Q2 2024 Editas Medicine Inc Earnings Call

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Operator: Good morning, and welcome to the Editas Medicine second quarter 2024 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. I would like to turn the call over to Cristi Barnett, Corporate Communications and Investor Relations, at Editas Medicine.

Speaker Change: Good morning and welcome to the Editas Medicine second quarter 2024 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.

Speaker Change: is being recorded at the company's request

Cristi Barnett: I would like to turn the call over to Cristi Barnett, Corporate Communications and Investor Relations at Editas Medicine.

Cristi Barnett: Thank you, Brittany. Good morning, everyone, and welcome to our second quarter 2024 conference call. Earlier this morning, we issued a press release providing our financial results and recent corporate updates. A replay of today's call will be available in the Investors section of our website approximately two hours after its completion.

Unknown Executive: Good morning, everyone, and welcome to our second quarter 2024 conference call. Earlier this morning, we issued a press release providing our financial results and recent corporate updates. A replay of today's call will be available in the investor's section of our website approximately two hours after its completion.

Cristi Barnett: Thank you, Brittany. Good morning, everyone, and welcome to our second quarter 2024 conference call. Earlier this morning, we issued a press release providing our financial results and recent corporate updates.

Cristi Barnett: A replay of today's call will be available in the Investors section of our website approximately two hours after its completion.

Cristi Barnett: After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC, as updated by our subsequent filings.

Unknown Executive: After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results made differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the risk factors section of our most recent annual report on Form 10-K, which is on file with the SEC as updated by our subsequent filings.

Cristi Barnett: After our prepared remarks, we will open the call for Q&A.

Cristi Barnett: As a reminder, various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for the purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995.

Cristi Barnett: Actual results may differ materially from those indicated by these forward-looking statements.

Cristi Barnett: As a result of various important factors, including those discussed in the risk factors section of our most recent annual report on Form 10-K , which is on file with the SEC, as updated by our subsequent filings.

Unknown Executive: In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change.

Cristi Barnett: In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. Now, I will turn the call over to our CEO, Gilmore ONeill.

Cristi Barnett: In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date.

Cristi Barnett: Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. Now, I will turn the call over to our CEO , Gilmore ONeill.

Gilmore ONeill: Now, I will turn the call over to our CEO, Gilmore O'Neill. Thanks, Kristi, and good morning, everyone. Thank you for joining us today on Editas' second quarter of 2024 earnings call. With me today are four other members of the Editas executive team, our chief medical officer, Bayko on Li, our chief financial officer, Eric Lucera, our chief scientific officer, Linda Burkly, and our chief commercial and strategy officer, Taren Deardorf.

Gilmore ONeill: Thanks Cristi and good morning everyone. Thank you for joining us today on Editas' second quarter of 2024 earnings call. With me today are four other members of the Editas executive team, our chief medical officer, Baisong Mei, our chief financial officer, Erick Lucera, our chief scientific officer, Linda Burkly, and our chief commercial and strategy officer, Caren Deardorf. Because it is summertime, we're going to keep today's prepared remarks brief and leave more time to take your questions.

Gilmore ONeill: Thanks, Cristi, and good morning, everyone. Thank you for joining us today on Editas' second quarter 2024 earnings call.

Speaker Change: With me today are four other members of the Editas executive team, our Chief Medical Officer, Baisong Mei, our Chief Financial Officer, Erick Lucera, our Chief Scientific Officer, Linda Burkly, and our Chief Commercial and Strategy Officer, Caren Deardorf.

Gilmore ONeill: Because of the summertime, we're going to keep today's prepared remarks brief and leave more time to take your questions. Let me start by saying that we are pleased with Editas' momentum and progress in the second quarter of 2024, as we pursue Editas' goal to deliver life-changing medicines to patients with previously untreatable or under-treated genetic diseases and the position Editas has as a leader in in vivo programmable gene editing.

Speaker Change: Because it is summertime, we're going to keep today's prepared remarks brief and leave more time to take your questions.

Gilmore ONeill: Let me start by saying that we are pleased with Editas' momentum and progress in the second quarter of 2024, as we pursue Editas' goal to deliver life-changing medicines to patients with previously untreatable or undertreated genetic diseases and to position Editas as a leader in in vivo programmable gene editing. Three pillars underpin our strategy. The first of those pillars is to drive Renicel, a gene-edited cell therapy for hemoglobinopathies, formerly known as EDIT301, toward BLA and commercialization. Second, to build a differentiated in vivo editing pipeline. And third, to increase business development activities with a particular focus on monetizing our very strong IP.

Speaker Change: Let me start by saying that we are pleased with Editas' momentum and progress in the second quarter of 2024 as we pursue Editas' goal to deliver life-changing medicines to patients with previously untreatable or undertreated genetic diseases and to position Editas as a leader in in vivo programmable gene editing.

Gilmore ONeill: Three pillars underpin our strategy. The first of those pillars is to drive Renicell, a gene-edited cell therapy for hemoglobin opopies, formerly known as Edit 301, toward BLA and commercialization. The second, to build a differentiated in vivo editing pipeline. And the third, to increase business development activities with a particular focus on monetizing our very strong IP.

Speaker Change: Three pillars underpin our strategy. The first of those pillars is to drive Renicel, a gene-edited cell therapy for hemoglobinopathies, formerly known as EDIT301, toward BLA and commercialization.

Speaker Change: The second, to build a differentiated in vivo editing pipeline. And the third, to increase business development activities with a particular focus on monetizing our very strong IP.

Gilmore ONeill: At the start of 2024, we announced the following 2024 objectives. For any cell, we will provide a clinical update from the RUBY trial for severe sickle cell disease and the EDITHYL trial for transfusion-dependent beta thalassemia in mid-2024 and by year-end 2021. We would complete adult cohort enrollment and initiate the adolescent cohort in Ruby and continue enrollment in Editas. For our in vivo pipeline, we would establish in vivo pre-clinical proof of concept for an undisclosed indication, and for BD, we would leverage our robust IP portfolio and business development to drive value and complement core gene editing technology capabilities. So how are we performing against this strategy and these objectives in the second quarter?

Gilmore ONeill: At the start of 2024, we announced the following 2024 objective. For Renicell, we would provide a clinical update from the Ruby trial for severe sickle cell disease and the Edithal trial for transfusion-dependent beta-thalassemia in mid-2024 and by year-end 2024. We would complete adult cohort enrollment and initiate the adolescent cohort in Ruby and continue enrollment in Edithal. For our in vivo pipeline, we would establish in vivo preclinical proof concept for an undisclosed indication. And for BD, we would leverage our robust IP portfolio and business development to drive value and complement core gene-editing technology capabilities.

Speaker Change: At the start of 2024, we announced the following 2024 objectives. For Renicel, we will provide a clinical update from the RUBY trial for severe sickle cell disease and the Edithal trial for transfusion-dependent beta thalassemia in mid-2024 and by year-end 2024.

Speaker Change: We would complete adult cohort enrolment and initiate the adolescent cohort in RUBY and continue enrolment in EDIFEL.

Speaker Change: For our in vivo pipeline, we would establish in vivo pre-clinical proof of concept for undisclosed indication, and for BD, we would leverage our robust IP portfolio and business development to drive value and complement core gene editing technology capabilities.

Gilmore ONeill: So how are we executed against this strategy and these objectives in the second quarter? Let's start with Renicell. First, we shared Ruby and Edithal's clinical data in June at EHA 2024, the European Hematology Association's Annual Congress. The Ruby data set included 18 sickle cell patients with 2.4 to 22.8 months of follow-up, and the Edithal data set included clinical data from 7 beta-thalassemia patients with 4.1 to 12.8 months of follow-up. These data from the Ruby trials support our continued belief that Renicell will be a best-in-class product for sickle cell disease.

Speaker Change: So how are we executed against this strategy and these objectives in the second quarter? Let's start with Renicell.

Gilmore ONeill: Let's start with Renicel. First, we shared Ruby and Edipal clinical data in June at IHAD 2024, the European Hematology Association's annual congress. The RUBY dataset included 18 sickle cell patients with 2.4 to 22.8 months of follow-up, and the EDITHAL dataset included clinical data from 7 beta thalassemia patients with 4.1 to 12.8 months of follow-up. These data from the RUBY trial support our continued belief that Renicel will be a best-in-class product for sickle cell disease. So why do we think that?

Speaker Change: First, we shared Ruby and Edita's clinical data in June at EHA 2024, the European Hematology Association's annual congress.

Speaker Change: The RUBY dataset included 18 sickle cell patients with 2.4 to 22.8 months of follow-up. And the EDITHAL dataset included clinical data from 7 beta thalassemia patients with 4.1 to 12.8 months of follow-up.

Speaker Change: These data from the RUBY trial support our continued belief that Renacel will be a best-in-class product for sickle cell disease. So why do we think this?

Gilmore ONeill: So why do we think this? All patients treated in the Ruby trials are free from vasocuse events post-Renicell infusion. All patients have robust correction of anemia, with a mean total hemoglobin level within the normal range for both genders at greater than 14 grams per deciliter. And all patients have high fetal hemoglobin, with levels well above 40% from six months onwards. We also demonstrate fastened graph with low variability with a mean utrophilin graph of 23 days, which may translate to short and hostile states for patients. For cell collection, we have a mean of two aphoresis cycles with a range of 1 to 4 per patient.

