Roche Holding Ltd (OTCQX:RHHBY) 2018 American Society of Hematology’s 60th Annual Meeting Call December 4, 2018 2:00 PM ET
Karl Mahler - Head, Investor Relations
Sandra Horning - Chief Medical Officer and Head, Global Product Development
Nancy Valente - Vice President and Global Head, Hematology Development
Gallia Levy - Global Development, Team Lead
Tom Fuchs - Hematology Franchise Head, Global Products Strategy
Tim Anderson - Wolfe Research
Peter Welford - Jefferies
Matt Weston - Credit Suisse
Ladies and gentlemen, welcome to the Roche Analyst Audio Webcast and Conference Call from ASH 2018. I am Sherry, the Chorus Call operator. [Operator Instructions] The conference must not be recorded for publication or broadcast. At this time, it’s my pleasure to hand over to Mr. Karl Mahler, Head of Investor Relations. Please go ahead.
Yes. Thanks a lot. So good afternoon ladies and gentlemen. I would like to extend a warm welcome to everybody joining us on the Roche analyst call following the 60th Annual ASH Conference in San Diego. This year, we had over 90 submissions and 30 oral presentations and I think this is amongst the strongest ASH, if I can recall.
Today, I am with Sandra Horning, Chief Medical Officer and Head of Global Product Development who will talk about Roche hematology portfolio and the indication of the data presented at this year’s ASH. With us is also Nancy Valente, she is the Vice President and Global Head of Hematology Development. She will discuss with us new data in the Hodgkin’s lymphoma, including long-term outcomes with GAZYVA. Then we have Gallia Levy, Global Development Team Lead of HEMLIBRA. She will talk about new data in pediatric patients as well as the changing standard of care in hemophilia A. And for the Q&A we have also Tom Fuchs, he is the Hematology Franchise Head in Global Products Strategy.
So what do we offer for you today? A few highlights of VENCLEXTA. We have shared at ASH the long-term data, follow-up data from MURANO in relapsed refractory CLL with deep MRD responses, which has been maintained over a long time. Second, it’s not as easy as ASH as the CLL14. We are excited about this data. We will share it with you in due course at one of the upcoming meetings in first line CLL. And last, we did show VENCLEXTA demonstrated good response rates, which were approximately double those of historical standards of care in first-line unfit AML. I think it is fair to say that here a new backbone for AML is formed.
For polatuzumab, overall survival data are now more than 12 months. Then we also have a new platform. I dare to say that the T-cell bispecifics, we showed this year two T-cell bispecifics and they actually showed the strongest single agent activities in monotherapy in lymphoma. And both of these bispecific agents offer the potential for combinations with other therapies in earlier lines of therapy.
Before handing over to Sandra, I like to highlight that in 2018, Roche has been granted 7 priority reviews and was recently granted approval for VENCLEXTA in first line AML in patients unfit for intensive induction chemotherapy.
And with this one, I would like to hand over to Sandra. Sandra, please.
Well, hello everyone and greetings from ASH. It’s been a really exciting meeting with lots of important data. And I think it’s been particularly exciting for us as it has really demonstrated our strong presence in hematology, where we are poised to maintain leadership and that’s really based upon three primary pillars.
The first is our broad portfolio where we have 14 assets in development in multiple diseases and disease settings, a variety of mechanisms of action and therapeutic classes and that breadth of the portfolio means that we can partner broadly either with standard of care or investigational agent and that includes those agents and combinations that are unique to our portfolio, so just calling out three of these, GAZYVA plus VENCLEXTA in first line CLL, the combination of VENCLEXTA and Idasanutlin in recurrent refractory AML and even the opportunity to combine polatuzumab with our CD20/CD3 bispecific mosunetuzumab in lymphoma. As leaders, it’s also about innovation and that includes early endpoints for drug development and potentially in cooperation into treatment such as MRD, innovative development plans, whereas that afforded the patient comparison with HEMLIBRA that was very well received in the pediatric inhibitor population at this meeting. And last but not least, acceleration as we have recently seen with VENCLEXTA in combination with hypomethylating agents in low dose Ara-C in first line unfit AML.
When we look at this overview of the portfolio, I just call your attention to a few features that is that we have 8 breakthrough designations across the hematology portfolio. You can see that we have ongoing Phase 3 trials in both first line and recurrent refractory AML as well as Phase 3 studies in diffuse large B-cell lymphoma and myeloma. You also see that we have a number of Phase 1 and 2 studies with particular attention to multiple Phase 1 agents of development and again 14 assets overall.
