethasone as the other arm. The median number of cycles administered was 5, with as many as 17 given, and the median duration of treatment was 5 months. Now if you look at the Phase II population, we set the same rigorous standard to their entry criteria. They had to have had prior lenalidomide and bortezomib. Almost every single one had, had prior dexamethasone. The majority had prior thalidomide. Three-quarters have had prior transplantation. And as you can see, patients were in the majority refractory to lenalidomide and bortezomib and almost 60% -- well, in fact, 60% overall were refractory to both. So the so-called double-refractory population. What I think's been very exciting is to see the following: that if you look at best response by intent to treat analysis, for the combination, we have a response rate of PR or better of 34%. What's also interesting is that there's clearly a signal from POM alone. What's also very important to note as well is that MR or better, which we identify with clinical benefit, we've done a lot of work in that regard, MR or better was 45% for the combination, almost 30% for pomalidomide alone. And what's really interesting is that the duration of responses are good. And some people say, "Well, goodness. I mean, look at that median duration of response to pomalidomide alone at 8.3 months." And what I'd remind you is that in those patients who respond to immunomodulatory therapy, we see this. We saw this in lenalidomide in the relapsed refractory setting. A group of patients can respond for a long period. And we saw this exactly with pom alone as well. Again, I think, very supportive that whilst the overall response rate and the quality of responses are clearly superior for the combination, the effect of the drug alone is also clearly apparent to me, not least of which because, of course, patients were all refractory to dexamethasone except in one case. And on that same basis, they were not only refractory just to one or more lines of dexamethasone, but multiple.

Now what about the progression-free survival and overall survival of the total population? Well, not surprisingly, pomalidomide and low-dose dex had superior PFS, but I think what's really interesting is the overall survival, it's very encouraging for the combination of 14.4. What's also interesting is that patients were allowed to cross over, of course, and so we had a very respectable survival for the monotherapy arm as well, recognizing that it would reflect also that effect. I will stress to you that I'm updating these results tomorrow and would encourage you to come and to see these improved values.

In any event, what about best response in certain subsets of patients? Well, in terms of the subsets of patients who were refractory to both lenalidomide and bortezomib, a couple of points to make. As you can see, to the combination of pomalidomide and low-dose dexamethasone, we saw a 30% response rate. MR or better was the same at 45%. And very interestingly, we saw a similarly strong and consistent signal from POM alone. Thus, I think it's very interesting to see this, because what you're seeing is a consistency of effect, and we were very encouraged by this. And remember, of course, that the definition of refractory was very rigorous. Similarly, when you look at PFS, the results do suggest durability in this effect. I'm particularly encouraged by the overall survival that was reported here.

Now what about adverse events? Well, the good news here is that they were very much what we would expect. Neutropenia, thrombocytopenia and anemia, non-hematologic adverse events actually prove very manageable. It's interesting that we saw pneumonia with the combination. It's important to recognize that sign of pulmonary infection is common in advanced myeloma, and obviously, the impact of steroid on that are maybe real in terms of immunosuppression. But obviously, these are manageable. Very important point is that these were infectious. Idiopathic pneumonia we did not see. So in that context, it's interesting to note discontinuation due to AEs, low, really, for certainly the combination and similarly, relatively low for monotherapy as well. As I mentioned, neutropenia was the most frequent, and again, manageable, although the rate of fibroin neutropenia was low at just 2%, and it was the same in both arms.

So I think in conclusion, we can say based upon these results in a very large multicenter setting, that a 4-milligram schedule of 21 days on, 28 -- I'm sorry, and 7 days off with a 28-day cycle, in combination with low-dose dexamethasone, is clearly efficacious in patients with advanced disease, and very importantly, in this exquisitely vulnerable population, both relapsed and refractory and, indeed, refractory to both len and bortezomib. I think there's evidence of synergy, clinically, which supports what we see preclinically, and the general -- the tolerability of this combination, I really want to stress, it's a very well-tolerated combination in our experience. The durability of responses is there, and the question is now, where do we go with this? Because clearly, to my mind, anyway, this is probably the most important new combination that we have.

With that in mind, there is an ongoing trial in Europe, comparative Phase III trial, and I think very importantly, in the United States, a combination approach of pomalidomide and bortezomib and dexamethasone versus bortezomib dexamethasone, is planned with a Phase I/II study now up and going and ready to go.

On that note, I want to say thank you very much to all the investigators that were listed on the front of the first title slide and also especially acknowledge our Phase II investigators who are summarized here as well as the institutions involved. I especially want to acknowledge the support of the Celgene team and in particular, the pomalidomide team, who've been a pleasure to work with. And at the same time, of course, last but no means least, acknowledge our patients and their families. Thank you very much.