Gilmore ONeill: All patients treated in the RUBY trial are free from vaso-occlusive events post-renal cell infection. Additionally, all patients have robust correction of anemia with a mean total hemoglobin level within the normal range for both genders at greater than 14 grams per deciliter. And all patients have high fetal hemoglobin, with levels well above 40% from six months on. We also demonstrate fast engraftment with low variability, with a mean neutrophil engraftment of 23 days, which may translate to shortened hospital stays. For cell collection, we have a mean of two apheresis cycles with a range of one to four per patient.

Speaker Change: All patients treated in the RUBY trial are free from vaso-occlusive events post-Renaissance infusion.

Speaker Change: All patients have robust correction of anemia with a mean total hemoglobin level within the normal range for both genders at greater than 14 grams per deciliter.

Speaker Change: And all patients have high fetal hemoglobin with levels well above 40% from 6 months onwards.

Speaker Change: We also demonstrate fast engraftment with low variability with a mean neutrophil engraftment of 23 days, which may translate to shortened hospital stays for patients.

Speaker Change: For cell collection, we have a mean of two apheresis cycles with a range of one to four per patient.

Gilmore ONeill: Finally, in addition to the clinical data shared at EHA, on the manufacturing front for Renicell, we have a robust manufacturing process with a low failure rate that continues to improve with the experience. This low rate of manufacturing failure can decrease patient burden and reduce overall cost as we avoid cell recollection and redundant cost of goods sold or caused.

Gilmore ONeill: Finally, in addition to the clinical data shared at EHA, on the manufacturing front for any cell, we have a robust manufacturing process with a low failure rate that continues to improve with experience. This low rate of manufacturing failure can decrease patient burden and reduce overall costs as we avoid salary collection and redundant cost of goods sold, or COGS, and we're on track to share additional clinical data for both the RUBY and EDITAL trials by the end of this year 2021.

Speaker Change: Finally, in addition to the clinical data shared at EHA on the manufacturing front for RNA cells, we have a robust manufacturing process with a low failure rate that continues to improve with experience.

Speaker Change: This low rate of manufacturing failure can decrease patient burden and reduce overall costs as we avoid salary collection and redundant cost of goods sold, or COGS.

Gilmore ONeill: and we are on track to share additional clinical dates for both the Ruby and Edith L trials by the end of this year, 2024. Second, Ruby Enromed and dosing continues to be strong. Indeed, we have now completed enrollment of the adolescent cohort. As a reminder, we completed the adult cohort enrollment in the first quarter of this year. We are manufacturing drug product and scheduling adolescent and adult dosing concurrently. We also continue to progress Edith L and are pleased to announce completion of the adult cohort enrollment and continue to dose patients. Finally, based on our continued and collaborative conversations with the FDA, we still expect our future BLA package to be similar in number of patients and duration of follow-up to what we've seen in the gene editing medicine field.

Speaker Change: And we're on track to share additional clinical data for both the RUBY and EDITAL trials by the end of this year, 2024.

Gilmore ONeill: Second, RUBY enrollment and dosing continues to be strong. Indeed, we have now completed enrollment in the adolescent cohort. As a reminder, we completed enrollment in the adult cohort in the first quarter of this year. We are manufacturing the drug product and scheduling adolescent and adult dosing concurrently.

Speaker Change: Second, RUBY enrollment and dosing continues to be strong. Indeed, we have now completed enrollment of the adolescent cohort. As a reminder, we completed the adult cohort enrollment in the first quarter of this year.

Speaker Change: We are manufacturing drug product and scheduling adolescent and adult dosing concurrently.

Gilmore ONeill: We also continue to progress EDIFEL and are pleased to announce completion of the adult cohort enrollment and will continue to do so. Finally, based on our continued and collaborative conversations with the FDA, we still expect our future BLA package to be similar in number of patients and duration of follow-up to what we've seen in the gene editing medicine field. Before I turn to Google, I would also like to state that we are very focused on the best use of capital as we develop Renicel and look to the future.

Speaker Change: We also continue to progress EDITAL and are pleased to announce completion of the Adult Cohort Enrollment and continue to dose patients.

Speaker Change: Finally, based on our continued and collaborative conversations with the FDA, we still expect our future BLA package to be similar in number of patients and duration of follow-up to what we've seen in the gene editing medicine field.

Gilmore ONeill: Before I turn to Google, I would also like to state that we are very focused on the best use of capital as we develop Renicell and map to the future. As part of that focus, we frequently evaluate opportunities, including the potential for partnering Renicell to most efficiently drive Renicell drugs, commercialization, undemodied, delivered to patients in need.

Speaker Change: Before I turn to Invo, I would also like to state that we are very focused on the best use of capital as we develop Renessel and map to the future. As part of that focus, we frequently evaluate opportunities, including the potential for partnering Renessel to most efficiently drive Renessel towards commercialization and ultimately deliver it to patients in need.

Gilmore ONeill: As part of that focus, we frequently evaluate opportunities, including the potential for partnering Renicel to most efficiently drive Renicel towards commercialization and ultimately deliver it to patients in need. As a reminder, our internal development efforts are differentiated from established modalities, and we are not pursuing the same gene editing approach as others. First, our strategy is to use our InDel technology for functional upregulation of gene expression to address loss of function or deleterious mutations.

Gilmore ONeill: Now let's turn to our In vivo pipeline, where we continue to strengthen our In vivo discovery capabilities and drive lead discovery work on In vivo therapeutic targets in hematopoietic extensiles and other tissues. Importantly, we remain on track to establish in vivo preclinical proof of concept for undisclosed indications by the end of the year. We want to take a moment, rather I want to take a moment to reiterate our in vivo strategy to develop a pipeline of gene editing medicines for patients with serious genetic disease. As a reminder, our internal development efforts are differentiated from established modalities, and we are not pursuing the same gene editing approach as others.

Speaker Change: Now let's turn to our in vivo pipeline where we continue to strengthen our in vivo discovery capabilities and drive lead discovery work on in vivo therapeutic targets in hematopoietic stem cells and other tissues.

Speaker Change: Importantly, we remain on track to establish in vivo preclinical proof of concept for undisclosed indication by the end of the year.

Speaker Change: We want to take a moment, rather I want to take a moment, to reiterate our e-review strategy to develop a pipeline of gene editing medicines for patients with serious genetic disease.

Speaker Change: As a reminder, our internal development efforts are differentiated from established modalities, and we are not pursuing the same gene editing approach as others. First,

Gilmore ONeill: First, our strategy is to use our In Dell technology for functional up regulation of gene expression to address loss of function or deleterious mutations. Let me be clear, our strategy is not the knockdown strategy that others in gene editing are pursuing. And it is worth highlighting that we have already demonstrated that our In Dell technology can drive functional gene up regulation, thus creating differentiated experimental medicines as in our X vivo development of Renicell. With Renicell, we leverage our In Dell CRISPR technology to up-regulate the expression of the gamma-globing gene, a functional homolog of the beta-globing gene through direct editing of the HBG12 promoter site.

Speaker Change: Our strategy is to use our in-dell technology for functional up-regulation of gene expression to address loss of function or deleterious mutations. Let me be clear, our strategy is not the knockdown strategy that others in gene editing are pursuing.

Speaker Change: And it is worth highlighting that we have already demonstrated that our INDEL technology can drive functional gene upregulation, thus creating differentiated experimental medicines, as in our ex vivo development of Renifel.

Speaker Change: With RenyCell, we leverage our Intel CRISPR technology to up-regulate the expression of the gamma-globin gene, a functional homologue of the beta-globin gene, through direct editing of the HBG1-2 promoter site.

Gilmore ONeill: We are now applying the same approach to in vivo therapeutics by using our In Dell technology to functionally up-regulate the wild-type allele or functional homolog of target disease genes as we build our differentiated pipeline.

Speaker Change: We are now applying this same approach to in vivo therapeutics by using our Indel technology to functionally upregulate the wild type alleles or functional homolog of target disease genes as we build our differentiated pipeline.

Gilmore ONeill: Why does the difference between our functional up-regulation strategy and the knockdown strategy used by other companies matter? Because with our in vivo strategy, we are not competing with existing modalities or technologies in development that are based on knockdown strategies. Second, our indication, selection strategy, targets rare and orphan diseases that we believe will allow us to be the first or best in class for a given indication. We expect to move into diseases with larger patient populations in the future. Our lead discovery work is in vivo therapeutic targets in hematopoietic stem cells and other tissues.

Speaker Change: Why does the difference between our functional upregulation strategy and the knockdown strategy used by other companies matter? Because with our in vivo strategy we are not competing with existing modalities or technologies in development that are based on knockdown strategies.

Speaker Change: Second, our indication selection strategy targets rare and orphan diseases that we believe will allow us to be the first or best in class for a given indication.

Speaker Change: We expect to move into diseases with larger patient populations in the future. Our lead discovery work is in in vivo therapeutic targets in hematopoietic stem cells and other tissues.

Gilmore ONeill: Third, Edith has this well positioned to achieve success with our In vivo strategy and pipeline with our established capabilities in four main components of In vivo gene editing. One, our guide RNA modifications that enable high-pognacy, gene editing and multiple cell types, including in the liver, and improve gene editing outcomes in vivo. Two, a superior editing enzyme in ASCAST128. Three, our messenger RNA, and four, delivery technology where we are currently evaluating lipid nanoparticles for delivery of gene editing cargo into multiple tissue types with multiple companies, as well as evaluating additional next generation delivery technology.