Our intention is to build upon our leadership and experience in hematology in really two ways and you saw that a bit from Karl’s first slide. The first is redefining the standard of care. And for lymphomas that means going beyond Rituxan to Gazyva, VENCLEXTA then on to polatuzumab and our CD20/CD3 bispecifics. And the second major area is expansion and that is in two ways expanding in malignant hematology as you can see to AML, myeloma, MDF, but also importantly, in benign hematology, where we have a very strong start with HEMLIBRA.
And as you know, we were the first to introduce a biologic Rituxan, which really defines the standard of care across large cell lymphoma, molecular lymphoma and CLL. And in large cell lymphoma, we are now in the process of redefining the standard of care through antibody engineering. So, for instance, polatuzumab, our anti-CD79 antibody drug conjugate and then the bispecifics that are directing T-cell killing and T-cell immunotherapy in large cell lymphoma. Whereas in CLL, we are redefining the standard of care through antibody engineering with GAZYVA, enhancing ADCC and Type 1 cell killing and then the unique Bcl-2 inhibition mechanism of action with VENCLEXTA. And essentially, all of these were present at this ASH meeting.
We are expanding to AML a hematologic cancer with high unmet medical need. As you see here with very exciting data and the recent approval with VENCLEXTA in first line AML unfit and we are in the process of our Phase 3 study in recurrent refractory disease with our MDM2 inhibitor, Idasanutlin, also in Phase 3 in myeloma. And last but certainly not least, HEMLIBRA is a transformative new therapy for hemophilia A with two breakthrough therapy designations and approvals in the inhibitor population and in the non-inhibitor population in 2017 and 2018.
Our leadership incorporating minimal residual disease in our clinical trials and our strategy to obtain deep remissions with time limited therapies I think is really paying off. We saw lot of that at the present meeting and I think it is attracting others to this philosophy. So, what you see here in this Kaplan-Meier plots across CLL follicular lymphoma and AML are the association of minimal residual disease as a surrogate for PFS or OS, a potentially early surrogate that can direct development and move into therapy.
In CLL and follicular lymphoma, you will note that actually the majority of patients are able to achieve a detectable minimal residual disease. And in AML I think we are gaining real ground with VENCLEXTA with this important marker of deep remissions. So we’re going to pause there and take a breath and we’ll move into the key data in CLL and AML. So at this meeting, we updated the clinical data and the minimal residual disease data from the MURANO study in recurrent refractory CLL with Venclexta/Rituxan versus the standard bendamustine/Rituxan. As you know, this combination of VEN+R was approved earlier this year, and we are quite excited by the fact that minimal residual disease was actually incorporated in the label. In this study, as a reminder, MRD was measured at 212-week intervals across the first 3 years of the study and we did see a really striking difference in undetectable MRD of 62% for VEN+R versus 13% for BR at the end of chemotherapy, and this was observed across all risk categories.
And if you focus on this figure, which hopefully, we’re all getting used to seeing now, very colorful, but the way I think is easiest to look at it is to focus on the green and that is where you want to be with undetectable MRD and observe, this was achieved in the majority of patients at the end of therapy with VEN+R and then has been maintained through the standard period of follow-up. We also noticed that for those patients that converted to detectable MRD, it was at the very low rate. And this MRD was highly predictive of longer PFS across those arms. I would also like to note that these data were just published in the Journal of Clinical Oncology.
Next, if we look at Venclexta in AML, we’re really pleased that Venclexta has demonstrated high rates of complete remission, gains in survival compared with control in first-line unfit AML. These are patients that were eligible for the study, who were over the age of 60 and met other criteria and as you can see in a smaller diagram on the left that around half of AML patients are considered to be unfit. In this particular study, the median age of our patient was 75 years.
On the table, you can appreciate the CR rate and CR/CR rate that are really striking compared to the historical data with azacitidine, and particularly, achievement of MRD negativity in 48% of the patients receiving Venclexta with azacitidine sets a new bar. Also observed and certainly, the most important is the median overall survival in excess of 16 months with this combination of Venclexta with hypomethylating agents. These data were recently published in Blood. And I might just add as a corollary and I think there was a lot of buzz at this meeting for the potential of Venclexta as a true backbone in AML.
And with that, I’ll conclude this section and turn things over to Nancy Valente.
