Good afternoon, ladies and gentlemen, and welcome to the bluebird bio, Inc. Third Quarter 2020 Earnings Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host speaker, Ingrid Goldberg. Please go ahead.

Thank you. And good evening, everyone. This is Ingrid Goldberg, Investor Relations at bluebird bio. And I'm joined today by several members of the bluebird management team to discuss our third quarter earnings and business update. Before we begin, I would like to remind everyone that our discussion today includes forward-looking statements under the Private Securities Litigation Reform Act of 1995. Such forward-looking statements are based on current expectations and assumptions that are subject to risks and uncertainties, and actual results may differ materially from those expressed today due to a variety of factors. Additional information concerning these risk factors is contained in our filings with the SEC and available on the investors section of our website at www.bluebirdbio.com. As a reminder, while we may elect to update forward-looking statements in the future, we do not undertake any obligation to update forward-looking statements 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 will now turn the call over to Nick Leschly, our Chief Bluebird.

Great. Thank you, Ingrid. And thank you, everyone, for joining the call to hear the latest update from the bluebird team, especially as we recognize it's been a very important and, quite honestly, stressful week for the country. The bluebird vision and mission are stronger than ever, as is our focus on the continuing [ our marks ] to deliver transformative products to patients with terrible severe genetic diseases and cancer. Despite challenging times amidst the backdrop of COVID-19, our birds have made tremendous progress this quarter across our entire portfolio. We're excited to see the bb1111 sickle cell disease program granted the priority medicines designation PRIME by EMA, helping ensure expeditious review. Importantly, in a recent type B meeting with the FDA addressing both our CMC and clinical plans, we are pleased to have reached general agreement on the path forward to a BLA. More details a bit later on this call. In thalassemia and despite COVID, our European team remains on track to infuse our first commercial ZYNTEGLO patient in Germany in short order and continues to make steady progress obtaining reimbursement and access in multiple additional European countries. On TDT and in the U.S., we remain on track to develop and validate the release assays requested by the FDA to support LentiGlobin for beta thalassemia U.S. BLA submission in mid-2021. We're also announcing today that, based on our further discussion with the FDA, we plan on including patients of all ages and genotypes in our TDT submission. And we have completed the final infusion of our Phase III HGB-212 clinical study. This completes patient treatment across our pivotal TDT studies 207 and 212. Our Lenti-D or eli-cel MAA filing for CALD was accepted by EMA, bringing us a big step closer to accomplishing our goal at the heart of bluebird's founding. We were also presenting meaningful long-term data from Starbeam study at the recent EBMT conference, including 10 boys reaching their 5-year follow-up, suggesting durability of response with continued MFD-free or major functional disability-free results, which is very exciting on a very, very human level. And of course, in our oncology business and in partnership with BMS, our ide-cel BLA filing for multiple myeloma was accepted for priority review by the FDA, with PDUFA date set for March 27, 2021. Looking ahead to data releases before the end of the year, we're on track to present updated clinical data for HGB-206 study in sickle cell disease, our Phase I 401 study of ide-cel; and also announced today our Phase I CRB-402 study of bb21217, our fast follower program in multiple myeloma. On a corporate level, this quarter, we're jazzed to announce that Denice Torres has joined our Board of Directors. Denice's extensive experience working through business evolution combined with her entrepreneurial and creative approach to solving problems brings another varied skill set to our Board. This continues to deepen BLUE's commitment to expanding our approach within diversity, equity and inclusion. And finally, we maintain our cash runway into 2023, so with a very strong financial position, clear line of sight for multiple near-term catalysts, it is inspiring to see the team step up in so many ways and amidst of a multi-wave pandemic, social unrest, intense election to deliver on our vision for patients. Before moving on to more specific product updates. We recognize that we are 6 months from our initial March COVID-19 guidance, so I'd like to provide a brief update on the operational impact as a result of this global pandemic. While our clinical studies continue to progress, with various degrees of impact, we have adapted how we monitor and conduct our studies. The current surge in COVID-19 cases and hospitalizations in the U.S. and Europe is likely to impact some of our clinical studies. A majority of our birds continue to operate and execute in a work-from-home model, while the core of the research, manufacturing and related groups continue to perform critical work in our labs and manufacturing facilities. This operating approach is challenging and we expect it to continue well into 2021. Of note, our external manufacturing ramp-up activities have also experienced significant disruptions. Our contract manufacturing partners or CMOs have been operating under stringent COVID operating protocols and in some cases have experienced significant local outbreaks as the pandemic continues. Specifically, the CMOs ramping up to support both commercial LVV or lentivirus vector and drug product for sickle cell disease have been affected, causing slower operational progress in their commercial readiness activities in the order of 4 to 6 months. I will come back to the impact on delivering the analytical comparability data agreed upon with the FDA in our recent type B meeting. We're, of course, working very closely and in partnership with these CMOs to navigate these challenges together. Next, I'll provide more detailed updates for our sickle cell program. As a reminder: We announced in May that we had reached alignment with the FDA on our plan to seek accelerated approval with data from a subset of patients in Group C of the 206 study based on the promising clinical results that we recently shared publicly at EHA. At that time, we updated the sickle cell filing guidance to be second half 2021, pending finalization of the CMC requirements. We recently had a productive type B meeting with the FDA and reached alignment on our CMC submission plans. First, for context, we reviewed with them the latest clinical data, and our alignment on the clinical requirements remain unchanged. On the CMC front, we reached general agreement with the FDA on the expectations for the future BLA analytical package, which will need to demonstrate continued analytical comparability of our drug product and lentiviral vector as we transition from clinical production to commercial manufacturing. Importantly, the analytical comparability strategy we agreed upon applies to both commercial manufacturing of suspension lentivirus and drug product and does not require additional clinical data. Given the recent challenges with regard to CMC regulatory guidance in our field, this agreement is a critical derisking event for the bb1111 sickle cell program. We now have a clear path forward for both clinical and CMC. While this interaction with the FDA confirmed the robustness of our clinical data package and overall CMC confidence, the requirements to demonstrate comparability are traditional and different than the plan we proposed and expected. First, comparability will now include not only a small number of drug product lots manufactured from healthy donors but also patients with sickle cell disease. The lots to be manufactured with patient cells to support this analytical comparability package will be manufactured within the HGB-210 study and are in addition to the patients already treated with the drug product manufactured with suspension lentivirus. Second, at this time, the FDA is requiring that we use commercial vector versus comparable clinical vector to demonstrate the comparability of our commercial drug product. Taking this together, both the new CMC requirements from the agency and the COVID-based CMO operational delays, we are adjusting the timing of the BLA submission back to the more conservative initial target timing of late 2022. From a broader perspective, expediting clinical development creates additional pressure on CMC plans that in turn also need to be accelerated to match clinical data time lines. As thoughtful as the agency was in their feedback, we believe there is still room for potential flexibility in the plan to close the gap between clinical and CMC time lines. Very concretely, we would like to explore ideas like real-time review of CMC module like the agency has implemented in oncology for clinical; or CMC flexibility allowing for submission of data either during review or post approval after pre agreement with the agency, similar to that accelerated approval for clinical development. In short, breakthrough and RMAT designation have been successful at accelerating clinical development, and it is now critical to resolve the misalignment on what accelerated means when through CMC portions -- or means for when thinking about CMC portions of a BLA. We will continue to work with the agency; and are hopeful they will use a flexible and innovative approach to avoid unnecessary delays and support acceleration of our CMC plans in line with the expedited clinical filing plans, our RMAT designation and, very importantly, the high unmet need in the sickle cell disease in the community. For now we are quite pleased with the overall derisking of the sickle cell program and have a clear path to BLA. While 2020 continues to present unprecedented challenges at both bluebird and around the globe, our team has continued to successfully advance our programs. We're excited for the next 12 months, as they are -- they present a catalyst-rich period for bluebird in the U.S. and Europe. We know the role of pioneering science and medicine is never easy for anyone involved, and I would like to specifically thank our birds for their passion and antifragility and for their relentless commitment to patients and families we aim to serve. With that, Ingrid, I suggest we move into questions.