Speaker Change: Third, Editas is well positioned to achieve success with our in vivo strategy and pipeline with our established capabilities in the four main components of in vivo gene editing medicine.

Speaker Change: 1. Our guide RNA modifications that enable high-potency gene editing in multiple cell types, including in the liver, and improve gene editing outcomes in vivo.

Speaker Change: 2. A superior editing enzyme in ASCAS12A. 3. Our messenger RNA. And 4.

Speaker Change: Delivery technology, where we are currently evaluating lipid nanoparticles for delivery of gene editing cargo into multiple tissue types with multiple companies, as well as evaluating additional next generation delivery technology.

Gilmore ONeill: I look forward to sharing more details about our in vivo pipeline later this year and our in vivo proof concept.

Gilmore ONeill: I look forward to sharing more details about our in vivo pipeline later this year and our in vivo proof. Finally, I'd like to refer you to our press release issued earlier today for a summary of our financial results for the second quarter of 2024. I will take this opportunity to briefly review a few items for the quarter.

Speaker Change: I look forward to sharing more details about our In Vivo pipeline later this year and our In Vivo proof of concept.

Eric Lucera: Finally, I'd like to refer you to our press release issued earlier today for a summary of our financial results for the second quarter of 2024. I take this opportunity to briefly review a few items for the quarter. Our cash, cash equivalents and marketable securities as of June 30, were 318 million compared to $377 million as of March 31, 2024. As you will note, our burn rate was slightly higher this quarter than the past. This higher rate is due to increased external research and development expenses, primarily related to clinical and manufacturing costs related to the accelerated progression of our RNA cell program.

Speaker Change: Finally, I'd like to refer you to our press release issued earlier today for a summary of our financial results for the second quarter of 2024. I take this opportunity to briefly review a few items for the quarter.

Speaker Change: Our cash equivalents and marketable securities as of June 30th were $318 million compared to $377 million as of March 31st, 2024. As you will note, our burn rate was slightly higher this quarter than in the past.

Speaker Change: This higher rate is due to increased external research and development expenses, primarily related to clinical and manufacturing costs, related to the accelerated progression of our RenyCell program.

Eric Lucera: We expect our existing cash, cash equivalents and marketable securities together with the near term annual license fees and the contingent upfront payment under our license agreement Vertex to fund our operating expenses and capital expenditures into 2026.

Speaker Change: We expect our existing cash, cash equivalents, and marketable securities, together with the near-term annual license fees and the contingent upfront payment payment under our license agreement vertex, to fund our operating expenses and capital expenditures into 2026.

Gilmore ONeill: Before we turn to Q&A, as always, it must be said that we could not achieve our objectives without the support of our patients, caregivers, investigators, employees, corporate partners, and you. We are energized by and proud of our progress and execution this quarter. With our sharp and strategic focus, our world-class scientists and employees are keen drive and execution and strong balance sheet. We continue to progress our strategy to deliver differentiated editing medicines to patients with serious genetic diseases and evolved from a development stage technology platform company into a commercial stage gene editing company.

Speaker Change: Before we turn to Q&A, as always, it must be said that we could not achieve our objectives without the support of our patients, caregivers, investigators, employees, corporate partners, and you.

Speaker Change: We are energized by and proud of our progress and execution this quarter.

Speaker Change: With our sharp and strategic focus, our world-class scientists and employees, our keen drive and execution, and strong balance sheet, we continue to progress our strategy to deliver differentiated editing medicines to patients with serious genetic diseases and evolve from a development-stage technology platform company into a commercial-stage gene editing company.

Gilmore ONeill: Thank you very much for your interest in Editas. We are happy to answer questions now. Thank you.

Speaker Change: Thank you very much for your interest in Editas. We are happy to answer questions now. Thank you.

Unknown Executive: At this time, if you would like to ask a question, please press the star and one on your telephone keypad. You may remove yourself from the queue at any time by pressing star two. Once again, that is star and one.

Speaker Change: At this time, if you would like to ask a question, please press the star and 1 on your telephone keypad. You may remove yourself from the queue at any time by pressing star 2. Once again, that is star and 1 if you would like to ask a question. And we will take our first question from Jack Allen with Barron. Your line is open.

Jack Allen: If you would like to ask a question, and we will take our first question from Jack Allen with there and your line is open. Great. Thank you so much for taking the questions, and congratulations on our progress made throughout the quarter. I apologize for any background noise here. I'm traveling today.

Jack Allen: Great, thank you so much for taking the questions and congratulations on all the progress made throughout the quarter. I apologize for any background noise here, I'm traveling today.

Jack Allen: But I wanted to ask about the pre-clinical proven concept from the INDVO program that's expected later this year. I'm hoping you could just elaborate a little bit more as it relates to what kind of data you look to put out.

Jack Allen: But I wanted to ask about the preclinical proof of concept from the in vivo program that's expected later this year.

Speaker Change: I was hoping you could just elaborate a little bit more as it relates to what kind of data you look to put out, will it be in a large animal model or a small animal model, and how should we think about the types of experiments you're looking to do to elucidate the off-target editing profile for this program?

Gilmore ONeill: So, Jack, I think you broke up near the end, but let me just restate the question in the way I heard it, and then hopefully, you know, if you need to correct it, let us know. So essentially, you just want to have an understanding of the data that we will have for our INDVO POC, the size or the species that we will use INDVO. And I think you want to talk about. I think I might have heard you talk about indications. I'm not sure.

Speaker Change: So, Jack, I think you broke up near the end, but let me just restate the question the way I heard it, and then hopefully, you know, if you need to correct it, let us know. So essentially, you just want to have an understanding of the data that we will have for our in vivo POC, the size or the species that we will use in vivo. And I think you wanted to talk about, I think I might have heard you talk about indications. I'm not sure.

Linda Burkly: Yeah, so I'm going to ask Linda maybe to address your question. Yeah, thank you, Jack. You did break up a little bit, so thanks, Gilmore, for elaborating there. So we, yes, we are on track to establish pre-clinical POC in vivo for this undisclosed indication by end of year. We've not yet disclosed the CGs in which we're working, but our evaluation process is going to entail evaluating the bio-distribution to the site of interest, the efficiency of editing, the level of target modulation measured, for example, by a biomarker readout, and, of course, the tolerability. We’ll be sharing more information, the forum, and the timing for our announcement of that data at a future time.

Speaker Change: Yeah, so I'm going to ask Linda maybe to address your question. Yeah. Thank you, Jack. You did break up a little bit So thanks Gilmore for elaborating there

Linda Burkly: So we, yes, we are on track to establish preclinical POC in vivo for this undisclosed indication by end of year. We've not yet disclosed the species in which we're working, but our evaluation process is going to entail evaluating the bio distribution to the site of interest, the efficiency of editing, the level of target modulation measured, for example, by a biomarker readout, and of course, the tolerability.

Linda Burkly: And we'll be sharing more information, the forum, and the timing for our announcement of that data at a future time.

Jack Allen: Great, thank you so much for taking the questions. Thanks, Jack. Thank you.

Operator: Thank you. We'll take our next question from Samantha Semenkow with Citi. Your line is open.

Speaker Change: Great. Thank you so much for taking the question.

Samantha Semenkow: We'll take our next question from Semenkow with City Hermione's open. Hi, great. Good morning, and thanks for taking the question. Just building on the prior question, you're using an LNP because of your strategy and non-viral.

Speaker Change: Thanks Jack. Thank you. We'll take our next question from Samantha Semenkow with Citi. Your line is open.

Samantha Semenkow: Hi, great. Good morning, and thanks for taking the question. Just building on the prior question, you're using an LNP because that's your strategy, non-viral. Do you expect to have an LNP targeted for the tissue of interest for the proof of concept readout indication optimized this year, or would you need to further optimize after the proof of concept is in hand? Thank you.

Samantha Semenkow: Hi, great. Good morning, and thanks for taking the question. Just building on the prior question, you're using an LNP because that's your strategy, non-viral. Do you expect to have an LNP targeted for the tissue of interest for the proof-of-concept readout indication optimized this year, or would you need to further optimize after the proof-of-concept is in hand? Thank you.

Samantha Semenkow: Do you expect to have an LNP targeted for the tissue of interest for the proof-of-concept readout indication optimized this year, or would you need it further optimized after the proof-of-concept doesn't hand? Thank you.

Linda Burkly: So Sam, thank you very much for your question. I'll have Linda take that. Yeah, thank you, Sam. Thank you for the question. We are evaluating LNPs with different partners because we are interested in targeting different tissue cell types for different disease areas of interest. We have it at disclosed, which tissues we're doing the non-clinical POC targeting in, and we'll be sharing that information at a future time when we disclose the data.

Samantha Semenkow: So Sam, thank you very much for your question. I'll have Linda

Linda Burkly: Take that.

Linda Burkly: Yeah, thank you, Sam. Thank you for the question. We are evaluating LMPs with different partners because we are interested in targeting different tissue cell types for different disease areas of interest. We haven't yet disclosed, you know, which tissues were doing the non-clinical.