Mark Alles

Hi, good evening. My name is Mark Alles, for those who I haven't met before. It's great to see everyone here. I want to again thank our faculty members, Dr. Palumbo and Dr. Richardson. In the next few minutes, what I hope to do is give you a little bit of sense of how we see ASH from a commercial point of view, and, of course, it's all built on the evidence in part that was presented tonight and throughout the congress. I'll also try to put in context, some of the segmentation, that when we think about the complexity, on the one hand, of myeloma as we see emerging combinations. For example, carfilzomib, with or without lenalidomide, we just looked at the pomalidomide low-dose dexamethasone data and all of the different strategies that are being advanced in myeloma, it makes segmenting the market out and trying to model what's happening with the opportunity is quite difficult. So I'll try to do that tonight and then close with a simple view to translate what Jean-Pierre presented in our comprehensive clinical program and blood cancers into some of the opportunity that remains for the company. But we think the data will come with time.

So from an opportunity point of view, I think there are 4 major themes one could consider from this meeting. There are many, many ways to talk about these themes, but let's start with what we saw from Dr. Palumbo tonight. Let's start with what Bob Hugin mentioned, which is that our day 120 submission is ready to go in from a regulatory point of view. And let's acknowledge that in the patients who are elderly, not transplant candidates, but who are in this group of 65- to 75-year-old patients with newly diagnosed myeloma, what has emerged is a profile with MPR-R. So the idea of induction maintenance, not as 2 separate strategies, chemo-induction followed by something, but a regimen that starts with a very, very nice induction response that is maintained. And as Antonio talked about, this congress is really representing and recognizing the notion that minimal residual disease is present even in those patients who we say in myeloma have complete responses. That's another theme that we could discuss for a long time. What does it mean in myeloma to have a complete response, and how should we think about those patients? But there's no question there is a unique differentiated clinical profile for MPR-R in the patient population we seek for our label as induction and maintenance, and we think that that's an important emerging theme. Antonio will update the data tomorrow, so please make sure you're there to see it. What you saw tonight is some data that I think you've seen before, but tomorrow's an important presentation.

There are, literally, from the abstract pool at this meeting, thousands of patients of data that looked to describe and investigate the observation of the low rate of second primary malignancies that emerged out of the 015 data a year ago. The IFM-0502 data a year ago, and the CLG B maintenance data. It is quite clear from a regulatory point of view and we think from an overall "risk to benefit profile" point of view that REVLIMID across all multiple myeloma patient segments, it has a quite positive benefit-to-risk ratio. We think the SPM data, when you look at event-free survival analyses, different types of sensitivity analyses and put those into the event rate, the overall benefit stays the same.

As Paul just very, very nicely presented, so Paul, thank you again, really, really nicely laid out. The clinical profile of POM low-dose dexamethasone is quite strong. Tomorrow, the updated data will show the maturation of some of the better outcomes that we could not show because they're not part of the abstract. But our regulatory commercial planning is now accelerated on the basis of the more mature data and the profile of pom low-dose dex.

I think also interestingly, after 10 years of thalidomide being one of the mainstays of the treatment of myeloma, now lenalidomide and pomalidomide to come, we're finding a unique marker, if you will, or target in the treatment of myeloma that is cereblon. You may have heard some of that data today. I think, interestingly, it builds on the notion that REVLIMID and then maybe pomalidomide, because of the unique mechanisms, is the ideal backbone for all treatments. So for example, look at the emerging combinations: elotuzumab from Bristol-Myers Squibb, the CS1 targeted inhibitor. Look at what's happening with carfilzomib with the confirmatory Phase III programs. Look at the combination of REVLIMID with Velcade. And the list goes on and on. So I think the mechanistic biological work that's being done by our group, by groups out of Mayo and a few other places is quite striking in that in this advanced stage of clinical development, we're going back to the beginning and understanding the mechanisms all over again.

How does this translate into an algorithm for treatment? Now let's be clear. This is a very simplified view of a very complex environment. This does not break down, for example, high-risk patients versus standard-risk patients. It doesn't put into context those patients who have mild to moderate renalin sufficiency or normal creatinine function. What this does is simply gives you, at a macro level, that decision-treated exists in the U.S. and the 18 major markets in Europe in terms of an epidemiological view of the decision tree to go to transplant or not and how we see the populations divided out. So out of about 60,000 patients who go on the treatment, and that pool will grow because why? Maria Mateos [ph] and the Fatima [ph] data are moving smoldering and high-risk patients into truly newly diagnosed, treatable patients. How that number changes, we will see. But about 40% will go to the eligible pool of transplant patients, or 25,000. About 60% in this group of markets are not eligible. And that's an important distinction, because that's where our initial newly diagnosed multiple-myeloma indication will participate, with that unique 65- to 75-year-old population.

Going back to the transplant side. Roughly 70% of patients who were eligible will go on to a transplant, but leaving a very large pool of roughly 35%, 30% to 35%, who even though they're eligible, the induction treatment is so effective, the continuous treatment is so effective that they're delaying the decision to a transplant, perhaps to second-line or some later point in the treatment. The 2 paradigms that, again, Antonio spoke to tonight is this idea that even if you have a post-transplant CR, you have minimal residual disease that requires and benefits from conditional -- from additional therapy, including lenalidomide and some of the other strategies that are being played out at this meeting. If you are a patient who's transplant-eligible but you don't get it, you are very likely to stay onto your induction regimen for a very long time. Think of the CLG B maintenance data, where rev/dex is used as induction and part of the strata, followed by transplant, followed by rev maintenance. And that group is doing beautifully well. Think of the ECOG-E4A03 data, where rev/dex is used and at 3 years without transplant, 80% of patients are still alive and doing quite well.

