bluebird bio Inc (BLUE) 2018 Q3 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the bluebird bio Third Quarter Update Conference Call. (Operator Instructions) As a reminder, this conference call may be recorded.

I would now like to introduce your host for today's conference, Ms. Elizabeth Pingpank. Ma'am, you may begin.

Thank you, operator, and good morning, everyone. Today, we will be discussing our development plans for LentiGlobin in sickle disease, in addition to touching on the ASH abstracts that were announced yesterday and some quarterly highlights. We issued 2 press releases yesterday covering these topics, which can be found on the Investor Relations section of our website.

Before we begin, let me review our safe harbor statement. Today's discussion contains statements that are forward-looking under the Private Securities Litigation Reform Act of 1995. Such statements are based on current expectations and assumptions that are subject to risks and uncertainties and involve a number of risk factors that could cause actual results to differ materially from projected results.

In particular, statements that include but are not limited to the risks that any one or more of our product candidates will not be successfully developed, approved or commercialized. Additional information concerning these risk factors is contained in our filings with the SEC, which are available on the Investor Relations section of our website, www.bluebirdbio.com.

While we may elect to update forward-looking statements in the future, we specifically disclaim any obligation to do so even if our expectations change except as required by law. You should not rely on these forward-looking statements as representing our expectations as of any date subsequent to today.

With that, I'll turn it over to Nick.

Thank you, Liz, and thank you, everyone, for joining us this morning. As you know, we do not normally do quarterly calls but thought it made sense this time around given the depth of new recent news flow across the sickle cell disease development plan, ASH abstract and our 10-Q.

Before we dive in, I want to reground us in the why as we always do. It never gets old, and this is important for the long-term success of bluebird. It is also quite honestly critical to the broader industry to remember our shared why and must be the centering force when we make decisions in the face of many complicated pressures across stakeholders.

I just returned from Asia and had a visit -- had a chance to visit several hospitals that are working tirelessly to treat patients with cancer and/or thalassemia. The need is intense and, in many ways, overwhelming. The excitement for what we do and the promise that we could bring was inspiring.

The magnitude of the challenge to get to patients globally is significant, but we must not be -- we must not let that deter us if we believe in the why of what we do and the very human importance of helping to bring hope to children and family in desperate need. I firmly believe that team blue is up to the task, and we'll do everything in our shared powers to succeed on our true blue aspirations for patients.

What is particularly inspiring is that hope is rapidly becoming reality. We recently announced that we submitted our TDT filing for approval in EU, and CALD and multiple myeloma are not far behind.

On the sickle cell disease front, we are excited to share with you on the call some important progress we've made to define our development path in collaboration with the regulators that will hopefully accelerate our ability to bring our product candidate to patients with sickle cell disease and families in desperate need.

Lastly, one of the most important and perhaps least appreciated differentiators emerging for bluebird is not tied to any one of the products but the broad establishment and validation of our end-to-end capability and product engine being built for the future. This can only be shown through day in, day out execution and delivering on what we promised. The depth and breadth of the ASH abstracts as well as the update on sickle cell are 2 more good examples. I also refer to this inside blue as building a team therapy company that has a soul.

Shifting gears to the news of today. Here, you see a list of some of the key recent accomplishments. First and foremost is, of course, the completion of our first filing ever as a company for TDT. It is a huge milestone, and the team delivered on the exact target date we set many months ago. Amazing. The other theme is our regulatory progress on not only thal but also CALD and now sickle cell disease. The details are certainly important, but these accomplishments also further validate the constructive 2-way relationship we have built with the regulatory authorities. They have been terrifically engaged and reasonable in their requests and guidances.

We've also been busy building for the future with our partner Celgene on BCMA getting 2121 into earlier live studies and also establishing high-potential relationships with both Regeneron and Gritstone. It is safe to say our oncology franchise is very active and aiming to build a powerful product pipeline for the future. More to come on this as we get into 2019.

Before we get into sickle, let's briefly shift gears to ASH, where we have our biggest and broadest ever showing.

Coming off a busy and productive third quarter, I'm excited to share that we have 10 presentations at ASH this year, 7 of which will be oral presentations. The abstracts you saw yesterday were largely placeholders, including those for our studies of LentiGlobin in beta-thal and sickle cell disease. In beta-thal, we'll show longer follow-up for our original Northstar Study, which was completed this year and served as a basis for EMA filing. We'll also update on Northstar-2, which is our Phase III study in patients with beta-thal and non-beta-0/beta-0 genotypes.

We'll also have a first look at the data from Northstar-3 in patients with beta-0/beta-0 genotype. This will be the first time we share the impact of the refined manufacturing process on these patients who produce very little to no endogenous hemoglobin. It's early days but an important part of the development plan for beta-thal.

In sickle cell disease, we have 2 separate updates on data from our ongoing HGB-206 study, one presentation of longer follow-up from the first 2 patient cohorts, A and B, and a second presentation of updated data from the patients in Group C. Again, longer follow-up from what we saw at EHA and any additional patients we have treated since then.

We will also present some new data for 2 clinical programs. The first of which is bb21217, our next-generation anti-BCMA CAR T in patients with relapsed/refractory multiple myeloma. The data is evolving as expected, but it's still early.

