Gilmore O’Neill: One key thing I think it’s worth highlighting when we talk about patient report outcomes is that fatigue is a significant complaint. In fact, again, we heard it at the patient testimonials, lack of energy, fatigue, not just the hospitalizations and pain, but fatigue and loss of energy. And so those are important elements or specific sub-domains of the patient for outcomes that we’re paying attention to.
Operator: Our next question comes from the line of Jack Allen with Baird. Pleased proceed with your question.
Jack Allen: Great. Thanks so much for taking my question and congratulations to the team on the progress made throughout the quarter. I wanted to ask a little bit about the RMAT discussions. To what degree was the differentiation on total hemoglobin discussed in the RMAT? And then, I believe during the prepared remarks, you mentioned a more substantial data set expected in mid-2024. During the RMAT discussions, did you have any conversations around what could be viewed as a pivotal data set here? And I’d love to hear your thoughts if so.
Gilmore O’Neill: Thanks very much, Jack, for your question. I think the first thing is it’s premature to go into the details of discussions about the FDA. However, I am glad that you highlighted RMAT because indeed the FDA does and did review clinical data including hematological parameters, which, as you quite correctly pointed out, include the correction of anemia. And as we said, it also included the non-clinical package to demonstrate how that happened by design. I think the other point about the RMAT, obviously, as we said in prepared remarks, is that it essentially increases our confidence in the timeliness review through the various mechanisms that are available to us, both with high frequency engagement with the agency going forward, as well as the possibility of a priority review and rolling submission.
You asked about the substantive data set, and I think what I would say is that if you look to exa-cel as a benchmark, we’ve actually seen that the original exa-cel BLA accepted by the FDA included an efficacy data set of 20 patients with 16-month follow-up. An additional efficacy data set of 10 patients was added to that during the review period. What that actually tells us when you look at our being on track to dose our 20th patient by January — in the January 2024 timeframe, and the continuing robust enrollment that we’re seeing in a RUBY study, it really validates our line of sight to creating or generating and present — being able to present in the middle of 2024 a substantive data set with robust follow-up around a period that shows the correction of anemia and fetal hemoglobin expression and validates line of sight to a BLA into 2025.
Operator: Thank you. Our next question is from the line of Dae Gon Ha with Stifel. Please proceed with your question.
Dae Gon Ha: Hey, good morning, guys. Thanks for taking the questions. Maybe I’ll briefly go back to the off-target editing and then a BD one for Caren. On the off-target editing, I guess Gilmore, you talked a lot about the differentiation of AsCas12a versus the Cas9 being used. Just curious, does that, in your view, think you need a little bit more characterization work on the molecular side, given that Cas9 is being a little bit more prevalently used on the CRISPR/Cas based medicine field? And maybe as an offshoot of that, I think there were also discussions around how exa-cel ran all these analyses in a more theoretical manner, but didn’t really test the treated patients blood samples pre and post. So can you confirm if you guys are doing the pre and post testing of the blood samples to see if off-target editing is actually happening or not?
And then, question for Caren, to an earlier question about BD and expansion opportunity, you talked about the in vivo HSC delivery, but I don’t know if that was intentional or not, but I didn’t hear you talk about non-genotoxic conditioning, so I don’t know if you can comment on a little bit more on that. Do you see that as part of your armamentarium going forward? Perhaps your magenta experience can speak to that. Thanks so much.
Gilmore O’Neill: So thanks very much, Dae Gon. With regard to the AsCas12a versus Cas9, I think the first takeaway is that we have published data from ourselves and other labs showing that there is a differentiated, significant reduction in off-targets with AsCas12a. Secondly, we have a variable — we don’t actually believe that the prevalence of Cas9 would change the requirements for off-target data package generation. Third, our data package that we have generated to-date is very robust, and as Linda said, we’re using multiple orthogonal, both in silico and in vitro evaluations. Also including by the way our non-clinical talks in vivo, but evaluations that go beyond what we saw presented and discussed at the AdCom. So, again, all of that adds to our confidence.
And then finally, we are actually testing the drug products. So that’s kind of the old target. If I could then turn to your question around non-genotoxic conditioning, this is an area that remains of interest to us. We have done internal work. We’re also monitoring the external landscape. One of the things — one of the additional benefits of having Caren join us is that she knows, as you quite correctly pointed out, that space very well. So, Caren, I don’t know if you want to add further commentary.
Caren Deardorf: Yes. Thank you. Thanks for the question and just want to comment how excited I am to be here with the Editas team to help move these therapies forward. Now, you bring up a really important point, something that’s important to all of us and will absolutely be part of the evolution of this market space and treatment modality. I think the benefit today is that the risk benefit for severe sickle cell and TDT does remain very strong with the current offering. But we take it very seriously, and we’re doing a lot of important work to try to make sure we are part of moving forward to evolve this to be an overall better treatment.
Dae Gon Ha: Excellent. Thanks so much.
Gilmore O’Neill: Sorry. Linda —
Linda Burkly: I just wanted to add to what Gilmore had said like to affirm that we do test we have tested drug product lots from a larger number of sickle cell disease patients to confirm the and have not detected off-target editing in that larger number of sickle cell disease patients with samples.
Operator: Our next question is from the line of Phil Nadeau with TD Cowen. Please proceed with your question.
Phil Nadeau: Good morning. Congrats on progress, and thanks for taking our questions. Two from us. First, in terms of continued recruitment in the clinical trials, do you assume any change in the rate that you’ll be able to recruit patients following what seems likely to be the approvals of the first two genomic medicines for sickle cell disease by the end of the year? That’s the first question. And then, second, a follow-up on differentiation. How long a follow-up do you think you’ll need to determine whether fatigue or the hemoglobin levels are truly differentiated? Is that something that kind of relatively quickly, or will that take months, if not years of follow-up to determine? Thanks.