Samantha Semenkow: So, in terms of the targeting aspects that you refer to, we'll share the information in the future. Thank you. Great. Love the summertime strategy. Very efficient. Maybe it'll continue into the fall and winter. We'll see.

Linda Burkly: Thank you.

Unknown Executive: Great. Love the summertime strategy. Very efficient.

Speaker Change: went with Cantor Fitzgerald, your last name.

Speaker Change: Thank you for joining us.

Speaker Change: Oh, great. Love the summertime strategy. Very efficient. Maybe it'll continue into the fall and winter. We'll see. In terms of my questions, first, with the Adolescent Ready So cohort now completed in terms of enrollment, can you start to estimate your timeline to a BLA?

Unknown Executive: Maybe it'll continue into the fall and winter. We'll see. In terms of my questions, first, with the Adolescent Ready So cohort now completed in terms of enrollment, can you start to estimate your timeline for a BLA?

Eric Lucera: In terms of my questions first, with the adolescent Renekso cohort now completed in terms of enrollment, can you start to estimate your timeline to a BLA? Thank you, Eric.

Erick Lucera: Thank you, Erick. I'm going to have Baisong take that question. Thank you for your questions.

Baisong Mei: I'm going to have Bay Song take that question for you. Thank you for the question, Eric. We have announced that in June, we have those more than 20 patients, and we'll continue to do those in patient. So that is moving along very well. And then we continue to consider the catch GV approval at our benchmark so that in terms of sample size, in terms of efficacy sample size as well as observation duration of 15 to 18 months. And the total sample size initial submission with 20 patients and with additional chem patients doing the review. So this is kind of the scope of that.

Speaker Change: Thank you, Erick. I'm going to have Baisong take that question for you.

Baisong Mei: Thank you for the question, Erick.

Baisong Mei: We have announced that in June we have dosed more than 20 patients and we'll continue to dose inpatients.

Speaker Change: So that is moving along very well, and then we continue to consider.

Speaker Change: So that in terms of sample size, in terms of efficacy sample size, as well as observation of duration of 15 to 18 months.

Speaker Change: and the total sample size initial submission with 20 patients and with additional 10 patients doing the review.

Baisong Mei: And we have now shared the specifics of the timeline because we have to get final alignment with the FDA, but we are very optimistic that we are collecting the data from. We are closing to the BLA data package we are looking for.

Speaker Change: So this is kind of the scoop of that, and we have not shared the specifics of the timeline because we have to get a final alignment with the FDA, but we are very optimistic that we are collecting the data.

Speaker Change: We are closing to the BLA data package we are looking for.

Baisong Mei: Thank you very helpful, and maybe Baisong or Gilmore, can you talk about what we hope to learn at the late 2024 update on the program, but it's Gilmore mentioned at this point we know a bit about where it starts profile. So Baisong. Yeah, thanks, Eric, yeah. So we expect to have data from longer duration of follow up for those patients we present at EHA, which means we're going to have more than 10 patients at one year exposure and additional patients have a different exposure. And then we also at EHA, we present data for 18 patients. We have seen DOSI multiple more patients.

Speaker Change: Thank you, very helpful. And maybe, Baisong or Gilmore, can you talk about what we hope to learn at the late 2024 update on the program? But as Gilmore mentioned, at this point, we know a fair bit about Renaissance Health's profile.

Erick Lucera: So we we, we expect to have.

Speaker Change: Data from longer duration of follow-up for those patients we present at EHA.

Speaker Change: which means we're going to have...

Speaker Change: More than 10 patients have one year exposure.

Speaker Change: and additional patients have a different exposure. And now we also, at EHR, we present data for 18 patients. We are sensing those in multiple more patients. So we're going to have more patient data also.

Baisong Mei: So we're going to have more patient data also. So with that, we are very excited for the data end of the year because we're going to have longer duration and we're going to have data packaged. Similar to the cash GBBOA, so we're looking forward to share data with you all. Thank you very much. Thank you.

Speaker Change: So with that, we are very excited for the data end of the year because we're going to have longer duration and we're going to have a data package.

Speaker Change: Similar to the CASTGB BLA, so we are looking forward to share data with you all.

Operator: Thank you. We'll take our next question from Terence Flynn with Morgan Stanley. Your line is open.

Mia: We'll take our next question from parents. Flynn, with Morgan Stanley, your line is open. Good morning. This is Mia on for Terrence. Thanks for taking our question.

Speaker Change: Thank you very much.

Speaker Change: Thank you. We'll take our next question from Terence Flynn with Morgan Stanley . Your line is open.

Mia ONeill: Good morning, this is Mia ONe for Terence. Thanks for taking our question. So recognizing it's still early in the launches of Cascavi and Lipgenia, but are there any learnings thus far that you hope to utilize for a future runny cell launch? Thanks.

Mia: So recognizing it's still early in the launches of Cascavi and Lithgenia, but are there any learnings that's far that you hope to utilize for a future running the launch? Thanks.

Unknown Executive: Thanks very much, Mia. Indeed there are, and let me pass you over to Karen Deardorf, our Chief Commercial and Strategy Officer. Great. Thanks, Mia, for the question.

Caren Deardorf: Thanks very much, Mia, and either are, and let me pass you over to Karen Durdor for our Chief Commercial Strategy Officer. Great. Thanks, Mia, for the question. First, we really want to say that we're encouraged by the vertex update of the 20 patients in cell collection, which is a nice bump up from the five in Q1, and we really see that as an acceleration that we have anticipated because we understand that there are multiple steps in the process to get a patient dose. And we anticipate that they probably have a number of additional patients in earlier enrollment phase before cell collection, including getting payer reimbursement.

Mia ONeill: Thanks very much Mia, indeed there are, and let me pass you over to Caren Deardorf, our Chief Commercial and Strategy Officer.

Caren Deardorf: Great. Thanks, Nia, for the question. First, we really want to say that we're encouraged by the Vertex update of the 20 patients in cell collection, which is a nice bump up from the five in Q1. And we really see that as an acceleration that we have anticipated because we understand that there are multiple steps in the process to get a patient dosed. And we anticipate that they probably will have a number of additional patients in the earlier enrollment phase before cell collection, including getting payer reimbursement.

Caren Deardorf: Great. Thanks, Nia, for the question. First, we really want to say that we're encouraged by the Virtex update of the 20 patients in cell collection, which is a nice bump up from the five in Q1, and we really see that as an acceleration that we have anticipated because we understand that there are multiple steps in the process to get a patient dosed.

Caren Deardorf: We anticipate that they probably have a number of additional patients in the earlier enrollment phase before cell collection, including getting payer reimbursement.

Caren Deardorf: We anticipate significantly more uptake over the coming quarters as we look at both companies. We know from our own enrollment and the excitement in our trial that there is a lot of patient and physician interest. And so that will continue as there is more exposure to our three therapies. In the U.S., we also know that payers are doing case-by-case approvals with few rejections. We know that patients are able to get access and that policies will be in place over time.

Caren Deardorf: We anticipate significantly more uptake over the coming quarters as we look at both companies. We know from our own enrollment and the excitement in our trial that there is a lot of patient and physician interest. And so that will continue as there's more exposure to our three therapies in the US. We also know that payers are doing case-by-case approvals with few rejections. We know that patients are able to get access and that policies will be in place over time. As a reminder, we really believe that our fast follower timing is an advantage, which gets to your question about the learning.

Caren Deardorf: We anticipate significantly more uptake over the coming quarters as we look at both companies.

Caren Deardorf: We know from our own enrollment and the excitement in our trial that there is a lot of patient and physician interest, and so that will continue as there's more exposure to our three therapies.

Caren Deardorf: In the U.S., we also know that payers are doing case-by-case approvals with few rejections.

Caren Deardorf: We know that...

Caren Deardorf: Patients are able to get access.

Caren Deardorf: As a reminder, we really believe that our fast follower timing is an advantage, which gets to your question about the learning. And that really allows us to be able to optimize our own launch plan. And another key component is that we understand the time it takes for centers to get up to speed, and for payers to put policies in place. All of that, we anticipate, will come together around the time that Renacel might launch.

Caren Deardorf: and that policies will be in place over time. As a reminder, we really believe that our fast follower timing is an advantage which gets your question about the learning.

Caren Deardorf: And that really allows us to be able to optimize our own launch plan. And another key component is that we understand the time it takes for centers to get up to speed for payers to put policies in place. All of that we anticipate will come together around the time that the rented cell might launch. We are already seeing a decrease in the amount of time for onboarding between Bluebird and Vertex and anticipates that that onboarding cycle from our own conversations and research will be significantly shorter at the time of our launch. So we are really encouraged, and we know how much it takes behind the scenes, and we're just really glad to see patients moving closer to dosing.

Caren Deardorf: and that really allows us

Caren Deardorf: And another key component is that we understand the time it takes for centers to get up to speed, for payers to put policies in place.

Caren Deardorf: All of that, we anticipate, will come together around the time that Renacel might launch.

Caren Deardorf: We are already seeing a decrease in the amount of time for onboarding between Bluebird and Vertex and anticipate that that onboarding cycle, from our own conversations and research, will be significantly shorter at the time of our launch. So we are really encouraged, and we know how much it takes behind the scenes, and we're just really glad to see patients moving closer to dosing. Thank you for the question.

Caren Deardorf: Thank you for the question. Thank you.