We'll also have a first look at data from our program targeting BCL11A, using a short hairpin microRNA. This program is currently being run by our friends and neighbors at the Boston Children's Hospital, and we look forward to seeing where this goes as the data continue to emerge.

Last but not least, with Philip, we'll look at some early signs that we think is pretty powerful. And coupling that with our recent collaborations with Regeneron and Gritstone as well as existing partners Medigene and TC Bio, you start to get a sense of where research -- our research engine is focusing.

I want to stress, and I'm sure Philip will as well, that this is still quite early, but it's an example of how we're thinking about new ways to pair the right tools with the right targets to impact disease.

Before I close, I want to take a moment to acknowledge the team at bluebird and the study investigators that have worked incredibly hard to bring these studies forward, whether late stage, early or preclinical to this stage. Great work all around.

Now I'll turn it over to Philip. Philip?

Thanks, Nick.

As you know, bb21217 is our next-generation BCMA-targeted CAR T cell product, which employs the same CAR construct as bb2121, but an improved manufacturing process that results in an enrichment of so-called memory T cells, a long-lasting subset of T cells. bb21217 is therefore expected to provide increased functional persistence of the CAR T cells that may result in more durable responses and, ultimately, longer progression-free survival.

In preclinical studies, bb21217 demonstrated improved persistence and antitumor activity, including the ability to eliminate disease in a stringent tumor rechallenge model. The abstract published yesterday reports on 8 patients treated at the first dose level of 150 million CAR T positive cells, with 7 of these evaluable for response.

Safety and tolerability for the bb21217 drug product appears comparable with the known toxicities of CAR T cell therapies. Specifically, 5 of the 8 patients developed CRS, and 1 patient with high tumor burden developed Grade 3 CRS and Grade 4 encephalopathy, with signs of posterior reversible encephalopathy syndrome on MRI. The patient received tocilizumab, corticosteroids and cyclophosphamide, improved neurologically and achieved a stringent complete response.

Following this event, the escalation cohort was divided into 2 groups based on tumor burden, and dosing continued at the 150 million CAR positive T cell dose.

In terms of efficacy, 6 of 7 patients have had an objective response, including 1 stringent complete response, 3 very good partial responses and 2 partial responses. 3 of 3 evaluable patients were MRD-negative, and 2 of 2 patients have detectable CAR positive T cells at 6 months post infusion. These data were encouraging and suggest that bb21217 is at least as active as bb2121, with early data on T cell persistence supportive of the proposed rationale for bb21217.

At ASH, we look forward to providing updated data on these patients, add on additional patients enrolled in the trial.

Now changing gears to sickle cell disease. I'm pleased to report the first clinical data from our program in collaboration with Dr. David Williams of Boston Children's Hospital, using a novel lentiviral vector mediated approach to the knockdown of BCL11A in patients with sickle cell disease. The goal of this program is to "flip the switch" from the use of HbS, the sickle form of beta-globin, to HbF, the fetal form, which is both unmutated in patients with sickle cell disease and has anti-sickling properties.

BCL11A is responsible for the repression of HbF, and we and others have shown that by reducing the levels of BCL11A, we can restore HbF expression. Importantly, as this is a true switch, turning back on fetal globin expression results in, in the switch off of HbS.

BCL11A is, however, an important transcription factor, with roles beyond the regulation of the globin genes. And thus, it is critically important to reduce BCL11A levels exclusively in the erythroid compartment, a feature we can achieve by the use of the exquisitely erythroid-specific mini LCR promoter system currently used in our Lenti-G vector.

Moreover, as the BCL11A targeted shRNA embedded microRNA, or shmiR for short, operates at the mRNA level, we expect to have a more complete reduction of BCL11A than editing approaches, which target a transcriptional enhancer sequence at the DNA level. The abstract reports data from the first patient dose with hematopoietic stem cells transduced with our lentiviral vector encoding the BCL11A targeted shmiR. Overall, the transplant was well tolerated, with a safety profile consistent with myeloablative conditioning.

As of day 76, the subject have sustained hemoglobin levels of greater than 10 grams per deciliter, consistent with the anticipated outcome for BCL11A knockdown. By day 76, we observed approximately 30% of all beta-like globin chains are now HbF.

Moreover, this marked increase in HbF resulted in 60% so-called F cells, i.e. red blood cells positive for HbF. Compared to baseline, there was absence of irreversibly sickle cells on peripheral blood smears and reduced reticular sites -- counts consistent with reduced hemolysis. This early data provide the first proof of principle for LVV-based shmiR knockdown in humans as well as proof of mechanism for the repression of BCL11A and its impact on globin gene expression.

Last but not least, we wanted to highlight a preclinical abstract from our cancer immunotherapy program, which employs our gene editing platform, known as megaTAL. Specifically, we have been working with our megaTAL technology to develop editing the T cell genome to improve the function of our T cells across both solid and liquid tumor settings.

Here, we report the megaTAL-driven knockout of a gene called sickle B, an internal checkpoint, if you will. I think PD-1 for the cells inner workings which suppresses the degree of T cell activation possible when a T cell sees its target. We show that knockout is very efficient with the megaTAL technology, routinely able to produce greater than 90% sickle B disruption. This efficient gene disruption results in markedly increased cytokine levels when the edited CAR T cells are exposed to tumor in vitro.