Alright. So this is Nancy Valente, and I’ll now move on to review the key data in lymphoma. So in the first slide for Gazyva, we previously presented the outcome of the GALLIUM study, which was the largest randomized Phase 3 ever conducted in first-line follicular lymphoma, which led to approval in the U.S. and EU, demonstrating that Gazyva in combination with chemotherapy provided a superior outcome for patients with follicular lymphoma.
At this year’s ASH, we now have updated data with the median of nearly 5 years of follow-up, demonstrating that the meaningful PFS benefit was maintained. The hazard ratio, you can see here, is 0.73. This is translates to a 27% reduction in disease worsening or death. Importantly, for this interpretation, the median for Avastin [ph] reached for either arm, but you can see it’s 4 years, the absolute difference in progression-free survival is higher for Gazyva at 78% versus 67% for the Rituxan containing arm.
We also presented data on time to next lymphoma treatment, which is very important for the patients with follicular lymphoma because they often progress and they don’t need treatment for extended period of time. This has also improved at a landmark of 4 years with fewer patients requiring new therapy in the Gazyva arm, 76% as compared to 84% in the Rituxan arm. There was also an evaluation of minimal residual disease, which Sandra previously showed you the Kaplan-Meier Curve 4, demonstrating a deeper response at the end of treatment and maintenance – at the end of treatment and the end of maintenance that was prognostic for longer-term outcomes. And the OS data remains immature with over 90% survival in both arms.
For polatuzumab, this is a novel antibody drug conjugate that allows targeted delivery of chemotherapy to the lymphoma cell. Data from our randomized Phase 2 study in relapsed/refractory disease CAR T-cell evaluating the addition of polatuzumab to the standard of care led to FDA Breakthrough Designation and EU PRIME. These patients have very limited treatment options and poor outcomes.
At this year’s ASH, we presented updated data now with nearly 2 years of meeting and follow-up. The data show a dramatic improvement in – for efficacy, all the efficacy endpoints including complete response, progression-free survival and OS.
For PFS, the pola containing arm has 11.1 months of median PFS compared to the control arm of 3.7 months. With the PFS hazard ratio of 0.36 translating to an 84% reduction in the risk of disease worsening or death. What is really striking is the overall survival benefit with a median that is over 1 year at 12.4 months compared to the control arm of 4.7 months, which is more than a doubling in overall survival benefit.
The hazard ratio you can see is 0.42. This was the first randomized study to demonstrate an overall survival advantage in this high-unmet medical need population. The randomized Phase 3 study called POLARIX in first-line diffuse large B-cell is ongoing and we look forward to providing further update.
I’m now going to review the first data that’s been presented for our 2 bispecific T-cell engaging antibodies. We are very fortunate to have both of these in development as they represent unique approaches to the treatment of lymphoma. We believe bispecific – the approach with bispecific antibodies is a paradigm shift for all of the hematologic malignancies and even more broadly for solid tumors. These bispecific antibodies bind the most – the CD20 on the B-cell and the CD3 on the T-cell, bringing them together, which leads to T-cell activation and release of the cytotoxic granules, which kill the B-cell. This will only occur in the proximity of the CD20 expressing B-cells.
I’ll begin with the data on mosunetuzumab, and you can see the efficacy data for single agent most of – verse the single agent in the Phase 1 dose escalation study for patients with relapsed or refractory lymphoma. You can see the overall response rate in both types of lymphoma is promising for Phase 1 dose escalation study and it’s higher in the follicular lymphoma cohort with nearly 70% of patients having a response and a CR rate of 38.5%.
Importantly, complete responses have also been seen in patients refractory to both CHOP and CAR T-cell therapy. The graph depicts both the depth of response and duration with each line representing a patient. And what you can see is that complete responses are durable with patients remaining in CR of 2 years and 3 years and even beyond, which is really impressive for multiply relapsed patients, also impressive for Phase 1 dose escalation data. Combinations with chemotherapy, polatuzumab and Tecentriq are ongoing and we’re already seeing that based on the safety of these therapies that these combinations can be given safely.
Our second T-cell engaging antibody has a different and unique format called the 2:1 and has 2 CD20 binding sites and 1 CD3. You can see the single agent Phase 1 dose escalation data in this waterfall plot demonstrating clear responses across the dosing levels and different types of lymphoma. The data in the box are representative of the patients with aggressive lymphoma and diffuse large B-cell with an overall response rate of 54% and a CR rate of 27% for patients treated at the 10-milligram level or above.