Great. Thank you. Nora, can you please start the question queue?

[Operator Instructions] Your first questions -- your first question is from the line of Cory Kasimov of JPMorgan.

This is Matthew on for Cory. So I guess my first question is a quick one. I'm just wondering if you can disclose how many patients you'll need to manufacture cell product for or drug product for in the HGB-210 study prior to BLA submission. And then the second one is I'm just curious if you're able to go into more detail or explain the rationale for why FDA wants to see comparability data with cells from sickle cell disease patients; and I guess, your view on how these might differ to healthy cells from a drug product manufacturing perspective.

Yes, fair enough. Thanks, Matt. Good questions. I don't think we disclosed the exact number there, but it's a handful, all right? It's a small number of patients. And so beyond that, I think that's -- I don't think -- that's not going to be a big determinant of any of the changes. I think it's the overall sort of requests that are having a bigger impact. As it relates to the second question there, I wonder if -- Derek or Dave, if you guys want to comment on the difference between healthy donor versus sickle cells and why we expect that to be a big difference or not a big difference and why the FDA is asking. Is that -- did I get your question right, Matt?

Yes, yes, that's right.

Well, this is Dave. I can take that, and then Derek can clarify. In the past, we have used healthy donor cells in terms of demonstrating comparability. The -- from the FDA perspective, you could appreciate that patients with sickle cell disease do have a genetic disease, so there's certainly interest in understanding how those specific stem cells might behave in a way that could theoretically be different from normal healthy volunteer cells, although as Nick suggested, our hope had been that normal volunteer cells would be acceptable given the robustness of the clinical data we're seeing, so far, and now that we're introducing, of course, our clinical vector into -- a suspension vector into the clinic in the 206 trial. Derek, any additional context there?