Moreover, in a solid tumor preclinical mouse model in which the unmodified CAR T cells failed to control genome, the sickle B edited CAR T cells resulted complete tumor elimination. This data highlight one of the tools we've been working on capable of boosting the activity of CAR T cells, and we look forward to sharing this data in its entirety at ASH as well as the clinical application of this and other enhancement technologies bluebird has as these make their way towards an IND.

With that review of the new program abstracts, I'll hand you over to Dave for an update on our sickle cell disease development strategy. Dave?

Thanks, Philip.

Despite recent progress, patients with sickle cell disease have few effective therapeutic option and suffer from high morbidity and early mortality. The FDA-ASH endpoint symposium held last month in Rockville pulled together stakeholders from across government agencies, academia, industry and patient groups to methodically address the need to expedite development of new therapies for sickle cell disease by assessing and prioritizing endpoints to facilitate the design of clinical trials.

During this meeting, the senior staff from FDA clearly acknowledged the need for innovative trial designs and endpoints to speed development of novel therapeutics and expressed an openness to engage in discussions with sponsors to accelerate the development of promising treatments using novel approaches supported by strong science.

Hematologic parameters reflecting the underlying pathology of sickle cell disease were generally recognized as compelling potential surrogates and biomarkers of clinical benefits that could demonstrate compelling efficacy more efficiently than it would be possible to demonstrate a definitive impact on a traditional endpoint such as vaso-occlusive events. Our development plan for LentiGlobin and sickle cell disease reflects this innovative approach, and we plan to use a novel composite primary endpoint based on the amounts and proportion of anti-sickling T87Q globin and the total hemoglobin level.

These figures on the next slide represent the data on LentiGlobin from study HGB-206 that we presented midyear at EHA. We will be updating Group C results at ASH with a podium presentation on Monday, December 3 by Dr. John Tisdale from NIH, as you saw from a recently released abstracts. The data we presented at EHA demonstrating relatively rapid production of large amounts of T87Q and robust total hemoglobin levels highlight the clinical relevance of hemoglobin endpoints to demonstrate the potential clinical benefit of LentiGlobin in sickle cell disease.

Importantly, the high levels of T87Q globin were associated with reciprocal reductions in hemoglobin S to the point that our patients had similar levels of T87Q and hemoglobin S, resembling the hemoglobin profile of individuals with sickle traits. The ability of T87Q to fundamentally alter the physiology of the sickle red blood cell by blocking hemoglobin S polymerization as reflected by meaningful improvements in the hemoglobin profile and hemolysis markers gives us hope that the clinical events we classically associate with sickle cell disease, for example, VOEs, will be substantially attenuated or eliminated by addressing the underlying pathology. Measurements of the impact of LentiGlobin on hemoglobin profile had the added advantages of being objective, robust and occurring rapidly.

Based on our emerging data and the evolving innovative environments, we have amended the HGB-206 trial to introduce a novel composite primary endpoint based on laboratory hemoglobin parameters, including the level and percent of T87Q globin and total hemoglobin. We've introduced a key secondary endpoint of reduction in severe VOEs and have expanded the sample size of cohort C. The increased sample size of cohort C will allow us to obtain more comprehensive data in forming the correlation between improvements in hemoglobin profile and the reduction in vaso-occlusive events. In this way, we plan to validate the primary hemoglobin endpoint as a surrogate for vaso-occlusive events. This study will include patients between the ages of 12 and 50.

In addition to the expanded 206 study, we intend to conduct a supportive single-arm, open-label multicenter international Phase III trial, HGB-210, in patients with sickle cell disease who have a history of vaso-occlusive events. This Phase III trial will share the same primary and secondary endpoint introduced into the HGB-206 trial through the recent amendment and is planned to start in 2019.

These 2 studies formed the basis of a potentially accelerated development path that enables us to consider registration plans for LentiGlobin as the clinical outcomes warrant. We will continue to engage with regulatory authorities and share more details in the future.

And with that, I will turn the call back over to Nick.

Thank you, Dave.

Here, I'll briefly highlight the 2018 accomplishments across our clinical programs and, of course, want to remind folks of our planned investor event at ASH at 8 p.m. on Monday, December 3, where we'll provide our next updates.

In closing, I'll summarize by saying it has been yet another truly transformative year for bluebird to date, not only as seen in our clinical programs, but also across many fundamental areas of our company, including research, manufacturing and commercial, that not -- are not adequately captured here and perhaps less visible to all of you on a regular basis.

From building and readying our EU team to launch, to scaling our manufacturing and platform capabilities, to greatly advancing our early-stage programs alone and in collaboration, to expanding our team by close to 50% in just 1 year, and just this year alone, while maintaining our purpose-driven culture, our team blue is fired up about our growing potential to truly make hope a reality for many, many patients and families in need.

With that, I'll close this call and look forward to engaging in the Q&A. Operator?

(Operator Instructions) Our first question comes from Salveen Richter with Goldman Sachs.