Operator: Thank you. We will take our next question from Gina Wang with Barclays. Your line is open.

Gina Wang: We will take our next question from Gina Wang with Barclays. Your line is open. Thank you.

Caren Deardorf: Thank you. We will take our next question from Gina Wayne with Barclays. Your line is open.

Gina Wang: I will ask the two questions. First one is, what is your average process time from patient enrollment to dose? Any differences between adults and at the lesson patients? And the second question regarding your indale technology, you say you would do up regulating. Just wanted to make sure that was the knocking down the repressor so that the target that Gina will be up regulating. Thank you very much.

Gina Wayne: Thank you. I will ask two questions.

Gina Wayne: First one is, what is the average process time from patient enrollment to dose? Any differences?

Gina Wayne: Between adults and adolescent patients and a second question regarding your indel technology you say you will do up regulating just wanted to make sure that was the Knocking down the repressor so that the target gene will be up regulated

Baisong Mei: Gina, what I'm going to do is have Baisong address your question about the process time or the vein-to-vein time or enrollment-to-infusion time for adolescents versus adults. And then I'll then I'll pass to over to Linda. I'll restate your question just so we all remember, Baisong. Yeah. Thank you. You know for a question. From the human. The enrollment to dosing, it is very quite significantly on patients and some are going to be very short like three or four months. And other can be a can month or even longer because some patients have really in the middle and doing the process before dosing of Renacel.

Gina Wayne: And then I'll pass over to Linda and I'll restate your question just so we all remember.

Unknown Executive: Yeah, thank you, Gina, for your question. From the enrollment to dosing, it varies quite significantly among patients. And some are going to be very short, like three or four months, and others can be 10 months or even longer, because some patients have VOE in the middle and during the process before dosing of renascent, from the between adult and adolescent and we see now is that we have very robust enrollment and that screening process was going faster than we had for adult and the free seed process also going very smoothly and that's probably also related to that the adolescent patient in a better health condition compared to older adult patients.

Linda Burkly: From the enrollment to dosing, it varies quite significantly among patients, and some are going to be very short, like three or four months, and others can be 10 months or even longer, because some patients have VOE in the middle.

Linda Burkly: and doing the process before dosing of RanaCell.

Baisong Mei: From the between a thousand at lesson and the we see now is that we have very robust enrollment and that screening process was going faster than we had for a doubt. And the a free speech process also going very smoothly, and that's probably also related to that the adolescent patients in a better health condition compared to older and down patient.

Linda Burkly: from the between adult and adolescent and we see now is that

Speaker Change: We have they, robot,

Unknown Executive: Thanks very much, Baisong. And then, Gina, you asked a question just to clarify how we're using indel technology to functionally upregulate genes, and specifically the inhibition of the regulator. Yeah, thank you, Gina, for the question.

Linda Burkly: Thanks very much, Baisong. And then Gina, you asked a question just to clarify how we're using in that tell indale technology to functionally up regulating genes and specifically the introduction of the regulator. Yeah. Thank you, Gina, for the question. So our functional regulation strategy is not is different. It is not a knock down strategy. So, as per your question, we would not be knocking down the repressor. If we use the Renacel example as a paradigm. In that case, we are creating an indale to disrupt the binding site for the repressor. And that way we are up regulating chemical open expression.

Gina Wayne: Thanks very much, Baisong. And then, Gina, you asked a question just to clarify how we're using index technology to functionally upregulate genes and specifically

Gina Wayne: Thank you, Gene, for the question. So our functional upregulation strategy is...

Gina Wayne: The Renaissance Renaissance is different. It is not a knockdown strategy. So we, as per your question, we would not be knocking down the repressor if we use the Renaissance example as as a, as a paradigm. In that case, we are.

Gina Wayne: Creating an indel to disrupt the binding site for the repressor and that way we are up regulating gamma globin expression.

Linda Burkly: So, using that as an example, we could do a similar type of thing for another target of interest. There are other ways that one can create indels to up regulate gene expression. This is the approach that we are taking that is differentiated from a knock down approach. Thank you for the question.

Gina Wayne: So using that as an example, we could do a similar type of thing for another target of interest.

Gina Wayne: There are other ways that one can create indels to up-regulate gene expression. This is the approach that we are taking that is differentiated from a knockdown approach.

Gina Wang: Thank you.

Mary Kate Davis: I'll take our next question from Mary Kate Davis with Bank of America. Your line is open. Good morning. Thank you so much for taking my question. I guess looking at your portfolio, how are you looking at the IP licensing opportunities in the future? Thank you.

Speaker Change: Thank you. Thank you.

Speaker Change: We'll take our next question from Mary Kate Davis with Bank of America. Your line is open.

Speaker Change: Good morning. Thank you so much for taking my question. I guess looking at your portfolio, how are you looking at the IP licensing opportunities in the future? Thank you.

Eric Lucera: Thanks very much, Kate. I'm going to ask our CFO, Eric Lucera, to address. Yeah, thanks for the question. We believe we have a very strong foundational position with respect to the IP license that we have from Harvard, MIT, and the Broad. We are very open having conversations with a range of companies in terms of getting a structure in place that is sort of bespoke and works for both us and them. We believe there's a high double-digit number of programs out in development, and a good number of those, about half, are with the eight to ten different companies.

Speaker Change: Thanks very much Kay. I'm going to ask our CFO Erick Lucera to address that.

Erick Lucera: Yeah, thanks for the question. We believe we have a very strong foundational position with respect to the IP license that we have from Harvard, MIT, and abroad.

Erick Lucera: We are very open to having conversations with a range of companies.

Speaker Change: We believe there's a high double-digit number of programs out in development, and a good number of those, about half, are with eight to ten different companies.

Eric Lucera: So we look forward to having conversations with folks. And as you can see, we've had some pretty good success in the last few years, as evidenced by some of the licenses that we've already put in place. So, very excited to have that as a potential source of non-delutive capital for our company. Thank you.

Speaker Change: We look forward to having conversations with folks, and as you can see, we've had some pretty good success in the last few years, as evidenced by some of the licenses that we've already put in place. So, very excited to have that as a potential source of non-dilutive capital for our company.

Operator: Thank you. We'll take our next question from Brian Chant with J.P. Morgan. Your line is open.

Brian Chan: We'll take our next question from Brian Chan with JP Morgan.

Speaker Change: Thank you.

Speaker Change: Thank you. We'll take our next question from Brian Chant with J.P. Morgan. Your line is open.

Brian Chan: Your line is open.

Brian Chan: Hey guys, thanks for taking out questions this morning, and happy summer. It sounds like you may have had an additional discussion of the agency this past quarter. Just curious, other than the clinical data, what other additional items have you discussed? And just based on Coach Javi package at the time of the BLA, I would assume that you can potentially file sometime next year. So outside of the clinical package that we're waiting for mature data, what other additional data or dating factor do you need to line up between now and then. In other words, any color on your readiness towards the filing.

Brian Chant: Hey guys, thanks for taking out the questions this morning and happy summer. It sounds like you may have had additional discussions about the agency this past quarter. I'm just curious, other than the clinical data, what other additional items have you discussed? And just based on the CASGEPI package at the time of the BLA, I would assume that you could potentially file sometime next year. So outside of the clinical package that we're waiting for mature data on, what other additional data or gating factor do you need to line up between now and then? In other words, any color on your readiness for the filing.

Brian Chant: Hey guys, thanks for taking out questions this morning and happy summer.

Brian Chant: It sounds like you may have had additional discussion of the agency this past quarter. I'm just curious, other than the clinical data...

Speaker Change: What other additional items have you discussed? And just based on the KASJABI package at the time of the BLA, I would assume that you can potentially file sometime next year.

Speaker Change: So outside of the clinical package that we're waiting for mature data, what other additional data or gating factor do you need to line up between now and then? In other words, any color on your readiness towards the filing thing.

Gilmore ONeill: Thanks. Thanks very much, Brian. I think there's a complex question in that you're asking about the multiple data sets that are required to actually go filing.

Unknown Executive: Thanks very much, Brian. I think there's sort of a complex question in that you're asking about the multiple data sets that are required to actually go filing. First of all, let me be very clear that we have not actually shared an estimate or given guidance as to when we would file the BLA. I think that's very important just to state.

Brian Chant: Thanks very much, Brian .

Speaker Change: I think there's sort of a...

Speaker Change: complex question in that you're asking about the multiple data sets that are required to actually go filing. First of all, let me be very clear that we have not actually shared an estimate or given guidance to when we would file the BLA. I think that's very important just to state. The second is that we are very happy from the clinical data point of view in the generation how we're actually progressing.

Gilmore ONeill: First of all, let me be very clear that we have not actually shared an estimate or given guidance to when we would file the BLA. I think that's very important just to state. The second is that we are very happy from the clinical data point of view in the generation, how we're actually progressing towards really meeting or matching up with the benchmark set by the cast Javi approval, with, of course, the additional data that we are generating from a differentiation point of view. The additional data sets obviously include the preclinical, and we know that a key focus of the agency, when you consider outcome, while looking at off-target editing.

Unknown Executive: The second is that we are very happy from the clinical data point of view and the generation of how we're actually progressing towards really meeting or matching up with the benchmark set by the CAS-JV approval with, of course, the additional data that we are generating from a differentiation point of view. The additional data sets obviously include preclinical, and we know that a key focus of the agency when you consider adcom was looking at off-target editing.