We also see complete responses for patients refractory to R-CHOP and no patients with the CR have relapsed. Dose escalation continues and combination studies with R-CHOP and Tecentriq are ongoing. For both antibodies, the safety profile appears tolerable, most of the adverse events are mild and transient and reversible. Importantly, in contrast to the CAR T cell therapies, these are off the shelf treatment and would be available for patients when they need their treatment. We are excited about the opportunities these therapies offer patients.
Okay. I am Gallia Levy, I am the Global Development Leader for Hemlibra and I am here to present the exciting Hemlibra data that we had, that we presented at ASH this year. On this slide, you can see on the left, the Hemlibra development plan that had four trials that are now all completed. The first, our HAVEN1 study was in patients with inhibitors and was the subject of that approval. HAVEN2 is in pediatric patients with inhibitors and those are the data I will show. Our HAVEN3 and 4 studies were in non-inhibitor patients. HAVEN4 had a few inhibitor patients as well. Those will fit also a q2 week dosing and q4 week dosing. And those two studies were the basis for the breakthrough therapy designation and also for the recent FDA approval in the non-inhibitor population. So the Hemlibra is now in the U.S. approved in both inhibitor and non-inhibitor patients of all ages with weekly, every other week and every four week dosing.
For HAVEN2, we presented the primary analysis data. We had previously presented interim data. HAVEN2 is the largest pediatric inhibitor study ever conducted with 88 pediatric inhibitor patients, including 18 under the age of 2 years and we presented the updated data with a median of 68 weeks of follow-up, data for both the weekly dosing, but also data in 10 patients each for the every other week and every 4-week dosing. What you see on the slide is the intra-individual comparison and we continue to feel that these intra-individual comparisons are incredibly powerful ways to look at the efficacy of agents, especially in hemophilia where the disease does not progress. It’s very useful to be able to look at one patient and see how they improve rather than comparing them to a group of patients who may have different features, clinical features. So what you see is 18 patients where we had data from our non-interventional studies in people who –children who then proceeded to enroll in the HAVEN2 study.
The majority had previously been on prophylactic bypass agents. There were a few who had been on prior episodic bypass agents. In the blue bars, what you see are the ABRs for the individual patients on the non-interventional study, so their prior ABRs on their bypass agent therapy either prophylactic or episodic. And then in the yellow, what you can barely see is the bleed rates when these patients were receiving emicizumab. So there were a few on the left that has little tiny yellow bars. But for the most part there are no yellow bars because most of the patients did not experience any treated bleeding while on study. So they were within 99% reduced risk of treated bleeding in this cohort with an ABR of 0.2 versus approximately 20 on the prior therapy.
One thing that we did not show in the presentation, but we thought – we think is very compelling and that I wanted to tell you about today is that we had 44 patients who have started the study with central venous access devices that they needed for their treatment for their bypass therapy given the frequency of administration, especially for prophylaxis bypass treatment. And 31% to 70% of those patients have now had those central venous access devices removed while on study. And that’s really remarkable for these patients and is really a huge change in quality of life and really sort of – and really represents the confidence that they have in their new therapy and that they are not going to be needing to access central venous devices anymore. From a safety perspective, Hemlibra was very well tolerated. There were no TMA, TE or fatality events reported. And so overall, we have now shown clinically meaningful prevention or reduction of bleeds for patients of all ages with weekly, every other week and every 4 week regimen.
The other data that we show – that we find very compelling were the preference data for the HAVEN3 and HAVEN4 studies and what we did here is a very simple questionnaire that we ask the patients on week 17, so we picked week 17 because we felt that is close enough to their prior treatments that they are able to remember their prior treatment well. It’s also enough time on liver treatments to have a really good sense of how they feel about it. And you can see it’s just – it’s a very simple question, easy to interpret, which of the treatments would you prefer to take as the treatment for hemophilia. And they could choose, they either prefer their old treatment, IV, prefer their emicizumab treatment sub-cu or have no preference. And when you combine the HAVEN3 and HAVEN4 data, 99% of patients who were previously on prior prophylaxis preferred their Hemlibra treatment and 92% of patients who were previously in episodic treatments preferred their Hemlibra treatment. And for those that chose preference, we had a list of possible reasons for them to choose from. And the most frequent reasons that were given from the preference over Hemlibra – preference of Hemlibra were the frequency of treatment was lower and also the route of administration was easier.