So I have 2. One is, are you planning to validate the endpoints in the 206 study and then start the Phase III post in 2019? Or will they be in parallel? And then with regard to the pivotal study, maybe you could help us understand timelines associated with this program. How quickly do you expect to enroll this study? Would the -- what time period would the endpoints be associated with? And then do you file on an interim basis? Or do you have to monitor for, let's say, 2 years?

Salveen, this is Dave. I think that was more than 2 questions, but let me tackle the first one, which is the most straightforward. We plan to initiate the Phase III 210 trial as soon as possible, so it is not going to be based on a particular milestone within 206. So those trials will be running in parallel. And in fact, that's one way to accelerate the cumulation of the key data we'll need. In terms of the more detailed questions about the design and timelines of the 210 trial, those will have to be addressed at a kind of a later date.

Our next question comes from Cory Kasimov with JPMorgan.

This is Matthew on for Cory. Curious to understand a little bit more about the inclusion of the VOE as a key secondary endpoint? Based on your discussions with the FDA, is there a path forward if you continue to have a profound effect on HB that this doesn't translate to a VOE benefit during the duration of the trial?

Yes. This is Dave. So at the current time, I can't share more detail on our discussions with the agency beyond what we're sharing now. But our sense is, of course, that as I mentioned during the presentation, the hemoglobin endpoints are very powerful and meaningful. We also agree that clinical endpoints in this population, particularly in the context of a transplant, are essential to demonstrate meaningful benefit there as well. And in terms of how the agency will explicitly weigh those outcomes, that's really going to be based on how the totality of the evidence evolves, and that's something we can discuss at a later time.

I think -- this is Nick. That's kind of the key point, right, which is this sets us up to collect the data and also be focused on the hematological endpoint, and then ultimate registration and timing and so forth will be data dependent as it always is and was as well for thalassemia. So it's pretty consistent with that approach and consistent with our ongoing dialogue.

Okay. One additional question. Did the FDA and you guys agree on the definition of severe VOC?

Severe -- I'm sorry. What is that, severe?

Severe VOE.

Yes. Well, we are using a relatively conventional and stringent definition of VOEs. And as more detail of the trial emerges, you'll be able to see exactly what that is.

Our next question comes from Chris Shibutani with Cowen.

Could you go into a little bit -- typically, when endpoint markers are evolving, there's kind of the regulatory threshold and then there's inevitably kind of the threshold that would have more of a commercial or clinical relevance standard. It's clear that the FDA is open to considering kind of a mosaic of clinical outcome. Can you talk about how different the regulatory versus clinical commercial thresholds might be? As we think about the literature, there's also references to various pharmacoeconomic benefits of providing benefits to these VOE patients. Some perspective and context would be helpful.

Yes. I think the best way to answer that is to reiterate what we've said from the beginning that with our platform in which we have a gene therapy in the context of myeloablative stem cell transplant, the expectations for benefit are quite high. Therefore, a truly transformative outcome. And that really addresses the commercial aspect of reconciling regulatory and commercial expectations. For our products to be successful, the magnitude of clinical benefit will be unequivocally clinically meaningful, both to patients, treaters and one would expect in a commercial setting as well.

And Chris, this is Nick. I think the magnitude of the effects, sort of the obviousness, if you will, is certainly important. But also, what we're doing on -- certainly on the commercial side as well is doing quite a bit of analysis to understand the impact on this over time for patients, to the system, et cetera. We're also trying to understand and continuing to explore sort of novel payment mechanisms, et cetera, that also are consistent with this tracking over time. Because clearly, if this data is, as we hope it will be, it'll deliver a lot of value, not only sort of day 1, if you will, but hopefully, for the duration and life of the patient. And that's something that as we think about how the system will digest and value that, that's something we're certainly working on under the assumption that first things first, which is what Dave outlined, which is the clinical data delivers registration package that is sort of clear to the regulators and the clinicians. And then we'll handle the rest subsequently.

Great. And then a quick follow-up. Nick, you mentioned that you returned from Asia, which has certainly been a hotbed of activity, particularly with regard to cell therapy. Can you just share with us some of your takeaways from that, particularly as it may relate to your own thinking with regard to competition, business development, intellectual property, et cetera?

Good question. I think at the end of the day, one of the things that's really important for bluebird is if our mission is to make hope a reality, that is not just make hope a reality for patients that live in developed U.S. and Europe, for example. So really, this was an exploration, and we've had -- we do that sort of on a global basis to make sure we understand what is the best way to make sure over time that our platform and the products that we hope to come from it will be able to get to patients and physicians all around the world of all economic classes and all sort of geographical locations. Now that is hard. So that's -- that was the basis of what we're trying to understand. And the conclusions certainly are that it's important, and the need is there. Exactly how to do it is something that we're working through, how to appropriately sort of either do it on our own or collaborate accordingly in the various regions. But as we've said, it's not just China. It's Southeast Asia. It's Middle East. It's Africa, as you can think about these diseases and the impact that treatments like this might be able to have. So that's the nature of the trip in exploration. I wouldn't overread it.

Our next question comes from Matthew Harrison with Morgan Stanley.