Yes, sure. The presumption, I guess, would be that the healthy donor cells, the more healthy cells clearly don't allow us to be able to check the actual resulting potency of the drug product. We are in fact looking at potency in the treated patients that we're doing now. And so as part of the comparability exercise, I want to presume that they are concerned about the potency, checking the potency of the results in drug product. It's part of comparability. And we'll continue to generate more data and we'll continue to have more conversations on how relevant that is with the agency as we get more data.

Thanks, Matt. Good questions.

Your next question comes from the line of Mani Foroohar of SVB Leerink. [Operator Instructions]

I guess my first is around how to think about the updated sickle cell timing, obviously a disappointment versus previous a little bit. You described that as going back to the original, more conservative timing. Should we think about late 2022 as sort of the mid range of your adjusted expectations? Or as sort of -- or more, as a more conservative, by late 2022. So I guess just trying to parse that out. And then secondarily, can you give us a little bit of a sense on the difference between where the sort of level of contract and manufacturing organization disruption is now versus what your expectations were when we -- when you had the conversation in March? And how to think about puts and takes around availability of additional capacity that's out there, just how constrained your options are to potentially accelerate some of those CMO contracts and buy back some of that time on this delay?

Yes. So thanks for the questions. First, on the timing there, right, we're doing the best that we can to sort of piece the various pieces together, to be very candid, right? So I think the -- what we're talking about here is a target, right, target certainly for end of '22. And as we expressed in here, there are multiple different ways we're certainly looking at. One is if we can engage, and we are very actively, and this is new information, with the CMOs and trying to facilitate them through. And Derek can get into more detail, but facilitate them through what we need them to do as they get ready for commercial. And so there's definitely puts and takes in there. We certainly hope that we can continue to sort of, for lack of better words, make sure that there's no further delay on that, if not speed it up. And then on the same side, and this is where AV, our Head of Regulatory and Engagement at the agency, is also to make sure that we continue our dialogue with the agency here as we step through this comparability process and we generate data, that we're going to continue to submit sort of our ideas and thoughts on how we think we can make sure that we at minimum don't lose time and, ideally, gain some time. But again we're trying to basically [ sail off ] with some reasonable set of assumptions what's the time frame, and that's what you saw here, and also working with the CMOs and working with the agency. This is pretty par for the course? I've been doing this for many years. And we're actually just happy that the agency could have taken actually a much more conservative approach. And given some of the recent past, that was a more existential concern, but this doesn't really touch our foundation. It does affect some things that we need to go execute in ways that, as you know, we proposed a sort of, I'd say, a more streamlined, flexible approach, but we'll do what we got to do. And the data hasn't changed.

Great. And as a follow-up on the financial side, can you guys -- maybe this is more of a Chip Baird question, to be fair. Can you guys remind us again where you are -- what you can give us in terms of the guidance around your adjusted operating expense base and how we should think about cash runway at the current burn with your balance sheet and where it is now?

Yes. Chip is on the line, so I'll have him jump in, but I said in my script too that we're still on to 2023. But Chip, anything you'd want to add?

No. I think that's the most important factor, and we're going to continue to manage to that number. We haven't given specific OpEx guidance for the year, but I think given where we sit in the third quarter and with about 7 of operating weeks left in the year, we would largely remain on the same trajectory for this year in the process of defining that trajectory for '21 and '22, of course. But yes, from where we sit today, cash runway maintained into 2023.

Your next question comes from Salveen Richter with Goldman Sachs.

And so with regard to accelerated pathways that may be open to you for the sickle cell filing, do you actually have an agreement with the FDA that, that is open to you? Or would you have to go back to them and ensure that that's a possibility? And I guess, what data would you then have to provide? Or at what time point would you be able to do that?

Salveen, it's Nick. I'll have Dave and AV jump in. I just want to be clear on the question. There's -- I was -- I said in my script there's no change from a clinical perspective, no changes in the development agreement and the clinical agreement we have with them and the accelerated path. The trick here is aligning sort of the requirements on the clinical front with the requirements on the CMC front, right? And it's the CMC front that are the ones that we're talking about here that have created a -- sort of a challenge, if you will, from an execution, but nothing from a clinical perspective or an accelerated approval perspective has changed. But we got to align those two. Does that make sense? And I'll ask either Dave or AV to elaborate if I got it right.

Well...

Yes. I guess I was just wondering like if there is real-time review, if that's on the table. Do you have to sign off on that? Or do you need to have a further meeting there for other paths for acceleration?

Yes. So...

Do you want to elaborate? Yes, go ahead.

Let me start with that. So in terms of the real-time review, analogous to what the oncology division is doing, that's sort of a separate type of pilot program. So I would focus more on the point Nick made, which is we have actually reinforced alignment now through our recent type B with the agency in terms of agreements on the overall clinical plan to the BLA. And so yes, the options that we've previously discussed remain open. And I would say, based on the robustness of the data, whether it's an accelerated approval or even a full approval, I think that will be determined by the data set we deliver. AV, additional perspective from you on that? Anne-Virginie Eggimann: You said it really well. I think on the CMC side we are on ongoing discussion with the agency. They've agreed to have multiple interactions with us for real-time review and submitting data during review or post approval. These are discussions that we will need to continue to engage with them on.