Also of note, all participants in both studies have chosen to continue Hemlibra beyond the primary analysis, so all of these people remain on study and this really therefore corroborates the preference for Hemlibra. And interestingly, even though who have chosen that they prefer their old treatment are still receiving Hemlibra despite the fact that the primary analysis is over and they have the choices to move back to their prior treatment if they would like to. So overall, we find this to be very compelling. It’s a very simple question that patients can understand and very simple answer is that we can understand and physicians can understand. And it’s – it really shows a strong preference for Hemlibra and we feel that this really has the potential to translate into improved adherence to prophylaxis and/or increased adoption of prophylaxis.
Yes. Thanks a lot, Gallia and Sandra and Nancy. So we have the – just to summarize and we have to enhance an extremely interesting ASH this year, very exciting data with potential new standard of care in AML, potential new standard of care in CLL, a new platform potentially for the T cell specifics with the highest single agent activities of the [indiscernible] lymphoma. And with this one I would like to open the Q&A. You will have the opportunity to ask questions via the web, but also via the telephone line. If you ask questions via the web then I will read it to the – to our people. If you of course from the telephone line, you can directly open the line then. Operator, if you could kindly open the Q&A.
[Operator Instructions] The first question from the phone is from Tim Anderson, Wolfe Research. Please go ahead.
Thanks. A few questions on T cell bispecifics, which of that to me, on something like Slide 21 is how patients with DLBCL for example, in that slide can get very divergent responses and good proportion have very fast progression, almost as if they received no drug, other patients have a very deep and complete response. So to me it kind of begs [ph] the question whether there could be a biomarker to identify who might respond to these types of therapies, also if you can talk about where you are with possibly looking at predictive biomarkers that will be helpful. And then the second question, you have two programs that are in the CD20 and CD3 space, can you just talk about the differences between those two products mechanistically, how are they different. And then last question, realistic timeline for first approval, accelerated approval or otherwise, for one of these programs?
Yes. Thanks a lot. I will give it over to Nancy and Sandra.
So I will start with your first question or maybe I will start overall. So we are excited to have the opportunity to have these two unique approaches to the treatment of lymphoma and we feel this is a real paradigm shift and is going to change how patients are treated. And because of the safety we are seeing, we see the ability to combine these and move them into earlier lines of therapy. We are – right now, it doesn’t look – we are looking at predictive biomarkers and we do get serial biopsies and we think it’s really important and we want to be able to in the future direct this therapy. We would love to – as we work for any therapy to patients who we think are going to respond. In regard to the two products, they have – as I mentioned they have different formats. So that’s the big difference. One of them is a one to one format with one CD20 binding arm and one CD3. And the other one is a two to one format with two CD20s and one CD3. And as we develop data with these products, we will probably be able to tell more about how the differences in the format of the antibody translates into the efficacy and safety for the patients. Your third question was relating to when we see the first approval. And right now, we really are again very excited. We think this is some of the strongest data that we see for any bispecific. And when we look at the spaghetti plot for the mosunetuzumab in particular, which has longer follow-ups, these kind of durable CRs are really not seen going out 2 years, 3 years, 4 years, typically in phase data for patients who would had a CR. And we see based on that efficacy and the Phase 3 that this really has transformational potential that would lead us to pivotal studies. I can’t give you the exact time of that, but we definitely see the opportunity to go there. Did you want to add, Sandy?
No, I think you have said it well. I think that one of the things to consider of course when you are doing Phase 1 testing that you do tend to get a very heterogeneous patient population with a great deal of heterogeneity in their underlying clinical features. And I think some of the same things have been observed in the development of CAR-T that responses or a lack of response has gone back to correlate with things like LDH, which are major elements of tumor burden and the aggressive nature of particularly DLBCL.
Yes. So there is a question via the web, Gallia maybe to you, if you could kindly update us on the safety – on the long-term safety if there was any new cases of TMAs and so on we had seen or what happened actually, if you could kindly update us on this one?