I guess, I wanted to ask another sickle cell question as well. And maybe you could just help us think about why you chose or why the dialogue with the FDA went to VOE as opposed to some of the other endpoints. Obviously, I'm sure you guys were watching and aware of the workshop that was hosted, and there was obviously talk about moving away from VOE as an endpoint. And there are obviously have been other sickle cell companies that have discussed alternative endpoints like TCD or transfusions or things like that. So I'm just curious why you settled on that and why you think that's the best sort of secondary endpoint to associate with your hemoglobin increase?

Yes. Matthew, this is Dave. That's a great question. As you can see from our choice of a -- an innovative hematology-based primary endpoints, we have indeed moved away from the classic event-based endpoint as the primary and for the reasons I mentioned. It's objective. It improves rapidly. Certainly, given the magnitude of benefit we're seeing, it's clinically meaningful in and of itself. But when we think of sickle cell disease and the different phenotypes of sickle cell disease, you simply cannot ignore the classic syndromes, if you will, that are associated with disease, VOE being prominent among them. And so it would be really hard-pressed for any of us in this space to feel as if we'd achieve success if we had ended up altering a hematology marker without actually addressing what morbidity is problematic for patients and causes patients to suffer. And so that's why it's a key secondary endpoint for us. And the innovative approach we're taking is to demonstrate a substantial improvement in the hematology endpoints to have that associated and correlated with the improvement in the classic events. And we do expect to see those hematology endpoints readout rather quickly, as you've seen from our initial data, and then that can be corroborated over time as we collect event rates. There are certainly other events that are -- essentially, you mentioned patients at risk of stroke who have elevated transcranial Doppler velocities. And that would certainly be, for instance, another major subpopulation of patients we would evaluate in the future. And that was recognized, for instance, TCD as a very promising and clinically meaningful clinical endpoint.

Our next question comes from Matthew Luchini with BMO Capital.

Two just for me. First, as we think about the new endpoints in 206, and as we think about the design for 210, how do we think about the types of patients that are going to be enrolled in a study? Said another way, do you expect to modify the inclusion criteria beyond the age, which I think you already mentioned, perhaps a higher rate of VOCs over the last 2 years, something like that, that might help amplify the effect of the targeted endpoints? And then secondarily, I was just curious if you could provide a little color on EMA and where things stand with them. I recognize that discussions are ongoing and perhaps you could give us a sense as to what the puts and takes are there.

Sure. Excellent questions, and you are precisely right. As part of the amendments in the 206 trial, we are requiring that the patients who are now going to be enrolled in the expanded cohort C have a history of VOEs to enable us to demonstrate a treatment effect to reduce VOEs following LentiGlobin treatment. In terms of our dialogue with the EMA, all I can share at this point is that we are in an ongoing dialogue with the EMA, and we'll provide additional clarity on the outcomes of that at a future date.

Our next question comes from Michael Schmidt with Guggenheim.

I just had one more on the VOE topic. Is there any existing data out there that already associates the frequency of VOEs with HBS levels that could be leveraged to inform some of the study features? And then I had a follow-up with that.

Yes. So the existing data correlating hemoglobin levels with clinical events, I think, is most powerful in the context of stroke risk, where we certainly know that transfusions can markedly attenuate stroke risk in many patients. What makes it a little challenging in terms of directly extrapolating the correlation between hemoglobin levels in sickle cell disease patients and outcomes is that we are indeed, with LentiGlobin, introducing an engineered anti-sickling globin, which is going to, we hope, interfere with the fundamental pathophysiology of the disease. So it's actually quite distinct from, for instance, approaches that might simply be elevating levels of hemoglobin S and elevating total hemoglobin made up of hemoglobin S, where, in contrast, we are taking a strategy which is radically altering the pathophysiology of the disease. So I think that's really the primary reason why we are showing this correlation or building the trial to show this correlation between essentially T87Q-driven hemoglobin changes and events.

Okay. And then just switching gears, a question on beta-thalassemia. Now that obviously the European filing is under review, maybe, Nick, I was wondering if you could just give us some more insights into your sort of discussions in Europe, maybe with payers to what are your latest thoughts on potential pricing models there and ways to interact the treatment if approved in the near term?

Yes. Michael, fair question, and you're probably going to be wholly unsatisfied with my answer, so I apologize, because as you can imagine, that's sort of an ongoing dialogue. But what I can say is we built a European team that's focused on, first and foremost, the clinical engagement across Europe as well as understanding market access, and that's been ongoing for the last couple years. So we are very actively engaged with each of the sort of many countries in Europe on that exact topic to understand what are the implications and the best approach to make sure that we can, first and foremost, provide the access that we'd love to have to this opportunity for patients and, at the same time, understand how the system can digest from a value perspective to make sure the innovation is appropriately rewarded in this regard. So that -- there is a broad range. As you know, we're fans of value-based payment over time as a mechanism. We think that's consistent and enables sort of all stakeholders to participate in a productive way to the extent that we can share risk and sort of pay-for-performance, et cetera. Those are also things that are very high on our list. How far we get as it relates to that for thal and over time, ALD, and then over time, hopefully, also sickle cell, that's to be determined. But you can sort of get a sense that's the direction we'd love to go in because we think these products are incredibly powerful and can be appropriately tracked. And so we're open to those pretty, what I'd say, advances as it relates to the access -- market access side of the equation.