Your next question comes from the line of Yaron Werber with Cowen.

Yes, great. So maybe I don't know if -- David or Nick, do you want to take this one? Just a question. So just remind us. For LentiGlobin for TDT in the U.S., to show the potency, what did you agree with FDA? Do you need to show comparability with healthy cells versus donor cells? Or is it -- and are you going to use suspension? If I remember, are -- you're potentially not using suspension for that. And then secondly, just so we understand: So we really kind of get what you're saying about the potential for acceleration here, to submit some of the CMC and clinical data, sort of maybe clinical post-marketing CMC in parallel. Have you discussed this with FDA? And so far, they're kind of moving to a more traditional approach and it depends on what you can submit over time. Or is it -- have they not sort of -- have you not had a chance to discuss this in detail with them?

Let me. Dave, maybe you can take the TDT potency assay one here. I think -- for the second question that you asked, I think the idea is, look, we're still driving forward, all right? I don't think there is a significant change in the approach that we're taking, but Dave, why don't you jump in to the TDT? We can come back to the other question as well.

I -- yes. And Yaron, thank you for like the 5-part question as usual. So...

And I have several follow-ups.

Of course. So we're planning to proceed with adherence, for the time being, with TDT. It's not the same size patient population as sickle cell disease, and so it's that's not a level of complexity we're dealing with, with that filing right now. We haven't really gotten into the details on the potency assays, so I will just say we don't have comparability issues there analogous to what we're now resolving with the agency on sickle cell disease -- let's see. I hope I covered it. Again, Anne-Virginie or Derek, did I miss anything pertinent there to Yaron's question?

No -- Yaron, can you also just repeat, sorry, your second question? Because I spaced out there.

Yes. No, no, the second question. I mean you commented, but I'm still a little confused on the potential for acceleration. And just like in cancer, right? We can submit the CMC in parallel and then maybe some clinical data [ you have ].

Yes, yes. So let's be careful here, all right, because I think we don't want to overstate. We don't understate. I think one of the things we've always done is to be very transparent. So what we have and what we're excited about is alignment around the clinical development plan and the acceleration and the end points required, et cetera, et cetera. None of that has changed. I think what is a challenge for the FDA, and [ Dr. Marks ], has spoken about this publicly and others, is to make sure that we do our best to align those clinical expectations with the CMC expectations because it doesn't help you accelerate clinical if you're not willing to be flexible on the CMC side, especially in the cell and gene therapy world. That is a what I'd say zoomed-out macro question. And what we're suggesting here is that, yes, they have laid out a more what I'd say traditional approach in the CMC side, and you heard it here, with not just healthy donor cells, which we've done in the past, but actually now needing, what I'd say, the patient cells, right; and are sort of requiring that, instead of using a clinical-grade vector that's comparable to demonstrate comparability of the drug product, you actually got to use the commercial side. So that -- those, all those things sequencing. And those are things -- and what we're hinting at or suggesting is, and AV just said it, there's going to be an ongoing dialogue with the agency. What we don't want to do is presume that they're going to agree or come off of any of their perspectives. So for right now, we're going to deliver what they ask, but at the same time, as we're developing the CMC package here, we're certainly going to engage with them. And hopefully, as that data continues to be clear and clear to us and clear to them, then we can start getting to potentially figuring out a way to navigate this a little bit more -- let's just say, less traditionally and a little bit more flexibly. And that's something we're choosing our words wisely there, Yaron, for obvious reasons, right, because this has to be a collaboration. And it's one, I'll admit, right, that I'm personally a little frustrated on here, but at the same time, this is complicated. It's complicated for us. It's complicated for the agency, but sickle is too important. And the data is simply too exciting to not get this in the hands of patients in the most expeditious manner that we can.

Your next question comes from the line of Difei Yang with Mizuho.

This is Alex on for Difei. In terms of the regulatory application for sickle cell and the updated U.S. time line here, do you expect a simultaneous submission for regulatory approval in Europe?

I'll cover that. No, we're still engaging with the Europeans, so we haven't been -- we haven't sort of provided an update on that. So there's an ongoing discussion. There's both clinical and CMC, so when we can update on that, we will.

Your next question comes from the line of John Newman of Canaccord.

Yes. Just curious if you believe that -- the use of the suspension protocol or procedure versus the adherence method that you're using for TDT. Just curious if you think that, that method sort of prompted some additional investigation from the FDA. Or was this just something that they had already kind of been contemplating?