Yes. Sure. So as you know, we are very closely monitoring the safety of Hemlibra and we have a very strong commitment to the hemophilia community to be – bring them, apprise of that safety. And one of the things that we have done is that we have a website now in the U.S. for our physicians and one for patients. And I believe we are the first company to ever do something like this where we update quarterly the safety of Hemlibra with key adverse events such as TMA and thrombotic events as well as such 0344 death. So if you go in our website, you can find the most updated information. Globally, that information is available not through websites, but through the local – the Roche affiliates, so everybody has the same information available. There was one recent new event of TMA that was reported and it is on the website that was from the marketing setting. Similar to the other events of TMA, that is not patient, there had been use of APTC at more than 100 units per kilo per day for more than 24 hours, so very consistent with all of the other cases. But the updated data is available for physicians on the website in the U.S. and updated quarterly.
Yes. Thank you. Yes. There is one more question on polatuzumab, the coexistence of the CD20 bispecific polatuzumab, how do you see the treatment paradigm evolving in the future?
So Karl, the question is how do we see the treatment paradigm evolving with polatuzumab and the bispecific?
Yes. Polatuzumab and the bispecifics how they [indiscernible] this is my understanding of the question, yes?
So both of our bispecifics and polatuzumab based on the promising efficacy and safety that we have seen so far, really give us a lot of opportunities to transform the way patients are treated with lymphoma. So that allows us to not only – not only polatuzumab to become a clear backbone for patients with relapse refractory diffuse large B cell and to combine that with the bispecifics, but also to move this up into earlier lines of therapy. In follicular lymphoma, in particular we and the community are very interested in moving into combinations of therapy that are chemo-free or with reduced chemotherapy or with a therapy such as polatuzumab, the targeted chemotherapy. In the diffuse large B cell, we have got a backbone that was established decades ago that has a survival benefit for patients. And there we still see an opportunity in the future to combine with that backbone or even – and people are talking about across the oncology community, de-escalate multi-agent regimen in the future.
Okay. Thanks a lot.
I will just add to that is that our strategy for some period of time has been to think about CD20 as the backbone and then that we could have a chemotherapy or we could have a new biologic agent. So when we think about the combination of polatuzumab with Rituxan, that sort of CD20 and the new way of giving chemotherapy as Nancy said. When we think about polatuzumab and mosunetuzumab, then it is the combination of the novel way of giving chemotherapy and now the new biologics, which is depending on T cell that’s directed to the tumor site by the CD20. So I think it’s really an evolution of the strategy that we have had for some period of time. And we are just really fortunate to be able to incorporate the new agents across our broad portfolio to do that.
Yes. Thank you. Operator?
The next question from the phone is from Peter Welford, Jefferies. Please go ahead.
Hi. Thanks. A couple of questions, firstly just on the CD20 bispecific, I wonder if you could comment on the difference you are seeing in the CRS rates between the two approaches and also with regard to the TCB, what potential rationale could be to some of the neurotoxicity that I think was reported there, whether or not there could be some dosing strategies that could be used to mitigate some of these. And then just going on Hemlibra quickly, just wondering with Hemlibra whether or not there has been any occurrences after the sort of initial few doses of anti-drug – antibodies are still detected or whether or not these are sort of very rare cases just on the initiation and very much confined to the few patients that were generally I think not – they are not sort of pediatric type patient population? Thank you.
Okay. Well, I will start with the questions about the T cell engaging bispecifics, so what we have seen, I think your first question was about cytokine release syndrome and we have seen comparable rates of cytokine release syndrome across the two products. Most of the cytokine releases were grade 1 and 2. And this is as compared to other T cell engaging therapies like CAR-T is much lower, so it’s one of the features that were really – we think is an important advantage. The second question was about the neurotoxicity and again they are fairly similar miles and most of the events or the most common events are headache and dizziness. So again we think both for the CRS and the neurotoxicity, it’s at a lower frequency, it’s manageable and we have been able to treat the patients through this without many discontinuations or more serious complications.
Yes. I think when you look at neurotoxicity, there are potentially many things that can go into this and really it was very minimal neurotoxicity. You can kind of count it on one hand. And what – for instance, one of the three events was post-herpetic neuralgia, which is really related to the status of the immune system and is not neurotoxicity as perhaps you would think about it for CRES or for the CAR-T so, we’re really quite encouraged by the minimal amount of neurotoxicity seen with our bispecifics.