Our next question comes from Jim Birchenough with Wells Fargo Securities.

This is Yanan, in for Jim. So just curious about the mentioning of trait, individual-like compositional hemoglobin, so -- and also, what is -- how it's relates to the, potentially, the VOE endpoint? Because the trait in individuals obviously has -- I believe, very few, if any VOE incidents. So is that an ultimate treatment goal for LentiGlobin? And also, a related question to that, is the trait individual obviously have homogeneous red blood cells with every cell expressing half sickling and half sickling hemoglobin, so -- which is probably not the case for LentiGlobin-treated patients. To that end, I think you're mentioning of a single-cell flow cytometry assay at the FDA workshop is very interesting. Could you share any data from the single-cell flow cytometry assay or give us a time line for when you might be reporting those kind of data?

Yes. Those are both excellent questions, and you're absolutely right. Our ultimate goal is to achieve a high proportion of anti-sickling T87Q globin in treated patients, driving down hemoglobin S levels and, hopefully, achieving a clinical outcome that is comparable to what individuals with sickle trait have, which is to be largely asymptomatic. And of course, we have the added benefit with T87Q of it being an anti-sickling globin. So perhaps more potent than normal wild type beta chain in that context. Certainly, as you allude to, the data on pan-cellular versus heterocellular correction suggest that we should be striving for pan-cellular correction. And you kind of threw in the comment that perhaps it was unlikely that we would see that. And I would -- I'm not sure I agree with you there because what we have certainly seen from the existing literature, particularly in the context of allogeneic transplant, is that there's such a profound peripheral survival advantage for red blood cells that are either from trait donors or normal relative to FS red blood cells that we would expect, in fact, our therapeutic effect to be amplified to the extent we would hope to see a near pan-cellular or pan-cellular outcome. And Dr. Mohammed Asmal, one of our senior physicians here at bluebird, did present at the FDA-ASH endpoints symposium on some exciting recent work we've done to develop assays to help interrogate exactly what an impact we are having on distribution T87Q and S in the red cells following LentiGlobin treatment. And we do hope to be able to share that data in the future. I can't comment on that today.

Our next question comes from Gena Wang with Barclays.

I will also ask a question on sickle cell. At the last EHA update, Group C, you had 14 patient enrolled. Just information for vaso-occlusive events for these patients? And also for the expansion cohort, do you have a -- number for prior vaso-occlusive events in mind?

Yes. Gina, I think I heard the first question asking if we would share insights into the frequency of vaso-occlusive events in the cohort C patients at ASH. And the answer on that is yes. In terms of the explicit details on the inclusion, exclusion criteria, we will share that in the future.

Okay. So at ASH -- can you -- so at ASH, we will see more color on the existing with VOE events?

So I'm sorry, Gina, one second here. Mohammed just wanted to follow up on the last question and you maybe can restate your second question.

Yes. So a couple of words that you just mentioned were -- are dropped out in the communication. But yes, we have previously presented data at EHA and, I believe, in the last ASH on the VOE episodes in our patients from Group A and showed some initial data that there was indeed an effect on this with LentiGlobin treatment even in these patients relatively modest expression of T87Q. And I think certainly now, we will be certainly presenting data both on the history of vaso-occlusive episodes that patients have had coming into our study as well as what they look like after getting treated with LentiGlobin. Does that answer your question?

Yes, yes. That's very helpful. And the related question is I know you cannot comment too much specifics. But just wondering if the FDA express any specific threshold, you have to meet for T87Q and the total hemoglobin in order for approval.

Yes. That's not information we can share at this time.

Okay, okay. Just lastly, very quick question for Philip. For bb21217, I think the initial data -- the dose isn't that high, it's 150 million cells compared to bb2121, but has some safety issues. Just wondering if you can help us understand the mechanism there, anything can explain the differences?

Yes. So I guess, first, I'd say that I'm not sure that we can extrapolate given the number of patients from 1 Grade 3 CRS and Grade 4 encephalopathy at this stage in a high tumor burden patient, I think that would be inappropriate. After 150 dose, we can be -- if you squint with relatively small number of patients, we could say that actually 21217 is a little bit more active than 2121 at the 150 dose. But obviously, that's something we have to see with more subjects. And as I said on the call, with 2 out of 2 patients out of 6 months with detectable CAR T cells, again, if you want to squint with the small numbers, that's an improvement over the -- over what we've seen with 2121 itself at 6 months as well. So I think at this stage, I mean, the way I would phrase it is we certainly haven't broken 2121 by adding the 7 components, and we're sort of on the right track to see whether these durability increases do the right thing.

Our next question comes from Edward Nash with SunTrust Robinson Humphrey.

This is Fang-Ke Huang for Edward Nash. I just want to follow up on bb21217. You just mentioned that the 2 patient who have detectable CAR vector copy [analysis] is better than the data from bb2121. Can you just tell us like how many patients had CAR vector copy analysis for bb2121 that dosed at a similar level?

Yes. So I think the data has been presented to date is about 44% of patients with -- treated with 2121 have detectable CAR T cells out of the 6 months, so about half.