Yes. I'll address that at a high level, all right? And I think Dave mentioned this. And then we'll have Derek here jump in. It's that we're already in the process of using suspension actually. And this is one of the things that's a little lost on folks who don't live it every day, but the development of that suspension took multiple years. And actually we're really excited about the suspension product. And we actually think it's best of breed and also allows us to scale in a completely different way, so that's incredibly important. We'd hate to get to a medicine as important as this to the sickle community but not be able to deliver in a timely manner and at the scale that we need. So that's already, sort of for lack of better word, it's cleared; and it's moving into the clinical studies, is in the clinical studies, as Dave talked about. So that's sort of less of a concern. What we're talking about here is simply the comparability that we're talking about. And we're very excited about not needing the clinical side of this, meaning you could have said, "Hey, give us 10 more patients," in this commercial setting with this product, and 18 months of follow-up, all right? That would have been a very different answer. So we certainly have eliminated that as a possibility, but at the same time here now, we're pretty focused on making sure we'll provide the analytical comparability, but Derek, can you provide a little color on that to make sure it's clear on what the FDA is asking and what they're not asking?

Yes, absolutely. The comparability that they're asking for is just simply making sure that any changes that we've made in the process are properly -- there's enough data there to show that we have comparability to all the clinical data that we have. And we're really excited about actually their response to -- allowing us to do the analytical comparability even with the suspension vector, which is fantastic. And we need the suspension vector as a way to provide product to the size of the patient population that we're hoping to treat in for commercially viable costs of goods, which is an exciting part of that too.

Your next question comes from the line of Luca Issi with RBC Capital.

Just a quick one here. The first one: I think we have seen multiple partnership here with GSK, J&J, Pfizer, Allogene and Precision bio, all exploring the combo of BCMA plus gamma-secretase, so I was wondering if you or maybe Bristol have a plan to explore such combo and/or if you have any high-level thoughts on that potential synergy between the 2 modalities. And then second, obviously we have seen data today from CRISPR on sickle cell disease. I'm wondering if you have any high-level thoughts on that data. And maybe more broadly, how are you thinking at this point of your timing advantage versus them given the delay?

Yes. So why don't we -- I don't know, Dave, if you will, or Philip, you want to comment on gamma-secretase sort of at a high level. And then we can come to the competitive side of sickle, which I can start with.

Yes. This is Dave. I can address that. That's been a question we've been fielding for some time, and the answer is we are planning to evaluate that within the overall development plan of ide-cel. And what we've also said in the past, though, is that it's unclear that, given the quite remarkable sensitivity of the ide-cel binder to recognize low antigen levels and kill those target cells, as well as the fact that it's not blocked or interfered with biocidal BCMA, it's not clear that it will be beneficial in the setting of ide-cel but absolutely something that is worth evaluating. In terms of...

Let me -- go ahead.

I'm sorry.

Sorry, Dave. I'll -- I didn't know if you were switching gears or if I was going to jump in on the CRISPR comment or question.

Well, I was going to just say, Philip, I don't know if you have any other comment on the gamma-secretase combo with ide-cel beyond what I said. And if not, we can switch to CRISPR.

Yes. This is Philip. So no further comments on the gamma-secretase. I think you said it well, yes. On the CRISPR side of things, we obviously saw the abstract. And they've got a little bit more data and obviously relatively early and looking at additional patients in TDT and in sickle cell disease. And certainly from our perspective, I think the -- nothing has really changed. I mean I think it's extremely early data and there are many things to discover over time. As you're now talking to us about what it takes to get data of maturity that we've shared over the goal line, I think it's going to be interesting to see how CRISPR -- how the CRISPR approaches fare as they try and achieve the same thing and -- but maybe just to reiterate that: I mean my perspective is that the data that we've already been able to share sets an extremely high bar for products in the gene and cell therapy space and sickle cell disease. And the impact on the most -- clinically most meaningful end points is remarkable. It's hard to see how you would beat sort of 99.5% resolution in events, but more important than that, I think, is the consistency with which we're seeing the changes in beta-globin T87Q expression, the control of sickle -- of the sickle globin expression as well as just the frequency of which we're able to manufacture these products and get the product to the patient. I think these are really important components to the robustness of the manufacturing processes that Derek and his team have put in place; and that we're now only enhancing further with the suspension LVV, which is a really -- is just -- has been a herculean effort but is really rewarded as in terms of the type of products we can make and also the number of patients that we can support.

Yes.

So I think it will just be interesting to see how this plays out over time, but I think it's with -- specifically with respect to CRISPR, I think it's just very early days.

Yes. Thanks, Philip...

Yes. And this is Dave. Maybe to drop down a level on that into the actual data. When they're showing 2 patients worth of data in sickle cell disease, 1 of whom only has 3 months of follow-up and still has transfused blood onboard, you really can't interpret any signal with regard to vaso-occlusive events. That's proximal to transplants. I mean we don't really even begun -- begin assessing the clinical benefit until 6 months post transplant, when we know the confounding transplant-related interventions have sort of washed out, including blood transfusions. So very, very early. And obviously we've just spent a long time talking about working through commercial manufacturing considerations, optimizing the challenges of manufacturing in a complex field. And so when you're as early as they are, those are also very fundamental questions that they're going to need to wrestle with. And with time, they'll gain more experience, but a lot of big questions remaining for them.