So, for the HEMLIBRA question about the anti-drug antibodies we have presented data where we used an optimized assay to retest all of the samples from HAVEN 1 through HAVEN 4 and what we found there was 3.5% overall anti-drug antibody rate and less than 1% or it was 0.75% rate of antibodies that we deem to have neutralizing potential and we called those there is not a neutralizing antibody assay so we called those based on looking at the pharmacokinetic profiles along with the detection of anti-drug antibodies the question was about the timing so in the one patient that we had reported previously from HAVEN 2, there was that one occurred very, very early and I think it was week 5 that it was Rituxan and what we showed in the presentation was another illustrative example where, in that case, it had occurred in it was okay, I have to go back and look at exactly when it was, but it was at approximately it was at week 33 for that patient so a little bit later. But they were all between that was the other neutralizing antibody all of the ADAs were between week 5 and 33, with about half of them prior to week 14 so I think the numbers are still very, very small to draw conclusions and we, obviously, continue to monitor this I think there was another part of the question about whether this is related to the pediatric population or not we don’t believe so when we looked across all of the 4 studies, the rate of ADAs seemed to be the same across approximately the same across the 4 studies so generally, numbers are small, but there doesn’t seem to be a predisposition in pediatrics with the data that we have now.
Thank you there is one more question on the update of HEMLIBRA in the number of patients recently approved if anybody could give us an update on the first feedback from the market.
Yes sure, Karl this is Tom so it’s too soon to say sort of where we are in terms of adoption in the non-hetero setting, but I think the early feedback has been really positive and we’re certainly encouraged by the potential here so too soon to say, but we think things are off to a really good start.
Okay thank you. Operator, are there more questions on the line?
We have a follow-up question from Tim Anderson, Wolfe Research.
Thank you. I was hoping to come back to that question on approval timeline for CD20/CD3 just mosunetuzumab, it’s technically a Phase 1 study, but it is, I think, around 600 patients and I know those are ranging, part of it so there’s multiple arms but it does beg the question whether you could possibly have enough data for an accelerated approval, so is that realistic? Or do you think with either of these programs that you really will need to run additional trials to even get accelerated approval? And then second question is not something you really talk about today, but it is mentioned a little bit on your slide in the multiple myeloma space, it’s a segment in hemonc where Roche doesn’t have historically much of a presence you have various initiatives ongoing, VENCLEXTA, for example, is in Phase 3 for that segment, and you have some other early-stage assets so can you kind of update us where you are with multiple myeloma? With VENCLEXTA, for example, I’m not familiar with what the data says about the potential that BCL-2s might work in a setting like this the high-risk program, that’s something you’re very excited about, what sort of color you can you give us?
Okay so this is Nancy I’ll begin to answer this the total number of patients we shared in this presentation from mosunetuzumab was, I believe, 131 we are we have a larger program beyond this beyond that, where the data is earlier but for the data we presented, this is the single agent data that you’ve seen in different types of relapse or refractory lymphoma the data we mentioned that where we haven’t reached the maximum tolerability for either of those and we’d like to reach that and have the opportunity to optimize the therapy alone and in combination with other molecules in our portfolio I can’t predict now when we’re going to have a pivotal trial I do think the data, as we gather the data, it looks fairly impressive and enhanced transformational potential, and so we would be evaluating what are the opportunities we have with this regarding VENCLEXTA in multiple myeloma, we do have it’s part of the broader program with VENCLEXTA we are really excited that VENCLEXTA has the activity in all these different types to hem malignancies I mean, there’s very few products that, at least I’ve seen, that go across as B-cell malignancies, the myeloid malignancies in multiple myeloma so we do have a randomized Phase 3 ongoing called BELLINI in second line multiple myeloma we hope to see data from that next year we have trials in further lines of therapy for both T11 14 patients and all patients in combinations with commonly used agents and yes, we’re excited about the potential that and believe multiple believe VENCLEXTA has a role in multiple myeloma as well as a role we’ve seen already in CLL and AML.
Tim, there was a data that was presented at ASH for VENCLEXTA in myeloma I think, some promising signals and there’s been a continuous signal in the T11 14 suspects in particular and as you may know, that’s translocation that’s actually shared broadly across myeloma and lymphoma and then with the Phase 3 study that Nancy mentioned, the BELLINI study, is one that’s really based upon understanding mechanisms of resistance that might occur with VENCLEXTA in myeloma and so a rationale combination that has started in earlier stage where we saw a positive signal and then built that out into the current randomized Phase 3 trial so I would say that if we’re looking at myeloma, our first foray in, certainly, in Phase 3 is with BELLINI, but we’re actually seeing some tantalizing signals that might allow some further and additional development in myeloma.