Great. And just one question on BCL11A. And so basically, you have showed that about 60% of sale are HbF positive. And what you are thinking regarding this going on trending over time? Do you think it's going to increase? And also comparing to the HGB-206 Group C, and can you remind us what percent of the sales is T87Q positive?

Yes. So I guess, the question on the BCL11A program is the reason you do a clinical study. We don't know what's going to happen. Obviously, we were hopeful that, that will be a selective advantage of the expression of F. And over time, that could increase, but that's something with what we're doing the study for. What we've described with the T87Q and the 206 studies, so at least in the Group C, we're -- from a drug product perspective, we're getting into the 90% or so of the cells transduced, and then that's relating to in the range of -- similar range of 70% to 80% of the peripheral cells being T87Q positive, so that is roughly in that range.

Yes. And this is David. The only thing I could add to that is based on our LentiGlobin data, and that is an entirely different therapeutic, but in the context of engraftment of the gene therapy modified cells, we typically see increases out to 6 months when we start seeing stabilization of sort of steady state of engraftment, but that's -- and many patients could continue to increase all the way out to a year and beyond before they reach a steady state of engrafted cells. So to Philip's point, we're optimistic, but we're actually in the midst of conducting that experiment. And so we'll be able to share additional data in the future.

Our next question comes from Ying Huang with Bank of America Merrill Lynch.

This is [Chen] on behalf of Ying. I have a couple, if I may. And the first one is, thinking about the potential surrogate endpoints. So if you're looking at a prior sickle cell patient, it looks like the hemoglobin T87Q started to stabilize between 6 to 9 months. Do you think that could be a potential right time frame to think about as the surrogate endpoints? And my second question is actually on the BCL11A program. So I think initial is encouraging that you started to see all this knockdown of BCL11A and also increase the protein, but is the kind of ratio for the -- as protein and also at the overall percentage of the sickle protein is actually kind of trending up and as proportion is going down? Just wondering how you were thinking about that approach or it's just because the target -- yes, can you just help us with that?

This is Dave. I'll tackle the first part of that. And so you're absolutely right. We would hope to be able to leverage the sort of accelerated improvements we see in hemoglobin endpoints relative to classic events, like VOEs, to accelerate the development program. And should we see very consistent and clinically meaningful increases out at 6 to 9 months, that might serve as a reasonable window. But you know what, it's really going to be data-dependent, so we need to see how the data evolves as the study progresses. I'm not -- maybe Philip caught the second question.

Yes. So yes, I think it's -- I think the answer is it's a little bit early to speculate with respect to the data that's -- we've had in the abstracts on the BCL11A program. This is for all -- just 75 days in, about 64 days or so since the last red cell transfusion. There's still adult blood -- transfused blood on board. And so things are still moving around. But I think the important thing is that we're seeing F at the reasonably levels. We're seeing a high percentage of F cells, which is certainly not explainable by the transplant alone. So mechanistically, I think it's very encouraging. Where this nets out is sort of -- well, it's going to require time. So I guess come to ASH.

Okay. Can I have a quick follow-up, please? So you think that the 6 to 9 months is a reasonable estimate, but is it possible that you can even consider before that when you meet a certain threshold? And my second question is, when are we going to get update on the durability data of the low BCMA expression in the bb2121?

Yes. So I really don't want to speculate at this point about data that's emerging, but you are correct that we will make a data-driven decision if we see a very clear and consistent and clinically meaningful efficacy signal that we and the regulators feel is appropriate, then certainly, we will be flexible, and everything you heard earlier that we alluded to about the willingness of the regulatory authorities to be innovative with sickle cell disease. Development programs sort of supports that. In terms of when we might see data on 2121, bear in mind, it's, of course, in a pivotal trial at this point, and so we're beyond the stage where sort of trickling data updates are appropriate or meaningful. And so when we have a more substantial new data set to present Celgene, and we will make that public.

Yes. And the emphasis right now, as I know we've -- I'm sure you know is to think about how do we explore 2121 in earlier lines of treatment, right? So with that now already in the third line, starting to explore second line, et cetera. So that's more of the, I'd say, the focus based on the data that we've seen to date, and that I'm confident that Celgene shares that perspective. So we're running a little short on time here, so I think we may have to jump to the next question.

Our next question comes from Mark Breidenbach with Oppenheimer.

A couple questions. Maybe one for Phil first. In the CRB-402 trial, can you give us a little bit -- a little more color on the use of tumor burden to stratify dosing? I'm just curious why this wasn't necessary in the CRB-401 trial. And how you're defining low versus high tumor burden?

Yes. So on the tumor burden stuff, maybe Dave can take that.

Yes. I mean, we have previously assessed patients based on low and high tumor burden. And certainly in this case, where we saw that significant safety signal upfront, our primary responsibility always is patient safety, to ensure we're conducting the trials in a way that maximizes, ensures patient safety. And so that was a prudent modification to make. And we are, as you've heard from Philip, at this point, continuing to proceed with the program based on the data we've seen. It was a single DLT. We were able to continue in that context, and we're doing so in a way that again ensures we do it appropriately.