Your next question comes from the line of Biren Amin with Jefferies.

What's your confidence that you can show drug product comparability with the commercial vector versus the clinical material? And how rigorous is FDA's requirements on comparability? And I guess, what's the risk that the time line could be pushed out beyond 2022? And I guess I'm trying to get a sense of if you've built in any cushion in case you have commercial material that doesn't meet comparability.

It's fair. And well, Derek, why don't you jump in to that? But Biren, remember there's 2 things going on, right? There is sort of making sure that our CMOs are ramping up, right? And that has played depending on how much we can assist and double down and get them sort of, for lack of better words, on a steady ramp towards being ready. And at the same time, how do we make sure, as the data emerges, that we continue this ongoing dialogue with the agency? And obviously everything is data dependent, but based on our experience to date, I'd be surprised if Derek said anything. But we have high degree of confidence, but you can't promise. But not to give you the answer, Derek, there, but feel free to disagree if you so do.

Thanks, Nick. I think you're right. We're generating data now, and that give us confidence that the comparability of the commercial drug product with our commercial suspension vector should be of low risk of not meeting that bar. We've got a lot of confidence in that. I think the challenge, as we talk about, is there's execution challenge in this COVID environment; and then just trying to do some very, very difficult things for the first time. And trying to do it at a level for commercial scale and commercial GMP everywhere is a challenge, but we're definitely up to that challenge and look forward to interacting with FDA on the data that we generate and being able to talk to them about it.

And one other thing, just real quick one. I think it's we've said it a few times. I just want to make sure that it's clear because it speaks to your questions. We've already generated drug product manufacture with suspension, all right? And it's in the study. It's going to patients, et cetera, so in that sense, I think we have a pretty clear line of sight. This is really about just moving from clinical facility and so forth. And that has its execution challenges, but from a technical risk point of view, I think we'd put that pretty low. Does that make sense?

Yes, it does.

Your next question comes from the line of Jason Gerberry with Bank of America.

So can you just clarify as it pertains to the sickle cell submission? The specific rate-limiting step, is it effectively just getting the cells from the disease patients for doing the comparability analysis? I just wanted to clarify the exact rate-limiting step as we think about the roughly 12-month kind of push in the time line. And then is the FDA asking for this just in sickle cell but not beta thalassemia? I just wanted to understand if there are specific disease differences that may pertain to that issue.

Yes. So let me just frame. Good question. Let me frame it up just sort of in 2 big buckets. And then Derek, maybe I'll ask you to jump in, but there's 2 things and they're related to each other, all right? One is the CMO effects and getting that ready, right? In order to have commercial lenti, in order to have commercial drug product, you've got to have those facilities ready to go, all right? And at the same slope, you've got to have those ready to go. And the agency is requiring that you have drug product out of those facilities in a sequenced manner, all right, commercial lenti in the commercial drug product facility. Right there you just connect those two. And then you add on top of it that, as you run these clinical studies, 210, you're doing them in the context of a COVID environment where there definitely is more variability than there would be on your average day, if you will. So it's in there that our estimate is, give or take, 4 to 6 months from a -- from, let's say, CMO perspective. And then the sequencing effect with the agency's request that -- to be clear, was different than what we expected and what we had sort of proposed. And that -- in there lies the ability to, hopefully, continue on an ongoing basis to discuss that with the agency. So it's kind of 2 buckets, but the way they knock together, that leads to our estimate, if that makes sense. And Derek, would you add anything to that?

No. I think you said it very well there. I think the biggest thing is just making sure that we have things in sequence, where the facility needs to be ready. And then we need to be having regulatory approval to treat patients with the material that adds some sequential things that just have to be done in order to be able to make that happen.

Yes. So this is where we say, look, we're really actually happy with the clarity. We know what we need to deliver. We know we've delivered it before. Now driving what we'd like is a more sort of flexible sort of approach to that. And that's what AV has been talking about, and that's the real-time review. That's the submission during different parts of the process, but again that's on the come. And that's sort of an upside in how we're thinking about it, but we remain committed to that, frankly, because one thing is timing. In the spirit of curing a disease, we'll kind of work our way through, but in the spirit of getting out to patients, this, we consider this a really important dialogue with the agency to make sure that we don't have any unnecessary delays. Okay, thank you for the question.

Your next question comes from the line of Raju Prasad with William Blair.

Would you mind putting kind of the CMC asks from the FDA in context of kind of the broader regulatory asks that have been -- you guys have had to do for both LentiGlobin and Lenti-D? Are you starting to see kind of a differentiation and based on indication or based on the U.S. versus the EMA? And just maybe a little bit on -- again kind of on the other question on disease state versus whether this question is based on kind of lentivirus in particular. Just a little clarity on that would be very helpful.