Speaker Change: December to see that the data set that we have already generated is a very robust.

Gilmore ONeill: We actually were very, how should say, gratified by the outcome last December to see that the data set that we've already generated is very robust and probably exceeds what was discussed at that outcome. So we feel very good that we're actually also very pleased with the progress of our manufacturing data. And as I said in my earlier prepared remarks, you know, our ongoing discussions with the FDA really gives a lot of confidence about the progress of multiple data sets into beyond just the clinical to bring us towards BLA.

Unknown Executive: We actually were very, how should I say, gratified by the adcom last December to see that the data set that we've already generated is very robust and probably exceeds what was discussed at that adcom, so we feel very good about that. We're actually also very pleased with the progress of our manufacturing data, and as I said in my earlier prepared remarks, our ongoing discussions with the FDA really give us a lot of confidence about the progress of multiple data sets beyond just the clinical to bring us closer to BLA.

Speaker Change: and probably exceeds what was discussed at that odd comm so we feel very good that we're actually also very pleased with the progress of our manufacturing data and as I said in my earlier prepared remarks

Speaker Change: Our ongoing discussions with the FDA really gives us a lot of confidence about the progress of multiple data sets, beyond just the clinical, to bring us towards BLA.

Unknown Executive: Okay, and maybe just one more follow-up. On the in vivo side, is that going to be a first-in-class or best-in-class approach? I'm just curious how you think about balancing the risk and reward for your next asset.

Brian Chan: Okay. And maybe just one more follow on the in vivo side. Is that going to be first in class or best in class approach? Just curious how do you think about balancing the risk and reward for your next assets.

Speaker Change: Okay, and maybe just one more follow-up on the in vivo side. Is that going to be a first-in-class or best-in-class approach? I'm just curious how do you think about balancing the risk and reward for your next assets?

Unknown Executive: And thank you.

Linda Burkly: And thank you. Thank you very much, Brian. I'm going to have Linda address that. Yeah. Thanks, Brian, for the approach. The question, I think the differentiated approach is for going after functional regulation, is really important. I think from an indication standpoint, because of the fact that we can go after targets that others may not be able to go after using a knockdown strategy. And that is established modalities or other technologies and development can't go after that target that really gives us the ability to be first in class. We can also envision editing strategies that would yield a better outcome than other approaches that are going after that particular indication, giving us best in class.

Linda Burkly: Thank you very much, Brian. I'm going to have Linda address that. Yeah, thanks, Brian, for the approach.

Speaker Change: Thank you.

Linda Burkly: Yeah, thanks, Brian, for the approach. The question about the differentiated approach for going after functional upregulation is really important, I think, from an indication standpoint, because of the fact that we can go after targets that others may not be able to go after using a knockdown strategy, and that established modalities or other technologies and development can't go after that target. That really gives us the ability to be first in class.

Speaker Change: Thank you very much, Brian . I'm going to have Linda address that. Yeah, thanks, Brian , for the approach.

Linda Burkly: I think the differentiated approach is for

Linda Burkly: , and Joe . I think going after function up regulation is really important. I think from an indication standpoint, because of the fact that we can go after function up regulation , we can go after function up regulation and we can go after function up regulation and we can go after

Linda Burkly: targets that others may not be able to go after using a knockdown strategy, and that is established modalities or other technologies and development can't go after that target. That really gives us the ability to be first in class.

Linda Burkly: We can also envision editing strategies that would yield a better outcome than other approaches that are going after that particular indication, giving us the best in class. So we can either have first in class or best in class opportunities here.

Linda Burkly: We can also envision editing strategies that would yield a better outcome than other approaches that are going after that particular indication, giving us best in class. So we can either have first-in-class or best-in-class opportunities here.

Linda Burkly: So we can either have first-in-class or best-in-class opportunities here.

Brian Chan: Okay. Thank you.

Speaker Change: Okay, thank you.

Operator: Thank you. We'll take our next question from Joon Lee with True Securities. Your line is open.

Joon Lee: We'll take our next question from Joon Lee, with True Securities. Your line is open. Hi, good morning. This is Mayday on for June Congress on the progress and thanks for taking our question. So maybe two parts question. Could you please provide any additional color on your in vivo, anything that approach, as you previously talked about, LSRs, and they usually require a landing site insertion first. So any color there would be appreciated. And then to follow on Gina's question, how many diseases do you see being amenable to indel-mediated functional operation? Thank you. Thanks for your questions.

Speaker Change: Thank you. We'll take our next question from Joon Lee with True Securities. Your line is open.

Unknown Executive: Hi, good morning. This is Mehdi from June Congress on the Progress, and thanks for taking our question. So, maybe a two-part question.

Speaker Change: Hi, good morning, this is Mehdi on for June , congrats on the progress.

Maydianne: And thanks for taking our question. So, maybe a two-part question. Could you please provide any additional color on your in vivo editing approach as you previously talked about?

Unknown Executive: Could you please provide any additional color on your in vivo editing approach as you previously talked about LSRs, and they usually require a landing site insertion first. So any color there would be appreciated. And then to follow on Gina's question, how many diseases do you see being amenable to indel mediated functional upregulation? Thank you.

Speaker Change: LSRs and they usually require a landing site insertion first.

Speaker Change: So any color there would be appreciated. And then to follow on Gina's question, how many disease you see being amenable to indel mediated functional upregulation? Thank you.

Unknown Executive: Thanks very much, Mary, for your questions. Let me start; I'll have Linda address both questions, and I'll restate the second question. Obviously, your first question was, you know, as we talk about our INDEL functional upregulation, how is that distinguished from the use of LSRs, Linda?

Linda Burkly: Let me start. I have Linda addressed both questions, and I'll restate the second question. Obviously, your first question was, you know, as we talk about our indel functional operation, how is that distinguished from the use of LSRs? Yes, thank you for the question. Yeah, the LSR technology that we disclosed at ASGZT. We're very excited about that. That is a technology that may enable us in the future to have large gene insertions. And so this would be gene replacement approach. This is something that we're working towards. What we're doing in the shorter term now is functional up-regulation of gene expression.

Speaker Change: Thanks very much, Mary, for your questions. Let me start, I'll have Linda address both questions and I'll restate the second question. Obviously, your first question was, you know, as we talk about our INDEL functional upregulation, how is that distinguished from the use of LSRs?

Linda Burkly: Yes, thank you for the question. Yeah, the LSR technology that we disclosed at ASGZT, we're very excited about that. That is a technology that may enable us in the future to have large gene insertions. And so this would be a gene replacement approach. This is something that we're working towards.

Speaker Change: Cylinder

Linda Burkly: Yes, thank you for the question. Yeah, the LSR technology that we disclosed at ASGZT, we're very excited about that, that

Linda Burkly: is a technology that may enable us in the future to have large gene insertions.

Linda Burkly: What we're doing in the shorter term now is functional upregulation of gene expression. This is increasing the expression of a gene in order to compensate for a loss of function or a deleterious mutation in a patient with a serious genetic disease. So if that answers your first question, I think you asked a question about how many diseases are amenable to INDO. And there are many, obviously; there are many genetic diseases caused by loss of function or deleterious mutations. And there are many ways in which they are regulated by various regulatory elements. And so there should be many, many opportunities here for functional upregulation of those targets. If I may, thank you very much, Linda.

Linda Burkly: And so this would be gene replacement approach. This is something that we're working towards. What we're doing in the shorter term now is functional upregulation of gene expression. And this is.

Linda Burkly: And it's increasing the expression of a gene in order to compensate for a loss of function or a deleterious mutation in a patient with a serious genetic disease. So if that answers your first question, I think you asked a question about how many diseases are amenable to indel? And there are many; obviously, there are many genetic diseases caused by loss of function or deleterious mutations. And there are many ways in which they are regulated by various regulatory elements. And so there should be many, many opportunities here for functional up-regulation of those targets.

Linda Burkly: increasing the expression of a gene in order to compensate for a loss of function or a deleterious mutation in a patient with a serious genetic disease.

Linda Burkly: And there are many ways in which they are regulated by various regulatory elements, and so there should be many, many opportunities here for functional upregulation of those targets.

Unknown Executive: If I may add, thank you very much, Linda. I think one of the key things is that, as we know from the human genome, only a small quantity of the genome actually encodes proteins. There's a large amount, the vast majority of the genome is actually non-coding, and much of that comprises regulatory elements that actually control the expression of genes. And as Linda very eloquently put it, this is what we're actually trying to target.

Gilmore ONeill: If I may add, thank you very much, Linda. I think one of the key things is that, as we know from the human genome, only a small quantity of the genome actually encodes proteins. There's a large amount; the vast majority of the genome actually is non-coding. And much of that comprises regulatory elements that actually control the expression of genes. And as Linda very eloquently put it, this is what we're actually trying to target. And just to be clear, we are talking about indel using our CRISPR technology in general and very specifically in the very near term, leveraging our ASCAST12A, which, as we highlight, is we believe one of the key differentiated tools in our toolbox, as we believe it is a superior editing CRISPR enzyme because of its high efficacy and its high fidelity.

Linda Burkly: If I may add, thank you very much, Linda. I think one of the key things is that, as we know from the human genome, only a small quantity of the genome actually encodes proteins.