On the non-transplant-eligible side. This idea of continuous therapy is a given. Treat to progression is a model that we're working on, and we think the product profiles we offer the marketplace are quite unique in that regard with a low level of hematologic and non-hematologic toxicity, allowing for continuous long-term duration of treatment. So let's translate this algorithm to the data algorithm that Jean-Pierre spoke to and many of the investigators this week and will continue to update all of us around the world.

So lenalidomide in newly diagnosed myeloma is being widely studied in the transplant-eligible and non-transplant-eligible group. We heard about 015 tonight. We'll hear about it again tomorrow from Antonio Palumbo, but remember, that Jean-Pierre spoke about MM-020. This is an interesting trial in that it crosses both the decision to transplant or not, because rev/dex, we think, will be superior to an alkylator-based regimen, in this case, MPT. That means the induction regimen, whether you transplant or not, potentially becomes REVLIMID dexamethasone. And that study is across the entire landscape of newly diagnosed myeloma. I won't belabor the point that the maintenance data from CLG B, from the IFM, yes, with respect to all of the considerations of survival in one study, not in the other yet, SPM's in or out of the equation, there's no question that the progression for your survival benefit is advancing the notion that after a transplant, you should be considering maintenance therapy for these patients. Paul Richardson with the IFM are conducting one of the most innovative important studies in the world that is RVD induction, with the question of continuous chemotherapy versus high-dose therapy with a traditional transplant approach and then REVLIMID maintenance. So that study is accruing nicely, and it's open in a lot of centers now in Europe and in the U.S.

The BMT group, Sergio Giralt talked about this if you were at some of the education sessions yesterday, is studying the important question of consolidation. But interestingly, all 3 arms of that trial have REVLIMID maintenance times 3 years. That is unchanged from before the emergence and the concern of SPMs. So duration, of course, has been ruled out as an issue. So the transplant group, it's very clear what's happening and what's emerging with additional studies. The non-transplant group, again, this idea of continuous treatment of what you get as induction therapy, which is typically 4 cycles, harvesting the patient so that they could go to transplant, but just continuing through until pure progression. The non-transplant side, we've discussed and I think it's very clear that rev/dex in its current use and the new data would just support that going forward. What does it mean in the relapse setting? Worldwide, REVLIMID dexamethasone is the market leader for that first relapse group, the pure second-line group. So again, we restrict our view to the U.S. and the EU 18, that's around 60,000 or so patients. But the prevalence pool, because of, as Paul talked about and Antonio talked about, of increasing survivorship, chronic sequential therapy, this prevalence pool is growing quite nicely, because we can continue to treat these patients and keep them alive. So that group is growing. Now Paul spoke to the data from 02 in a different way, by line of therapy, by prior treatment, by a definition of resistant or refractory. Translating that into the marketplace at large, there will be a segmentation effect on about a 45,000- to 50,000-patient pool, where we'll look at patients who had prior REVLIMID and a refractory. That could be a newly diagnosed, or that could be through a second-line. These patients will be in the market. The homogeneity is that they had prior REVLIMID in our refractory. The next group is bortezomib refractory. They got Velcade or a vel-containing regimen, first or second, in some cases, third. A pool of patients at greatest need, as Paul pointed out, is the double-refractory group. And many of these markets we're talking about, EU 18 and U.S., at the time agents like pomalidomide would be commercially available, these are the patients who need the therapy the most, and interestingly, the response rates are not different in the rev refractory group, from the bortezomib refractory group, from the double refractory group. So this consistency of benefit is a testament to the right dose and schedule of pomalidomide but a very, very active regimen.

Now a group that is more difficult to define are these patients who had prior transplant, prior thalidomide, double refractory to bortezomib and to REVLIMID. But this is a homogeneic [ph] population that is broken out in the 02 data by our clinical team and by the investigators who were following these patients. Surprisingly, there are other regimens, DNA-damaging agents like bendamustine. In fact, some of the patients who were accrued to some of the carfilzomib trials made their way into the pom 002 study, and we have a small fraction of patients who had prior carfilzomib and are in the responder category across this paradigm. So we think the market is going to be segmented in this roughly 45,000- to 50,000-patient pool. This is another segment of the market that is growing rapidly, because salvage therapy gets better and better all the time. Pomalidomide comes in, in 1, 2, 3, or all of these categories, depending on the more mature data that we'll see tomorrow and the ongoing investigation of MM-003, our international trial. So remember, in 02, the median number of prior therapies is 5. In 03, we think it's at least that, and it's probably potentially going to be 6, even 7. This is an unmet medical need of the highest order. From a clinical, regulatory point of view, it becomes difficult to say that an agent like this that has very, very strong activity across these categories isn't something that the marketplace needs and will customize based on prior therapy, how to use pomalidomide with low-dose dex.