Yes. Overall -- maybe, AV, I'll kick this over to you because I think that's an important sort of macro question, right, because we're not alone in this space, right? And I think what you're referencing there, there certainly is -- whether it's the Sarepta crew or the BioMarin crew or it's TDT or it's ide-cel, right, there is an ongoing evolution with the agency to make sure that we land the plane. And a lot of those come in and around how we manage through the CMC dialogue and the unknowns and knowns, et cetera. And how do we do that in a thoughtful manner that is consistent with the clinical data and the approach we're taking to clinical data? But maybe, AV, you can speak to that. I know you've been working that through industry-level and at a bluebird-specific level. Maybe you have some comments. Anne-Virginie Eggimann: Sure. Maybe 2 comments. One is what's specific about sickle is that our clinical development was accelerated in a manner that's unprecedented and is certainly faster than what we've seen in our other programs compared to our manufacturing path. So we had to have extra dialogue on that, which went really well, as we just shared. With regards to the macro environment, I think the agency is really thinking about how to accelerate CMC development when they've agreed to accelerate clinical development, and we're engaged in that dialogue. And I think they are thinking about it. And it's challenging because there is not a lot of precedents and it's complicated. And product-specific versus general rules is challenging in this space, but they're engaged and they're clearly listening, so this dialogue is going in the right direction. And a lot of groups are involved in this discussion. It's not just bluebird. A lot of companies and a lot of trade associations. So we're confident that it's going to move in the right direction.

Thanks, AV. And the other thing is, if you've heard [ Dr. Marks ] speak recently, it generally gets in on the topic of CMC, balancing it with clinical expectations and the importance of gene therapy. It gets in on resourcing. How do we make sure that we have the appropriate level of resource? So there's a lot of factors going on here that are really important to the rest of the ground, but there have been enough examples of, quite honestly, communication not being ideal, awareness of expectations and/or just dialogue and getting creative, all right? How do we make sure we're taking context of clinical data as we do often on the oncology side, saying, how do we make sure that we're sort of seeing the forest for bear trees. And that is we're working through that. AV is working at that at multiple levels. And we're doing it on a programmatic level but also a macro level, and it's very clear. This is a number of other CEOs in the space I know are probably more vocal on the outside than I am on this, but it's not lost on anyone and I think we'll make a lot of progress.

Your next question comes from Matthew Luchini with BMO.

Great. So I guess, first, I thought I heard in the prepared remarks something to the effect of -- or in the context of the small number of patients needed something with the effect of "for now." And so I'm just wondering if that -- if you're trying to suggest or imply that perhaps there's some risk that FDA could actually end up wanting more than the small number of lots that they've suggested that your -- that they've sort of suggested so far. And then secondarily, on the EU, just wondering if you had interactions with EMA since these -- since the regulatory path with FDA has become more clear and if they're aware of where things stand in terms of what FDA is looking for.

Yes. This is Nick. Since I read the remarks, I can just be clear there, yes. I don't think anyone should anticipate that we're taking away the need for patients with sickle cell. So that meaning using cells from patients with sickle cell disease. The question that was more around saying as we go through that comparability program, I said at this time the FDA is requiring that we use commercial vector versus comparable clinical vector to demonstrate comparability of our commercial drug product, all right? That's what Derek has been talking about, AV has been talking about, saying, listen, as we go through this process and reiterate, we hope that we can look at the data together and determine what is the appropriate path forward. Right now you take a base case and you play it out and say, "Listen, we're going to do what you asked us to do." At the same time, we expect to sort of zoom back as the data is being generated and make sure that we're making still the right decisions on behalf of the sickle cell community and the balance, the totality of the evidence. So that's where we kind of put in that word, if you will, at this time, because we do believe this warrants a dialogue on an ongoing basis. And the agency is game for that.

Great. And on the EU?

Sorry. I didn't hear that question. Go ahead.

Yes. Maybe I can field that, Matthew. Our discussions with the FDA and the EMA are independent. As you know, we have an excellent track record in Europe with ZYNTEGLO approved; the MAA for eli-cel, our Lenti-D product, accepted last month. And we look forward to continuing positive and constructive dialogue with the EMA, but at this point we're not sharing detail on those conversations around sickle cell disease. But you could expect that in the future.

Your next question comes from the line of Vincent Chen with Bernstein.

A couple from me. The first is simply, aside from the move to suspension-based lentiviral vector versus adherence, are there any other differences between the sickle cell and the beta thal situations that contribute to the higher FDA requirements and greater complexity with sickle cell? And then the second is, I guess, just hop onto a different topic for a moment. I was wondering. For bb21217 and CRB-402, I guess we'll see data that on that soon. What would you want to see in that study for you to say that, yes, bb21217 indeed looks like it offers not just more persistency than bb2121, which I think we've seen some evidence for already but that this actually indeed translates into meaningfully better efficacy. Or is it still going to be far too early to judge?

So Derek, do you want to take the first question. And then maybe, Dave, you can jump in on 21217, and if Philip has things to add on that. Does that work, Derek? Go ahead.