Speaker Change: There's a large amount, the vast majority of the genome actually is non-coding and much of that comprises regulatory elements that actually control the expression of genes. And as Linda very eloquently put it, this is what we're actually trying to target.

Unknown Executive: And just so we're absolutely clear, we are talking about indel using our CRISPR technology in general, and very specifically in the very near term, leveraging our ASCAS12A, which, as we highlight, is, we believe, one of the key differentiated tools in our toolbox, as we believe it is a superior editing CRISPR enzyme because of its high efficacy and its high fidelity.

Speaker Change: And just so we're absolutely clear, we are talking about indel using our CRISPR technology in general, and very specifically in the very near term, leveraging our AS-Cas12a, which, as we highlight, is, we believe, one of the key differentiated tools in our toolbox, as we believe it is a superior editing CRISPR enzyme because of its high efficacy and its high fidelity.

Gilmore ONeill: Thank you.

Operator: Thank you. We'll take our next question from Daegon Ha. By default, your line is open.

Dae Gaon: We'll take our next question from Dae Gaon. How was the full year minus open? Hey, good morning, guys. Thanks for taking our questions, and congrats on the progress as well. Maybe first question for Linda. Going back to the in vivo, recognizing you're going to be disclosing. So I don't want to probe too much, but at least help us appreciate it a little bit more. Is this, are you guys kind of driven by the limitations of LNP-mediated delivery? In terms of what cell types and what organ types you can go into, or is this more dependent on how big of a size market you have potential out?

Speaker Change: Thank you. We'll take our next question from Daegon Ha with Beful. Your line is open.

Unknown Executive: Hey, good morning, guys. Thanks for taking our questions and congratulations on the progress as well. Maybe the first question for Linda, going back to in vivo, recognizing that you're going to be disclosing, so I don't want to probe too much, but at least help us appreciate it a little bit more. Is this, are you guys kind of driven by the limitations of LNP-mediated delivery in terms of what cell types and what organ types you can go into?

Daegon Ha: Hey, good morning guys. Thanks for taking our questions and congrats on the progress as well. Maybe first question for Linda, going back to the in vivo, recognizing you're going to be disclosing, so I don't want to probe too much, but at least help us appreciate it a little bit more. Is this...

Unknown Executive: Or is this more dependent on how big of a market you have the potential for the first indication as well as the potential subsequent indications that can come after this first one? And then, second question, maybe high level, Gilmore or Baisong. You know, year end, we're also expecting BEAM's first data set coming out of BEAM 101. You talk about RenyCell being best in class, so I was just wondering what kind of data set would keep you more confident about that notion going into that ASH presentation? Thanks so much.

Dae Gaon: First indication as well as the potential subsequent indications that can come after this first one.

Linda Burkly: And then second question, maybe a high level Gilmore on Baisong. Year end, we're also expecting Beam's first data set coming out of Beam 101. You talk about Renny Cell being best in class, so I was just wondering what kind of data set would keep you more confident about that notion going into that ASH presentation. Thanks so much. Thanks very much, Dae Gaon. So, Linda. Thank you, Dae Gaon. So, to your first question, yes, in terms of the LNP, the delivery obviously is critical for getting POC. So we've shared our interest in targeting hematocytic stem cells, and this is obviously to translate the remarkable success we're having with our Renny Cell asset.

Speaker Change: You talk about RenyCell being best in class, so I was just wondering what kind of data set would keep you more confident about that notion going into that ASH presentation. Thanks so much.

Linda Burkly: Thanks very much, Dagon. So, Linda. Thank you, Dagon.

Linda Burkly: Thanks very much, Dagon. So, Linda. Thank you, Dagon. So, to your first question, yes, in terms of the LMP, the delivery obviously is critical for getting POC, so we've shared our interest in targeting hematopoietic stem cells, and this is obviously to translate this remarkable success.

Linda Burkly: So, to your first question, yes, in terms of the LMP, delivery obviously is critical for getting POC. So, we've shared our interest in targeting hematopoietic stem cells, and this is obviously to translate the remarkable success we're having with our Renacel asset. So, we are obviously trying to target hematopoietic stem cells in vivo. We've also, though we haven't disclosed all of the disease areas that we're interested in, and other than HSEs, we have mentioned that we are interested in targeting the liver.

Gilmore ONeill: So we are obviously trying to target hematocytic stem cells. We've also, though we haven't disclosed all of the disease areas that we're interested in, and other than HSEs, we have mentioned that we are interested in targeting the liver. And so there are validated LNPs for targeting liver. So there is a pragmatic approach here based on delivery. If I may add, Linda, thank you. It's not just the delivery tool that we are leading with an LNP that actually determines how we select our targets. Obviously, delivery is an important element. Obviously, amenability to functional up regulation is important.

Linda Burkly: We are obviously trying to target hematopoietic stem cells in vivo. We have also, though we have not disclosed all of the disease areas that we are interested in. Other than HSCs, we have mentioned that we are interested in targeting the liver. There are validated LMPs for targeting liver. There is a pragmatic approach here based on delivery.

Linda Burkly: And so, there are validated LMPs for targeting the liver. So, there is a pragmatic approach here based on delivery. If I may add, Linda, thank you, it is not just the delivery tool that we are leading with at NLP that actually determines how we select our targets. Obviously, delivery is an important element.

Linda Burkly: If I may add, Linda, thank you, you know, it's not just the delivery tool that we are leading with at L&P that actually determines how we select our targets. Obviously delivery is an important element. Obviously amenability to functional upregulation is important. We're actually also selecting diseases based on their clinical translatability in that we want to ensure that we can actually get obvious clinical signals in our human proof of concept.

Unknown Executive: Obviously, amenability to functional upregulation is important. We're actually also selecting diseases based on their clinical translatability, meaning we want to ensure that we can actually get obvious clinical signals in our human proof of concept. And obviously, then, obviously, we also further filter that by ensuring that we are truly differentiated to ensure maximized probability, not just from a technical clinical regulatory perspective but actually also commercial. And then, with regard to your second question, you know, what do we expect to see from the BEAM data set?

Gilmore ONeill: We're actually also selecting diseases based on their clinical translatability in that we want to ensure that we can actually get obvious clinical signals in our human proof of concept. And obviously, then obviously we also further filter that by ensuring that we are truly differentiated to ensure maximized probability, not just of technical, technical, regulatory, but actually also commercial success.

Gilmore ONeill: And then, with regard to your second question, what do we expect to see from the beam data set? You know, frankly, obviously we're looking forward to seeing it. It is always good to see continued pursuit of therapeutics within a clinical space for which there is an enormous, enormous unmet need in the context of sickle cell disease and transfusion-dependent alicemia. It's very hard. I can't speculate on what beam would show. I look forward to hearing it. And we all look forward to hearing it. But I will tell you that we are very happy with the different stated profile that we are developing for Rene Cell.

Speaker Change: And then with regard to your second question, you know, what do we expect to see from the BEAM data set?

Unknown Executive: You know, frankly, obviously, we're looking forward to seeing it. It is always good to see continued pursuit of therapeutics within a clinical space for which there is an enormous, enormous unmet need in the context of sickle cell disease and transfusion-dependent thalassemia. It's very difficult.

Speaker Change: You know, frankly, obviously, we're looking forward to seeing it. It is always good to see continued pursuit of therapeutics within a clinical space for which there is an enormous, enormous unmet need in the context of sickle cell disease and transfusion-dependent thalassemia. It's very hard. I can't speculate on what BEAM will show. I look forward to hearing it, and we all look forward to hearing it. But I will tell you that we are very happy with the differentiated profile that we are developing for Renaissance Cell. And it's important to point out that we are very happy with the biological profile, the hemoglobin.

Unknown Executive: I can't speculate on what BEAM will show, but I look forward to hearing it. We all look forward to hearing it. But I will tell you that we are very happy with the differentiated profile that we are developing for Rene cell. And it's important to point out that we are very happy with the biological profile, the hematological profile, and the clinical profile, all of which are very strong. And in addition, as we've alluded to, our confidence in the evolution of the current state of and the continued evolution of our manufacturing from the success rates is very gratifying.

Gilmore ONeill: And it's important to point out that we are very happy with the biological profile, the hematological profile, the clinical profile, all of which are very strong. And in addition, as we alluded to, we are our confidence in the evolution, in the current state of and the continued evolution of our manufacturing. From the success rates, it's very gratifying. So overall, we actually feel very good. And of course, it's important to us to remember, as I said earlier, that an additional piece of the data includes our non-cynical, including our off-target editing, which is very robust, as I said, in the packages we've generated.

Unknown Executive: So overall, we actually feel very good. And of course, it's important to also remember, as I said earlier, that an additional piece of the data includes our non-clinical data, including our off-target editing, which is very robust, as I said, in the package we've generated. And of course, some of that robustness stems from us using ASCAS12A as opposed to CAS9 with its differentiated, high-efficacy,

Speaker Change: So overall, we actually feel very good. And of course, it's important to also remember, as I said earlier, that an additional piece of the data includes our non-clinical, including our off-target editing, which is very robust.

Gilmore ONeill: And of course, some of that robustness stems from us using ASCAST12A, as opposed to CAST9, with its differentiated high efficacy, high fidelity characteristics.

Speaker Change: As I said, in the package we've generated, and of course, some of that robustness stems from us using AS-Cas12a as opposed to Cas9, with its differentiated, high-efficacy, high-fidelity characteristics.

