EDIT - NASDAQ

Good morning and welcome to Editas Medicine’s Third Quarter 2022 Conference Call. All participants are now in a listen-only mode. There will be a question-and-answer session at the end of this call. Please be advised that this call is being recorded at the company’s request. I would now like to turn the call over to Ron Moldaver, Investor Relations at Editas Medicine. Please go ahead sir.

Thank you, Gilmore. Let's start with EDIT-301. As Gilmore noted, we recently dosed a second sickle cell disease patient in the Phase 1/2 RUBI study. Beyond the first two patients dosed with EDIT-301, we also have completed apheresis and successfully added 334 test positive sales from several additional patients. The RUBI study's Independent Data Monitoring Committee, or IDMC, is expected to review the available data this month. Once the committee has endorsed further dosing per protocol, we can then move to parallel patient dosing. We are taking multiple measures to accelerate patient recruitment, including expansion of our trial sites. We will be able to include efficacy data from all treated patients in the RUBI trial in the future registration package. So what to expect from the RUBI data released by end of this year? We plan to provide an update on safety and tolerability from both those patients, neutrophil and platelet engraftment data from both patients and key hematological parameters from one dose patient that will include total hemoglobin, fetal hemoglobin as well as cell construct erythrocytes, with measurable fetal hemoglobin known as F cells. Taking a step back, EDIT-301 is targeting the gamma-globin promoter, limiting the nature mechanism of Hereditary Persistence of Fetal Hemoglobin or HPFH. In sickle cell patients with HPFH when fetal hemoglobin level is 30% the patients usually have no vessel occlusive complications or end-organ damages. Therefore, as a threshold, we're aiming to achieve fetal hemoglobin level at least 30% in at four to five months after dosing. If we can achieve these objectives, this would meaningfully increase our confidence in EDIT-301, being a differentiated and competitive product. By using our Engineered AsCas12a with high editing efficiency and specificity by targeting the promoters of gamma-globin Gen 1 and 2, we expect this will deliver robust fetal hemoglobin expression. Suppressed vaso-occlusive crisis and provide long-term clinical benefit to those leading with sickle cell disease. Moving to our development efforts in transfusion-dependent beta thalassemia in our Phase 1/2 EDITHAL trail of EDIT-301. The study is designed to assess the safety, tolerability and preliminary efficacy of EDIT-301. The first patient in the study has been enrolled and completed apheresis. We have complete editing of the CD34+ cells to be infused back into the patient, and we are scheduling the dosing date for this patient. Let me turn over to EDIT-101 for LCA10. The BRILLIANCE studies IDMC recently met as part of the normally planned meetings. We are pleased that EDIT-101 has maintained a satisfactory safety profile. Following its review of the available clinical data, the IDMC recommended a continued the BRILLIANCE study and has endorsed continued enrollment in all active cohorts. As Gilmore mentioned, we are on track to provide an update on available clinical results from the BRILLIANCE study this month. The update will include available safety data on 12 adult and two pediatric patients and efficacy data on adult patients. The adult efficacy update was including one year of data from adult mid-dose cohort and six months data from the adult high-dose cohort. The BRILLIANCE study has multiple efficacy-related endpoints. The goal is to identify optimal outcome measures for demonstrating clinical meaningfulness in LCA10 patients, who suffered from significant and disabling early offset visual impairment. These endpoints measure psychophysical outcomes that including full-field sensitivity, functional outcome, including visual navigation course, visual function outcome, including best-corrected visual acuity or BCVA and the measures of visual quality of life that including National Eye Institute VFQ-25 instruments. I'm happy with the progress that we are making in improving the execution of our clinical program, and we want to thank our patients, investigators and the staff members at the study site for their contribution and support in helping us advance these new therapeutics. With that, I will now turn the call over to our Chief Scientific Officer, Mark to discuss our preclinical programs.