So in putting ASH into context, many of you have seen a version of this slide before. The reason we put it up again tonight is because Celgene and our portfolio in hematology is largely reserved for the far left of the slide, the roughly 100,000 or so patients in MDS, the roughly 300,000 patients in the world who have some degree of multiple myeloma, early- or late-stage, first or later lines of therapy. Now CLL becomes a very, very important pool. We have 3 studies that are at or ahead of their accrual target, 02, 08, 09, maintenance and elderly randomization, and then, very, very important, dose-finding study. We're excited about where we are in CLL, and that is a very, very important pool of patients.

In lymphoma, when we add that in, we're talking about a portfolio of drugs with high activity levels, very strong clinical programs that would participate in a pool of patients globally of about 1 million. Now what percentage of that we get depends on the data. Ultimately, the globe has roughly 2 million patients who need one or more of the Celgene therapies to extend and improve their lives with blood cancers. So we like where we are, we think this is an important way for us to contextualize the clinical program, the evidence that we're producing and then, ultimately, what the commercial opportunity can be.

So thank you very much for your attention. I hope this was helpful, and then what we would do now, is remind you if you can tomorrow, please visit the myeloma session in the afternoon, where Dr. Richardson, Dr. Palumbo will update the data you saw tonight. And I'd invite both Antonio and Paul to come to the stage with Jackie Fouse and Jean-Pierre for our Q&A. Thank you.

Question-and-Answer Session

Jacqualyn A. Fouse

Is my mic on? There we go. Okay. So I will be your moderator for this evening, then I'll wrap up with a few comments as soon as we're done with the panel discussion and questions. So again, if you would, go to a microphone there in the middle of the room. I'll try to direct the question to the person that we think is the best to respond. If you want to direct your question to somebody, please feel free to do that, too, and we'll try to make sure we get it to the right person.

Matt, please.

Matthew Roden - UBS Investment Bank, Research Division

Great. It's Matt Roden from UBS. I want to say thanks to doctors Palumbo and Richardson for your time tonight. Dr. Palumbo, you've mentioned in your talk that MPR-R is a new standard option for transplant in eligible patients. Assuming that you think that that's true for all transplant-ineligible patients, but do you think that the EMEA will -- do you think of this in terms of just a subset of patients where the benefit is greatest? Or do you expect them to consider that to be true in all patients who were transplant-ineligible?

Antonio Palumbo

You should ask this to the EMEA more than me. Generally speaking, I would answer this way. Certainly, the most prominent advantage is seen in patients 65-75, where you can see advantage from induction and from maintenance. In the patient over the age of 75, you see a major advantage in maintenance. You don't see a major advantage in induction. Generally speaking, from a formal point of view, the old population is showing an advantage in terms of progression-free survival. So generally speaking, you see an advantage in the old population. Then if you split in the 2 groups, you have to acknowledge that while maintenance is a major advantage in both, induction is mainly related to 65-75, which will be the answer of the EMEA. I'm not there.

Matthew Roden - UBS Investment Bank, Research Division

Okay. And then secondly, so maybe this is for Jackie. You mentioned, or actually, Bob mentioned that the intent was to file for approval in the U.S. for pomalidomide as soon as possible. Is that formally a commitment that you actually do plan to file for accelerated approval?

Jacqualyn A. Fouse

Is that a good question for me or is that a good question for Bob? We continue to be pleased with the data. As it matures, you'll see, I think, in some of the updates tomorrow that we like what's going on. That being said, the regulatory environment in the pathway on this is complex. You've seen other news out there today to show you that it's a complex environment. So our teams are very focused on trying to move this ahead as quickly as we can in a way that gives us the best chance for an ultimate successful outcome. And I think that's where we should leave that for the time being. You've seen it up on the slides, it's a key corporate objective for us, so we're forging ahead with that. I think the news in Europe that you heard tonight is quite encouraging. We're happy about that. We have been pleased with the feedback that we got from the regulators in Europe and a potential pathway there. So in that context, you will hear more from us on that.

We'll switch back and forth, so why don't we -- it's hard for me to see you guys because of the lights ...

Brian Abrahams - Wells Fargo Securities, LLC, Research Division

Brian Abrahams, Wells Fargo. Another follow-up question on pomalidomide. You alluded in your talk to the design of a Phase III U.S. study. I was wondering if you could give us a little bit more details on the design, the potential timelines, whether that's contingent on -- whether starting that is contingent on the Phase I, II being completed, and what the population you're planning to look at in that study would be.