Thank you there’s a question via the web from Steve Scala from Cowen he asks about HEMLIBRA data versus BIOVERATIV 001 data presented at ASH Gallia, I think this is one for you and I guess one for me could you forbid [indiscernible] first line in 450? Yes, I mean, we do expect an approval by the PDUFA date I have to say, I’m not sure how the current situation of [indiscernible] is doing because of these unfortunate situation with former President Bush, so that could basically slip by 1 day, but we have no negative indications on the approval of the 450 it could be either today or day after tomorrow let’s put it this way good then maybe Gallia, one question for you on the comparison of the HEMLIBRA data with Bioverativ?
Sure yes, absolutely it was really exciting ASH for hemophilia and there continues to be some really great innovation and we love to see that I’m really happy to see that people haven’t stopped trying to innovate in hemophilia the data for the BIVV molecule were presented and they are early data and no, I’m not going to comment specifically on the data because, now, we have the unmet need is now really for patients and we have HEMLIBRA now for them with the potential for an every 4 weeks subcutaneous regimen, and we’re really starting to hear the stories of how that’s transforming people’s lives I mean, I’ll tell a story of a non-inhibitor patient, a 15-year-old boy who have had more than 1,500 infusions in his life and have not been able to play sports as a kid because he tried with helmets and pads and he couldn’t because he was bleeding so much and that boy has now been 1.5 years in HEMLIBRA and he’s playing varsity lacrosse and his mother is talking about how she had not realized how much stress she was under because of his disease so those are the sorts of things we’re hearing from the community on HEMLIBRA, and that’s where we are today.
Absolutely thanks a lot I hope we couldn’t answer your questions, Steve so all confidence on this 450 and the questions on BIOVERATIV next question, please.
[Operator Instructions] The next question is from Matt Weston, Credit Suisse. Please go ahead.
Thank you very much. Just one question left on my side. So the whole innovation or non-innovation presented in ASH, I’m very interested in the commercial update and the penetration of GAZYVA in indolent NHL, please?
I didn’t completely get that question.
I think a question from Matthew was the current penetration of GAZYVA in indolent non-Hodgkin’s lymphoma and what how we see the future I translated enough for you because the line was very bad, Matthew, and I’ll try my best now but I guess this was your question.
Karl, thank you. Yes, so the launch for GALLIUM in first-line follicular is ongoing across worldwide and we think the data here that were presented will sort of help build upon the overall story for the benefit of GAZYVA in first line so the uptake is ongoing we one of the things I think to keep in mind is this is an indolent disease and we don’t patients are treated for 2 years, so we don’t think it will be we’re not seeing patients having switched from rituximab to GAZYVA so the launch is ongoing we are still very optimistic about the use of this product in the setting the data are really strong as we’ve shown at the conference today.
Yes, thank you for the question, Matthew last one from my side here what I can see is any possibility to compare the CD that’s so bispecific which have been presented this year at ASH I guess there was only one from another company and our so if you could kindly frame a bit the opportunities or the if you have other different approaches then?
Okay this is Nancy, and I’ll start so our bi-specifics compared to other bi-specifics, we...
Nancy, the question was [indiscernible].
Maybe I can talk about lymphoma and then Sandra can talk about this in a broader way but we actually think we may have an advantage in our bispecific approach as we compare the data to what we’ve seen at ASH there could be advantages and exposure in dosing and things like that, and we’re very excited in particular about our opportunity to advance our bi-specifics into combinations with other therapies within our portfolio because we have a very unique advantage with such a broad portfolio and this allows for internal combination and the safety of our bi-specifics also allows us to go earlier I think when you look at this across all the different therapies, there’s a lot of different approaches I think we have some of the earliest bi-specifics and with the longest follow-ups so I clearly I see our us as leaders in this area and based on our portfolio, things we have in earlier in Phase 1 and even in research, I think, we’ll continue to be a clear leader for many years to come. Sandy?
I think you said it well we recognize this is an interesting, exciting and competitive area however, we are also really excited about our advantages, which we think are the ability to achieve good exposure with good safety, and then with our broad portfolio to combine as well as to potentially move in to earlier lines of therapy.
Thanks a lot. I don’t have any more questions here. Operator, do you have any more questions on the telephone line?
There are no more questions from the phone.
Okay. So I want to thank Sandra, Nancy, Gallia and Tom for the comprehensive thoughts and making this [indiscernible] for having these events for us together with our IR department and I wish all of you a nice day or a nice evening and thanks for your interest in Roche. All the best. Thank you.
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