Okay. So maybe another one for Dave. I don't think we've heard at all about the CALD program today. Can you give us a sense for why a new trial is necessary before registration for Lenti-D given the high quality of the results you've seen so far from starving?

Okay. Yes. I think you're alluding to the 104 trial, which is a trial that's going to explore additional options for conditioning, which as you may know in the transplant community, different centers, different transplanters, different regions have their own favorite conditioning approaches. And so we're trying to ensure that we provide the data that will inform treatment practices around the world and to sort of maximize the ability of clinicians to use Lenti-D.

And just for clarity, I think your question was whether we were using 104 for a gate for registration. The answer is no, that it's based on our historical statements about our anticipated times and the trials that we're going to leverage.

Understood, understood. And just finally, are you anticipating we'll get an update from Celgene regarding KarMMa trial enrollment progress at ASH? Or is that something that they're going to keep quiet for now?

We can't really comment on what Celgene may or may not do.

Our next question comes from Vincent Chen with Bernstein.

One on the CAR T for a moment. We saw a range of CAR T abstracts released yesterday, including initial data from your partner Celgene's JCARH125 program. How do you get the chance to see this? Can I ask you for your thoughts on the data they've presented and how it compares to the other programs out there? And then I have a follow-up.

Yes. Vince, this is Nick. I don't think -- and maybe, Phil, if you can comment a little bit more. I think right now, there's a number of programs out there, and that's certainly one of them. But we certainly haven't really seen anything that is sort of what I'd say in the range of something that would make us clearly superior to 2121, et cetera, especially since all that data is quite a bit earlier than the data that we've seen on 2121. So emphasis, along with Celgene, actually remains, as I mentioned just a few minutes ago, is to drive 2121 into earlier based on the efficacy and the safety profile that we've seen, which we think is certainly as good, if not still better than any of the other options that are starting to emerge out there. But Philip, if you had any additional...

No, I totally agree with that.

Okay.

And I guess, switching gears, back to BCL11A program. Love to sort of revisit how you are thinking hemoglobin F might trend as the patient goes further. So I guess you're getting 30% hemoglobin F with a fraction of beta-like globin, quite impressive. And I guess, as you alluded to, that's just early days, and it's likely to go up further. If I recall it correctly, though, you get to much higher levels pre-clinically. I could be misremembering, but something in the 70% to 80% range. Help us walk through what gap we should likely expect sort of longer term. Should hemoglobin F in this patient ultimately get to nearly this level? Or should there be some meaningful discrepancy between sort of what you can achieve preclinically and what you actually get in patients due to factors like (inaudible) and so forth? And if so, what are the sort of the gaps that we should expect and sort of the magnitude there?

Yes. So I think you've sort of answered your own question, really. I mean, the data is very early. And well, that is exciting. So it's really too early to speculate on where things will go. That said, as Dave mentioned with T87Q, and we expect the same for HbF, there should be a selective advantage to cells that express a sufficient amount of HbF on a per cell basis to extend the lifespan of those cells. And so that should drive to a longer lasting cell in that case and obviously to a higher percentage of F cells over time. How long that's going to take to stabilize is new for the BCL11A approach versus LentiGlobin, and so we'll just have to wait and see.

Our next question comes from Raju Prasad with William Blair.

Just a couple clarifying questions. Regarding the efficacy endpoint of HB -- T87Q into hemoglobin and 206, is there one or the other that you think will be more important when submitting to regulatory authority? And is there is upper cap that you may discuss with the agency regarding total hemoglobin?

Right. So it's a composite endpoint, so each of the components are individually meaningful. How one versus the other might predict benefit over time will need to be determined as the data emerged. In terms of an upper limit, total hemoglobin, no. I mean, that's a very interesting point because, of course, as we know, in patients with sickle cell disease, you do have to be careful not to over transfuse them to achieve hyperviscosity. But of course, by virtue of the way T87Q works to essentially try and reverse that underlying red cell pathology, we would expect that not to be an issue. Again, analogous to the case of individuals who have sickle traits, they generally have normal total hemoglobin levels and do not suffer the sequelae we think of associated with sickle cell disease. And as we've discussed in the past, the vector itself contains the endogenous regulatory element for beta-globin production, the locus control region. So we do expect there to be feedback regulation of how much T87Q has produced. So we really don't expect to see sort of a dramatic overshoot in total hemoglobin. Does that answer your question?

Yes, yes. It's great. And then just to clarify one on 104. Regarding the additional condition regimens that you're using, is that more of just based on a potential global launch of that product and catering different markets? Or is that more of a tolerability issue that maybe could be extrapolated or in use for other programs when you're dealing with younger patients, for example?

Yes. I think -- I mean, in a sense it's both. It gives -- it's going to give transplant physicians alternatives for conditioning, which in specific settings may provide improvements in safety for patients, be more consistent with institutional guidelines for transplant and policies and preferences. So yes, it's all about improving patient outcomes and improving optionality for the treaters.

I'm not showing any further questions. At this time, I would now like to turn the call back over to Nick Leschly for any closing remarks.

No. I think I'll just let us go. I appreciate everyone taking the time to hear this step forward, and we look forward to seeing everybody at ASH.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude today's program, and you may all disconnect. Everyone, have a great day.