Mark Alles

So it's Mark. So as you saw from Dr. Richardson tonight, we are envisioning and are opening aggressively a Phase I program that would look to combine pomalidomide with Velcade dexamethasone, so you saw that tonight. What's interesting is that there's one absolute, and that is the Phase III trial will have an active control arm, such as Velcade, in the control. So the exact design of the trial continues to be envisioned. It would be something that we would consider would end up as a SPA in the context of the overall development of pomalidomide. So I think it's a little early for us to commit exactly on what the program would be. But of course, pomalidomide, like all image, should be combined in a true Phase I fashion with other active agents, and Paul is leading that effort right now. So I think we will have much, much more detailed clarity on that very soon. But I think tonight, to commit exactly to the protocol, the schema, the number of product therapies, the next question would be so is it powered for survival? So we're working on this very, very hard in the context of accelerating our work to file and be able to get an approval.

Michael J. Yee - RBC Capital Markets, LLC, Research Division

Michael Yee from RBC. 2 questions. The first is on the front line newly-diagnosed indication. The 65- to 75-year-old group, is that a pre-specified analysis that you've looked at that's going to be presented tomorrow? And is it actually possible to a label carved out by said group, is that something you can -- that you're actually asking for? And the second question is if it's not an approval or a sub-group that is actually approved, what is the next step? Is that to wait for MM-002 data, is that -- what is the next step?

Antonio Palumbo

I didn't understand clearly the first question. Besides 30 or not...

Michael J. Yee - RBC Capital Markets, LLC, Research Division

The 65 to 70, is that the actual pre-specified analysis?

Antonio Palumbo

Yes, pre-specified analysis, yes, the answer is yes. It was a pre-specified analysis, yes.

Michael J. Yee - RBC Capital Markets, LLC, Research Division

And the follow-up to that is, is it possible to get a label with that?

Antonio Palumbo

I mean, you know that when you pre-specify the study, the analysis and the protocol, you can do it. That's basically the goal is to have -- to be able to select this population, because you already believe there is a benefit of that. So the answer to the question is yes.

Michael J. Yee - RBC Capital Markets, LLC, Research Division

Okay. And then if not approved, is the plan to look at MM-020 as the follow-on to submit to that? And when is the first look for that data?

Antonio Palumbo

I mean, I don't think we should comment if it is not approved. I mean, the first thing to do is basically to consider that you will be approved because of the data you've set.

Mark Alles

Quickly, because MM-020 may come up again. There's no question that the MM-020 study is part of the overall comprehensive development program to make sure that REVLIMID, either with just dexamethasone, or with melphalan prednisone or in other strategies, would be able to treat all patients who have newly diagnosed myeloma. So each of these trials stands alone as we try to describe in the algorithm to deal with the reality of myeloma, which is a more customized approach based on age, based on risk strata, all of the different things that a meeting like this is pointing out. So one size, literally, doesn't fit all, except we believe the one size should include REVLIMID, irrespective of the combinations. So it's not either/or. MM-015 should stand on its own in a population, and 20 would then have broader populations or not based on the data. So please don't look of these as one or the other. They're complementary.

Jean-Pierre Bizzari

And I would make a comment on this. This is increasing the opportunity of treatment. Because generally speaking, you have from one side, the treatment to follow by maintenance, if you want a more intense approach. On the other side, you have a tablet followed by maintenance, more gentle, less intense, with less toxicities. So you can -- you have basically 2 opportunities. You have a more intense opportunity from one side, the less intense, less toxic opportunity on the other side. That's basically should be from this point of view considered the 2 option, not competitive one with the other, but to some extent, one complimentary to the other.

Geoffrey C Meacham - JP Morgan Chase & Co, Research Division

Geoff Meacham, JPMorgan. So just to be clear, the filing for first-line myeloma in Europe, and there's been a lot of confusion on this, so is there anything in the EMEA feedback, either so far now or post-day-120 questions that makes you want to change your claims from transplant-eligible and ineligibles into just one or the other?

Antonio Palumbo

I don't know anything about it myself.

Jean-Pierre Bizzari

No, but I think the answer is clear. We answer to the question of the authorities. And basically, they ask us some question regarding the analysis and things like that. We've done that, and we're going to discuss with the regulatory authorities. So we're very, very confident that our answer to the question are legitimate and correct.

Mark Alles

I'm sorry, I didn't understand your question. Did your question ask that we would change our strategy of both ineligible and eligible to one or the other?

Geoffrey C Meacham - JP Morgan Chase & Co, Research Division

Right, instead of both.

Mark Alles

But do you understand that MPR-R data is only for the ineligible population?

Geoffrey C Meacham - JP Morgan Chase & Co, Research Division

No, I get that. I'm just trying...

Mark Alles

Okay, because I'm not sure I understand your question.

Geoffrey C Meacham - JP Morgan Chase & Co, Research Division

Trying to clear that point up -- I think that's been in the marketplace for quite a bit.

Mark Alles

Yes. But it's very clear, this is an elderly population [indiscernible] or so they're not transplant-eligible.

Geoffrey C Meacham - JP Morgan Chase & Co, Research Division

So in your view, MM-015, as it is right now, is more than justifies approval in ineligible patients?

Mark Alles

Yes, and in particular, the subset 65 to 75.