Thank you, Baisong. I would like to start with EDIT-103 for redoxin autosomal-dominant retinitis pigmentosa. EDIT-103 uses two adeno-associated virus vectors to knock out the mutant rhodopsin and correct the toxic gain of function, while simultaneously replacing that aberrant gene with a functional one. This approach can potentially address more than 150 gene mutations that cause RHO-adRP. The program employs a different mechanistic approach in EDIT-101 and we have previously reported highly promising preclinical data. Last month, during an oral presentation at the European Society of Gene & Cell Therapy annual meeting, we highlighted data demonstrating nearly 100% productive editing in nonhuman primates and the generation of over 30% functional redoxin gene replacement, which proved to be therapeutically effective in that NHP study. We expect to initiate IND-enabling studies next year following completion of the AAV vector analytical testing. Moving now to our Ex-vivo cell therapy programs. Our EDIT-202 iPSC-derived NK cell program for solid tumors is advancing towards IND-enabling studies. This program offers several important key advantages over many existing NK cell approaches. In preclinical models, we've shown that EDIT-202 has potent antitumor activity and substantially increased persistence. We utilize a feeder cell-free system for INK cell production, thereby mitigating potential risks of introducing exogenous cellular material. Through the development process, we are able to select a fully characterized clone, helping us avoid potential abnormalities and differentiating the iPSCs into NK cells. And finally, the program utilizes our proprietary editing platform such as our engineered AsCas12a nuclease and sleep knock-in technology, which we believe provides superior editing capabilities in engineered NK cells. Last month at ESGCT, we presented new preclinical data further supporting the continued development of EDIT-202. The data showed that using SLEEK to knock in membrane-band IL-15 and cleavable CD16, the EDIT-202 cells had prolonged cytokine independent persistence in-vitro as well as regulated and continuous expression of CD16 after tumor cell exposure, thereby enabling the edited cells to significantly enhance serial killing of SKOV-3 tumor cells. In the SKOV-3 intravenous solid tumor model, when combined with an antibody, the EDIT-202 cells resulted in a significant reduction in tumor burden and increased overall survival, demonstrating a 100% no-survival rate after 100 days compared to 0% using just the antibody. As we continue development of EDIT-202, we believe our approach has the potential to create an allogeneic off-the-shelf NK cell therapy medicine with enhanced activity against solid tumors. We plan on presenting additional preclinical data at the Society for Immunotherapy of Cancer Annual Meeting next week. I'll now hand the call to our Chief Financial Officer, Michelle, to review our financial results.

Thank you. We will now be conducting a question-and-answer session. [Operator Instructions] Our first question is from Gena Wang with Barclays. Please proceed with your question.

Thank you.

Our next question is from Greg Harrison with Bank of America. Please proceed with your question.

Our next caller is from Chardan, Geulah Livshits. Please proceed with your call.

Got it. Thank you.

Our next question is from Joon Lee with Truist Securities. Please proceed with your question.

Hey, thanks for taking our questions. For EDIT-103, what's the rate limiting step for IND and when should we expect that in the clinic? And why are you using Cas9 for that versus Cas12, which you think, it sounds like you're excited about? And you're claiming 100% editing in the transduced area, but what is that transduced area? How does it relate to devolve retinal space? Thank you.

Thanks, Joon. This is Mark. So we are using Cas9 in this particular product, because this fits conveniently in a single AAV. And as you know, this is a dual AAV approach where we are knocking down the mutant rhodopsin with the Cas9 nuclease and then replacing it with a codon-optimized human rhodopsin. In terms of the data, we admit in a non-human primate study, we typically administer a 100 microliter blood. So the 30% elevation is the average change in expression within that leg region. So we take tissue punches from the transduced area versus the untransduced area and make that calculation. Regarding the IND-enabling studies, as we mentioned in the script, when you move from a research setting to a GLP toxicology study setting, there's more rigor and detail around the analytical testing and requirements. And this is taking a little longer than we had initially anticipated, and that's basically the explanation for pushing out the start IND-enabling study start. And typically, we don't give specific timelines on IND submission until we've completed that work.

Our next question is from Matthew Harrison with Morgan Stanley. Please proceed with your question.

Yeah. Just to add on that about the RUBI study, Matthew, and also related to Tina's question a bit earlier. So in my comments, about 30% of fetal hemoglobin level is really based on the hypothesis of the clinical observation of the HPFH and it's not our target of the fetal hemin expression level. As Gilmore mentioned, we believe we have a differentiated and competitive product, and we are looking forward to share the data with you later this year.

Okay. thanks

Our next question is from Dae Gon Ha with Stifel. Please proceed with your question.

Excellent. Look forward to it. Thanks.

Our next question comes from Phil Nadeau with Cowen & Co. Please proceed with your question.