Yes. So yes, good question on the -- so the -- you called up a big difference between TDT and sickle is just -- sickle, we are planning to launch with the suspension lentiviral vector. So that is a difference. And it's a comparability -- additional comparability thing that we have to do for sickle that we're not doing for TDT. Otherwise, it's simply the maturity of the manufacturing processes -- not processes but actually the sites and the readiness. They're just in a little bit different trajectories there, and clearly there are some different things with the patient cells. They're just of different types, and thus the drug products are different. So there's -- there are just some different things to do with the analytical methods to actually verifying potency on that.

Yes. And Vincent, we made a decision sometime ago, and I think it was the right one because -- to make sure that we had the suspension product for this. So at the same time, how do you get what you need to get to get in the commercial virus and commercial drug product manufacturing capabilities. And that's complicated, all right? Especially in our space, there aren't a lot of options to do that. At the same time, that's where we're looking for a little bit of flexibility based on all the data that we have, the fact that suspension is already in. And there was some flexibility from the agency, not as much as we would like. And that's what we're suggesting. We're going to continue to have that dialogue as we roll through this process. 21217 and the needs for that, Dave, do you want to comment on that, or Philip? I -- either one. Maybe Dave first.

Yes. I mean just at a high level, Vincent, as you recall, the thesis is that enriching in memory phenotype T cells that will persist in patients could prolong the therapeutic effect of the CAR T; and lead to longer responses, longer DOR, longer PFS. Of course, from a clinical trial perspective, to assess that requires time. And so that's the stage we're in now. We just disclosed that we [ treated ] our last patient in the 402 study. We'll be presenting updated data end of the year. And so we'll certainly start seeing how that's playing out. We saw some intriguing data last ASH supporting the underlying hypothesis, and as we have longer clinical follow up, we'll get a better sense of whether that's translating into the clinical outcomes that we care about.

Your next question comes from Gena Wang with Barclays.

This is [ David ] on for Gena. So I just want to get some more understanding around the compatibility assay for -- specifically for sickle cell but not for thalassemia. I want to understand. What's the difference between the 2 diseases that prompted the FDA to ask for the compatibility assay for sickle cell but not for beta thal.

Well, yes, I think pretty straightforward answer on that. Do you want to handle that, Derek? As it relates [ to the difference ]. I think we just talked through it.

Yes. So you can say we're -- we didn't need to do a comparability exercise on the -- on TDT and just because we weren't making the same level of changes in clinical-to-commercial sites as we were doing for sickle.

Yes. And we can also -- obviously the reason for that is it's a different kind of market dynamic, different market needs. And also one of the things is, as we saw the clinical data evolve, we're focused on the medium to long term too, all right, making sure that we can drive down cost of goods and continue -- while we're continuing to improve the product. So the suspension product is critical in that regard. And there's a number of other manufacturing improvements and optimizations that were -- that are well underway that we're working on. So this is, in our view, sort of playing a little bit of the long game, especially since we have multiple products. And there's lots of -- the innovation cycles, what wins here, all right? People being able to understand what's going on. That was a bit of the answer back to CRISPR as well, which is there are many -- it's easy to sort of look at very small data sets and get excited, but at the end of the day, you're not proven. We already know this can work, all right? We already know it can really well, but we've shown it for a long period of time and in commercial and we're scaling up. So I think there is just a lot of water to go under that bridge that, quite honestly, not everything that we've solved for is in the public domain. So I think a lot of other people are going to be getting the same issues. And that sort of underestimates any given moment in time, and reality is bluebird is in the middle of what I'd say a pretty significant show-me phase. "Listen, you guys are right in the middle of a bunch of filings and a bunch of launches, and go do it." And that's what we're doing. And it gets bumpy, and in many ways this is where bluebird actually shines the most. I think, Ingrid, we -- was there one more question?

Yes, presenters. Your last question comes from the line of Mark Breidenbach with Oppenheimer.

Just really quickly. I'm wondering if the next clinical update from the 206 study will have any focus or analysis of non-acute symptoms that affect sickle cell patients kind of every day. Are we going to see any quality-of-life metrics like daily pain, fatigue, opioid use or any of the other factors that are affecting these patients have nothing to do with the acute events like VOCs or acute chest syndrome?

Thank you for asking that question there. And I think, Dave, obviously, I think that would be best for you to respond to.

I -- yes. So you'll just have to stay tuned in terms of the data we'll be sharing, but importantly when you look at patient-reported outcomes, duration of follow-up is essential. And obviously having a complete data set is essential, particularly when you're looking at an uncontrolled small trial. So those are data points we're capturing. They are very important ones, but for interim data, the focus really appropriately is on the very objective measures and the key clinical parameters that we are following.

Okay, Ingrid, are we good to call it? I know there are probably some other questions here, but we can follow up with people individually. I'm sure they'll reach out to you. Anything closing thoughts, Ingrid?

No, that's perfect. You know where to find us if you need us. And we'll be reaching out to many of you momentarily, so talk to you soon.

All right, thank you for taking the time, folks. Take care. Bye.

Ladies and gentlemen, this concludes today's conference. Thank you for your participation, and have a wonderful day. You may all disconnect.