Antonio Palumbo

And we have the patients, the subsets, yes.

Antonio Palumbo

Again, I don't know anything about EMEA. I take it as it is. But you have a protocol, you have a primary endpoint. The primary endpoint is PFS, the primary endpoint has been positively reached. These are the facts on the table.

Geoffrey C Meacham - JP Morgan Chase & Co, Research Division

And the follow-up is on MM-020. And what's the risk of this study in pomalidomide, potentially, looking better than you think and what have you sort of built into that estimate? I know it's a low risk, but it's not zero.

Paul Richardson

Well, I'm sorry, just if I may, just to chime in, because I think that my perception of MM-020 is that the risk is very low, and I think RD will emerge clearly the winner. And I think the point you're making, I think, Geoff, and correct me if I'm wrong, but if you have an approval in a specific segment, how will that impact in prescribers more broadly. That's what you're driving at, I think. And I think if we see 020 being positive, if we have, of course, already Antonio's data meeting its endpoints, the message is the same. The backbone is lenalidomide, that it can be used broadly, and it will be. And the safety profile is established, and the efficacy signal is clear. And certainly speaking with the sort of U.S. hat on, I think it will just reinforce what we already have, which is very -- a substantial comfort zone and appetite for using the drug up front. But having that regulatory approval behind us will obviously be important in the U.S. and, of course, very important in Europe.

Antonio Palumbo

Yes. But I would make another comment here, the issue from your point of view is not really to see how much MPR-R or RD is induction or suitable for that kind of treatment here. The major issue is that treatment and tiered progression is becoming more and more, I would say, a standard of care. And if you comes [ph] want a couple of numbers, induction is less than one years, maintenance is now going between 2 and 3 years, so you are triplicate or quadruplicate the length of treatment. That's what is changed from your point of view.

Subita Srimal - MP Advisors

This is Subita from MP Advisors, Mehta Partners. You've been insisting that pomalidomide is more potent than REVLIMID. So will the regulatory authorities also be more vigilant on the safety profile, long-term data on the secondary malignancies?

Paul Richardson

It's good question. I think that the potency of lenalidomide versus pomalidomide is clearly observed in the laboratory setting in the context of its anti-myeloma effect. I think in the context of second malignancies, it's important to recognize that we really haven't seen any signal when lenalidomide is not used with particular genotoxic drugs. And I can speak very much with authority to this as one of the leading roles on the CLG B trial and now the new Alliance myeloma chair. From the CLG B trial, we are very confident with what we've seen. There is clearly a stop after 2 years post-transplant for this observation. We are not seeing the same that the French saw in their trial in terms of the pattern of second primaries. And the signal is very low. And I think, I want to especially acknowledge Phil McCarty [ph], my co-chair, who's done an extraordinarily good job of actually dissecting out the signal. Genotoxic therapy interacts with it. Genotoxic therapy drives the process, as best as we can tell, and DCEPT, [ph] for example, as part of the French trial, clearly, was a contributor, as was [indiscernible] exposure. And in fact, the highest risk group appeared to be those who got DCEPT [ph] and tandem transplantation. So the genotoxic therapy drives it. In terms of our plans for pomalidomide, obviously, we have not seen second primary issues with pom. And where we envisage using it, as Mark, I thought, so nicely and so clearly laid out, we don't expect second primaries to be any kind of major concern. I have to say that with emphasis, because at the end of the day, that's what I do day in, day out, is look after relapsed and refractory patients. And if I may, we'll be damn lucky if we're worrying about second primaries in that population, frankly, in 10 years' time. Our goal is to get the disease under control. And I'm quite confident that pom is a very major important step in that direction.

Antonio Palumbo

Can I make a comment on this? With the limitation that before saying the last word on second primary malignancy, we need, let's say the -- a longer follow-up, as usual, because we are now around -- we know the story up to the 3 to 4 years. But after the initial, how can I say, the newspaper advertisement on the issue, if you really, today, take everything under the right perspective, the risk of second primary malignancy is around projective, cumulative at 5% at 5 years. The risk of progressing of myeloma, that is a cancer, is 15x higher. So if then you consider the relative risk of the different tissue, melphalan and len, because len alone doesn't seem to have the same risk of melphalan, and len is doubling the risk of the second malignancy. Radiotherapy is triplicating the risk of second malignancy. Cyclophosphamide is duplicating the risk of second malignancy. Mitoxantrone is a 64x increase in the risk of second malignancy. The risk of dying for toxicity for a given chemotherapy is 5x more. So you see, of course, it's not the same, and I don't want to underestimate the issue. Of course, it's not the same and dexamethasone alone is a treatment. But the risk is really something that has been already seen and seen in many other treatment approach during cancer and is not higher than other treatment approach.

Mark Alles

Part of your question was the regulatory piece, and just want to make sure it's not different. The standard is the same for all the trials we do, all the products we are testing in myeloma, pomalidomide inclusive, so there's not a difference. We do screening, we do everything equally effectively on surveillance to measure that.