Thanks, Phil. For the RUBY efficacy data, as I mentioned, we will provide safety as well as key hematological parameters. We certainly will report VOC. But as I mentioned earlier, a short-term duration of observation may not be most meaningful, but system will report a data on that.

Yes, Phil, it's Mark. I think – we perhaps have discussed at the last earnings call. We're completing the -- any animal pharmacology data that's necessary to support the IND-enabling tox study design and conduct and as we mentioned in the script, that's planned for some time next year.

Perfect. Thank you.

Our next question is from Jay Olson with Oppenheimer. Please proceed with your question.

Yes. Thanks for the question. Yes, as I mentioned, we did have IDMC meeting as planned, as we previously scheduled a normal meeting. And at that meeting, the IDMC reviewed all the clinical data and they see a satisfactory safety profile. And regarding your question about high dose pediatric cohort – it was discussed at IDMC. And although they are satisfactory with the safety profile, recommended continue the study as planned, but they recommend to review additional three months of data from the existing patients before starting the high-dose cohort in pediatrics. This will not impact our plan to release the data this month as we just previously mentioned. And it will also will not impact our decision about the program. We feel we have adequate data to make a decision about this program.

Thank you very much.

Our next question is from Joel Beatty with Baird. Please proceed with your question.

And maybe just one other comment. I think one reason why we are getting such high productive editing for the RP4 program, is it's a single guide. So, we're simply introducing indels, which caused frame shifts in the transcription and therefore, loss of the endogenous rhodopsin. That's different to the 101 program where you have a dual guide and so the productive editing, which in this case is deletion or reversion is a low percentage.

Great. Thank you.

Our next question is from Luca Issi with RBC. Please proceed with your question.

Great. Thanks for taking our questions.

Our next question comes from Yanan

Hi. Thanks for taking my questions. So first on the sickle cell program, I think, Baisong, you mentioned that the minimum HbF level of 30%, which is considered clinically meaningful, is not necessarily the target HbF level. Could you elaborate a bit more on the target HbF level? And secondarily, for this program, where could you talk about the venue for the sickle cell data update? And also in terms of the length of the follow-up for the first patient, where do you plan to make the data cut in terms of, for the month -- month follow-up? Thanks.

Yes, yes. sure. That Yanan is a good question that about the endpoint, right, as Gilmore mentioned earlier about the purpose of this premium study as well as why we actually conducted the Natural History Study. So, we will be able to use the data from Natural History Study to contextualize, as you pointed out for FST or Visual Navigation Course. The challenge is actually not only for the pediatric patient, could it be for other adult patient too, so we fully understand that. So, we are analyzing testing and retesting variability and all those reliability of the endpoints. Yeah.

Great. Thanks, Baisong and thanks Gilmore for all the color.

Our next question comes from Madhu Kumar with Goldman Sachs. Please proceed with your question.

Hi, this is Mario [ph] here on for Madhu, we have two questions. So, first, how should we think about the internal pipeline development versus external partnering for X-ocular or hemoglobinopathies programs, particularly for oncology cell therapy programs? And then second, what impact could the Inflation Reduction Act or IRA have on indication expansion on pipeline candidates?

Thanks very much for your questions, Mario [ph]. With regard to the internal pipeline, as I said a little earlier in my prepared remarks, we are -- continue -- we have and I've been very excited and happy with the work I've done with the executive team in actually looking across our portfolio as we evaluate our strategy and looking forward to sharing that in the coming months. But I think, the one thing I can say that has been said consistently is that we believe we have a very exciting technology and we want to find ways to unlock its full potential by appropriate focusing of the pipeline internally, as well as seeking powerful and robust partnerships to enable us to expand our bandwidth to fully realize the potential of our technology. But as I say, we will be able to share more about that in the coming months. And with regard to the IRA, thank you for that. We actually -- I know that there has been a bit of pressure, some companies have actually talked about IRA restricting their approaches, I think it's important and we certainly looked at that legislation and the regulation around it, and we believe that there is -- and it is designed to enable us to develop new technologies to target, difficult and challenging human diseases that has struggled with a very high unmet need. And so we actually feel very optimistic that our technology can operate and innovate, continue to innovate within the context of the IRA or into the way the regulation is written.

Our next question comes from Liisa Bayko with Evercore ISI. Please proceed with your question.