Subita Srimal - MP Advisors

No, from your point it's fine, but from the regulatory point of view, they may delay or ask for more detail.

Mark Alles

But the information as it's known is collected prospectively. It's available in real time.

Subita Srimal - MP Advisors

And just another quick question. You say you plan to file in China. What do you think about the reimbursement position over there?

Mark Alles

I think it's a very, very important question. We're studying the market quite carefully now. I think everyone in the room knows that the private market is, on a relative basis, quite healthy, and we see that as our first opportunity, with pricing from a public point of view coming after that. So we're studying it, and we feel comfortable that we understand it, but we would clearly be gating it to private, then public and keeping the timing between the 2 as close as possible.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

2 quick questions. Rachel McMinn from BofA Merrill Lynch. Just one question on Europe, whether your REVLIMID frontline application, whether you think there's going to be any specific language talking about duration in the label. And then just on the U.S., you gave kind of vague 2012 guidance for filing. Is there something specifically gating? I thought your prior guidance was that once the European Article 20 was set, that you'd be ready to file. But you didn't give specific guidance.

Jacqualyn A. Fouse

I mean just one thing on the guidance, though. I mean, I think that we've spoken a lot about that lately in terms of, again, making sure that we have the highest-quality submission that we can have. And we know that there are differences in the commercial environments in the U.S. versus Europe, so that timing issue is less important. So again, we will file when we feel like we've got the best package that we can file in the U.S. And I'll let Jean-Pierre answer the first part of your question.

Jean-Pierre Bizzari

Your question on the duration of strat b [ph], the only way we can really assess that is by doing multivariate analysis. And the issue we're facing is that the number of event we have in SPM is low. So basically, we don't have a lot of events, of a power, of a multivariate analysis, of course, it's limited. But what we've done is that when you pull the 2 III studies and when you look at the multivariate analysis, you do not see, and that was really a nice slide, you do not see any impact of the duration of therapy on SPM. So with the limitation of a small number of cases and with the limitation of the statistical analysis, we didn't see any impact of the duration of REVLIMID therapy on the occurrence of SPM.

Antonio Palumbo

Can I just add another small comment? As far as we know today, with the limitation of today, of course, actually, the risk of second malignancies seems to plateau to some extent. This is certainly true for hematologic cancer, because to some extent, it looks like that you have a predisposition to myelodysplastic syndrome. And this is something happening as an early event, and it's not a late event. In terms of solid cancer, the risk seems not really increasing. So the major concern, if you want, was related to hematologic cancer, and this seems to be an early event and not a late event. The other consideration on the length of treatment, I know, is probably not related to your interest on the thinking of the authorities. But from a scientific point of view, there is no question that the maintenance, by medical definition, is in the progression. Otherwise, it's a consolidation. And as lenalidomide is concerned, there is not really an increase in response. The efficacy is coming from the continuous treatment. And this will probably take some more time to clearly demonstrate this, but I think this is the main path for the future.

Patrick E. Flanigan III

If I may make one additional comment is that in the IFM Dana-Farber trial, with the decisions around apsacs [ph], there had been a decision to stick with the original one-year maintenance until we had more information. But I can share with you that at this meeting, the consensus of the investigators is now to extend that to 2 years, and we will engage in that process with the regulatory authorities in France as well as in the U.S. In the U.S., I will share with you, based on the strength of the CLG B data, the U.S. investigators in the majority wanted to continue until progression. But we obviously want to be symmetric with our French partners, and so 2 years was the agreed compromise. So that gives you some idea of the sort of way we, as clinicians, are thinking about this. I would strongly echo Antonio's point in that regard.

Jacqualyn A. Fouse

All right. So we've got a little bit of time left. We do kind of need to move it on, but let's take the last 2 questions, if we could, please.

Ryan Martins - Lazard Capital Markets LLC, Research Division

Ryan Martins from Lazard. Jean-Pierre, you made a comment saying you've seen some further differences in the SPM risk. Is this a certain magnitude level lower than what you've -- you had at the conclusion of Article 20, which is, I think, about a full high-risk?

Jean-Pierre Bizzari

I think what we're seeing basically is what Antonio is saying. We're saying 2 things extremely important. One is the plateau. We don't see any increase. I mean, when we have a stabilization, we are quite comfortable. This is the first point. The second point, which is in my opinion also extremely important, is that the rate in the placebo, the contour arm is increasing. Because now you know we're looking very, very actively. So if you look at all the studies, IFM, for CLG B and for MM-0015, we see an increase in the placebo. Therefore, the difference, the magnitude between the control and [indiscernible] is decreasing. And that's quite interesting for us and very encouraging, of course.

Jacqualyn A. Fouse

On Tuesday, Dr. Palumbo will give you, I think, some updated data from MM-015 on the SPM, so you might look for that. And if we could take one last question.

Sapna Srivastava - Goldman Sachs Group Inc., Research Division

Sapna Srivastava, Goldman Sachs. Just 2 quick questions. The first one is just for relapsed refractory accelerated approval. Could you help us understand, in your conversation with regulators, what do you think the bar is for the drug to show specifically for you just in pom for the drug to actually gain an accelerated approval? And the second question is on MM-020. I just wanted to understand the powering [ph] of the study, to understand how -- like, what data do you need to show for the study to get halted in 2012 or like in the first interim look?

Jean-Pierre Bizzari

So the first question is on pom. Basically, the key element is the definition of patient. So what we want, and I think Paul has been extremely clear, is patient with an unmet medical need, which mean basically patients who have the best response to a therapy, its progression and other therapies. So PD as a best response. So what you've seen, and tomorrow, you will see more, of course, at Paul presentation, is the fact that if you take the patients treated with lenalidomide, with bortezomib, with both lenalidomide and bortezomib, with both plus the transplant or any kind of therapy, what kind of activity you want. So basically, what the regulatory are really interested is the patient definition; and two, what kind of activity you have in this different group of patient definition. And of course, they don't want to see only the response rate but also the duration of response and the overall survival. So I cannot comment, because tomorrow, you will see. But you will see we're quite encouraged by the data we are presenting, because if you look at the subset of patient, once again, the definition, very strict criteria, very stringent criteria of entering to the trial. If you look at the consistency of data, if you look at the duration of response and if you look at the overall survival, I mean, it's quite impressive. So that's basically the basis for the dossier. To answer your second question on MM-020, I think you are asking what we're doing with MM-020. You know that the last patient was accrued on October 2009. Basically, this is an event-driven analysis, so we're just waiting for the number of event to happen. We've done adjudication, which means that we prepare all the background. As soon as we will reach the number of event, we will have a meeting with an independent data monitoring committee, and we'll look definitely at the primary endpoint, which is PFS, and the boundary for overall survival according to the protocol design.

Mark Alles

There's a point to make on the study. We've got this question a few weeks ago in a different setting, and I don't remember the exact context, but someone asked the question of what is the statistical plan for improvement in PFS? And at that time, I said 50%. It's actually a 25% improvement in PFS in the trial.

Sapna Srivastava - Goldman Sachs Group Inc., Research Division

And for your interim look, for it to be halted in the interim look, it will be what percentage improvement?

Mark Alles

It's event-driven.

Jean-Pierre Bizzari

It's event-driven.

Mark Alles

When the events happen, there is a planned interim.

Paul Richardson

And if I may, just one comment on the relapse and refractory population, because I think it's very, very important to understand the rigor that we applied in this trial. We required source documentation to demonstrate that they met the entry criteria we needed. We also figured out dose and schedule. There was no question that we were at the right dose in this population, and we had the right schedule. And again, to have Dr. Leleu confirming in a randomized Phase II that the 3 weeks on, 1 week off is the best approach in this population, to have that validated independently by him and the IFM, I think, is additional strength. So what I'm very hopeful for with pomalidomide and low-dose dex, we define the population for the agency, we define the dose and schedule, which I know they want and they like, and we've been very rigorous in so doing. And we have a response rate PR or better of 34%, and you're going to see more data tomorrow that tells you that these are quality responses as well. And I think that, that, to me, anyway, from the clinical standpoint, is what's so powerful about the 020 trial.

Jacqualyn A. Fouse

Great. So I think that there are 2 slides left. I'll cover them in about 30 seconds. So thank you very much for staying here tonight late, spending the time with us. I want to thank my colleagues here and the physicians who are with us tonight and for the great quality of the panel discussion. I hope that we're all happy with that. And we want to leave you with the message, too, we think that you've heard some exciting presentations tonight, some great information, some new things. We wanted to place everything in context for you, do this again on Sunday night, so that as you hear the presentations over the course next couple of days and you see updates to the data that you know how to put that into the context that we've laid out for you tonight. So hopefully, that will be helpful. In addition to being very focused on a successful ASH, we also have our teams around the world ensuring a successful finish to what's been a great year for Celgene, and as you watch us moving into 2012 and next year, some of you have seen this slide before, I'm not going to into every item on there, but we've got many, many, many things happening over the course of the next 12 months, lots of data readout, enrollments on a number of trials. There are some things that appear on this slide that don't have to do with hematology. We've got apremilast and some of the other projects there, so it's going to be an extremely exciting year yet again for Celgene, so please stay tuned. And then when we look from where we've been in 2010, being on a very strong trajectory in 2011, moving our way into the 2015 timeframe that we've highlighted for you in a high-level basis in the past and we'll talk to you more about when we come into the first of the year in the JPMorgan conference in January. But when you look out even beyond that, there's a lot of really very exciting things going on, many products in the pipeline there to sustain our growth trajectory for quite a long period of time, the fruits of some of the things that Jean-Pierre talked about in the early stage pipeline and all of our colleagues in research and development have been working so hard on. So I want to leave you with that excitement. Stay tuned, you'll get a lot of -- out of the next couple of days, I think, and then we'll look forward to seeing most of you again in the first or so week of January to set the stage for what we think is going to be a great 2012. So thanks very much for staying around tonight.

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