Dae Gaon: Great, thanks so much. Thank you.

Speaker Change: Great. Thanks so much.

Operator: Thank you. We'll take our next question from Luca Issi with RBC Capital. Your line is open.

Luca Issi: We'll take our next question from Luca Issi with RBC Capital. Your line is open. Well, great. Thanks so much for a thank you. My question and congrats on the progress. I have two quick ones. You know, sickle cell disease. We have seen the US Health and Human Services issuing a negative opinion here on covering fertility preservation for a federally insured patient who received in therapy for sickle cell disease. So just wondering, what is your take on that. And then maybe second Gilmore bigger picture. You seem very excited about the INVivo Uppergulation Strategy here.

Speaker Change: Thank you. We'll take our next question from Luca Issi with RBC Capital. Your line is open.

Luca Issi: Well, great. Thanks so much for taking my question and congrats on the progress. I have two quick ones.

Unknown Executive: Maybe on sickle cell disease, we have seen the U.S. Health and Human Service issuing a negative opinion here on covering fertility preservation for federally insured patients who receive gene therapy for sickle cell disease. So just wondering what your take on that is. And then maybe second Gilmore, bigger picture, you seem very excited about the in vivo upregulation strategy here. Is there a version of the world where you just partner with any cell, both U.S. and ex-U.S., instead of building a commercial infrastructure and just focused on your in vivo strategy?

Speaker Change: In Sickle Cell Disease, we have seen the U.S. Health and Human Services issuing a negative opinion here on covering fertility preservation for federally insured patients who receive gene therapy for sickle cell disease.

Gilmore ONeill: And then maybe second, Gilmore, bigger picture, you seem very excited about the in vivo upregulation strategy here. Is there a version of the world where you just corner RenySAL, both US and ex-US, instead of building a commercial infrastructure and just focused on your in vivo strategy? Any thoughts there? Much appreciated. Thanks so much.

Luca Issi: Is there a version of the world where you just partner or any cell, both US and XUS instead of building a commercial for structure and just focused on your INVivo strategy. And you thought they're much appreciated. Thanks so much. Thanks very much, Luca.

Unknown Executive: Any thoughts there? Much appreciated. Thanks so much.

Unknown Executive: Thanks very much, Luca. So I'm going to pass your first question to Caren on the HHS Decision. Yeah.

Caren Deardorf: So I'm going to pass your first question to Karen around the HHS decision or. Yeah, Luca, thank you for calling that out. Look, we are deeply disappointed by this decision. And we join the voices of, you know, Vertex, Bluebird, really the whole field in this decision, which seems very out of touch with the severity of sickle cell and the unmet need. And it just continues to drive a discrepancy between the commercial patient's ability to access therapies and have companies cover the fertility preservation, as you know, and Medicaid patients. So we are very disheartened. We also know that there are a lot of voices who are within Congress and within the industry and other organizations, including the patient advocacy groups, who have a very strong voice.

Caren Deardorf: Luca, thank you for calling that out. Look, we are deeply disappointed by this decision. And we join the voices of Vertex, Bluebird, really the whole field in this decision, which seems very out of touch with the severity of sickle cell and the unmet need. And it just continues to drive a discrepancy between commercial patients' ability to access therapies and have companies cover fertility preservation, as you know, and Medicaid patients.

Speaker Change: Luca, thank you for for calling that out. Look, we are deeply disappointed by this decision and we join the voices of, you know, Vertex, Bluebird, really the whole field in this decision, which seems very out of touch.

Speaker Change: With the severity of sickle cell and the unmet need, and it just continues to drive a discrepancy between the commercial patient's ability to access therapies

Speaker Change: and have companies cover the fertility preservation, as you know, and Medicaid patients. So we are very disheartened. We also know that there are a lot of voices who are within Congress and within the industry and other organizations, including the patient advocacy groups, who have a very strong voice.

Caren Deardorf: So we are very disheartened. But we also know that there are a lot of voices within Congress and within the industry and other organizations, including patient advocacy groups, who have a very strong voice. And our hope is that all of us together will be able to really raise this issue and have it reversed in the coming time. We believe that things will sort themselves out. We are disappointed for the patients who are seeking treatment today.

Caren Deardorf: And our hope is that all of us together will be able to really raise this issue and have it reversed in the coming time. We believe that things will sort themselves out. We are disappointed for the patients who are seeking treatment today. Our belief in our own timing of fast follower is a lot of these unfortunate decisions will be figured out at the time that they were ready to come to market. But thank you for calling it out. It is really an out of touch decision. And we will hope for the best into our part.

Speaker Change: Our hope is that all of us together will be able to really raise this issue and have it reversed in the coming time. We believe that...

Speaker Change: Things will sort themselves out. We are disappointed for the patients who are seeking treatment today. Our belief in our own timing as fast follower is a lot of these unfortunate decisions will be figured out at the time that we're ready to come to market. But thank you for calling it out. It is really an out-of-touch decision, and we will hope for the best and do our part.

Caren Deardorf: Our belief in our own timing as a fast follower is that a lot of these unfortunate decisions will be figured out at the time that we're ready to come to market. But thank you for calling it out. It is really an out of touch decision, and we will hope for the best and do our part.

Erick Lucera: Thanks very much, Caren. And then Luca, to your second question around, I think it sort of stems from our prepared remarks, why we're extraordinarily excited by the progress of Renaissance Aranvivo. We're also very conscious of how we deploy our capital, and I'm going to ask Erick to address that. Yeah, Luca, just following up as we go.

Caren Deardorf: Thanks very much, Karen.

Eric Lucera: And then Luca, to your second question around I think it sort of stems from our program arcs, how why we are extraordinarily excited by our Renacent Aaron Vivo progress roles are very conscious of how we deploy our capital. And I'm going to ask Eric to address that. Yeah, Luca, just following up, as we've said for many years, our intention was to look for partners outside of the U.S. And I can tell you as someone who invested in biotech for 15 years in doing business development and CFO for about 15 years. You never know where those discussions may go.

Erick Lucera: Yeah, Luca, just following up. As we've said for many years, our intention was to look for partners outside of the US. And I can tell you, as someone who invested in biotech for 15 years and has been doing business development and CFO for about 15 years, you never know where those discussions may go. But what we can assure you is that we're going to do the right thing in terms of what's in the best interest of getting our products to as many patients as possible and driving shareholder returns to the best level possible.

Speaker Change: And I can tell you, as someone who invested in biotech for 15 years and has been a...

Eric Lucera: But what we can assure you is that we're going to do the right thing in terms of what's in the best interest for getting our products to as many patients as possible and driving shareholder returns to the best level possible. Thank you so much. Thank you.

Operator: Thank you. We'll take our next question from Phil Nadeau with TD Cowan. Your line is open.

Phil Nadeau: We'll take our next question from Phil Nadeau with TV Cowling.

Speaker Change: Thanks so much.

Speaker Change: Thank you. We'll take our next question from Philip Nadeau with T.D. Cowan. Your line is open.

Phil Nadeau: Your line is open. Good morning. Thanks for taking our questions. Two from us.

Unknown Executive: Good morning. Thanks for taking our questions. Here are two from us.

Baisong Mei: First on Renice Allen and the prospects for clinical differentiation. We're curious where your most recent thoughts are on the time to see that clinical differentiation on things like end organ damage. It's possible that we could start to see strong signals of that in the ash presentation.

Gilmore ONeill: And then second on the in vivo development program, Gilmore, I think you said the initial indication will be orphaned, and then there will be larger indications perhaps later. Give us some sense of what size patient population you think is necessary for a good return on an investment. What's too small, what's the sweet spot for an orphaned population? Thanks. Thanks very much, Phil.

Phil Nattu: And then second on the In Vivo development program, Gilmore, I think you said the initial indication will be orphaned and then there'll be larger indications perhaps later.

Unknown Executive: First, on Renacel and the prospects for clinical differentiation, we're curious what your most recent thoughts are on the time to see that clinical differentiation on things like end organ damage. Is it possible that we could start to see strong signals of that in the ASH presentation? And then second, on the in vivo development program, Gilmore, I think you said the initial indication will be orphaned, and then there'll be larger indications, perhaps later. Can you give us some sense of what size patient population you think is necessary for a good return on an investment? What's too small? What's the sweet spot for an orphaned population? Thanks.

Baisong Mei: So I have based on talk about the differentiation and how we see that evolving. And then I will take your question on how we think about the size of the population. Yeah. Thanks. Thanks for the question. And as we stated before, in clinical trial, we're looking three categories of evidence about differentiation, including ecological parameters and an organ function and the patient reported outcome. And then the in terms of timing of those end points and when we see the change, and so for the end organ function, you specifically mentioned that it is relatively new field. And fortunately, we already see more publications in allogenic transplants for treating sickle cell disease.

Speaker Change: Thanks very much, Phil. So I'll have Baisong talk about the differentiation and how we see that evolving, and then I will take your question on how we think about the size.

Baisong Mei: Yeah, yeah, thanks. Thanks for the question. And as we stated before, in clinical trial, we're looking at three categories of evidence.

Baisong Mei: They have presented encouraging data that after allogenic transplants, you can see the end organ function improvement, including cardiovascular, central nervous system, and so on and so forth. And in our clinical trial, we monitor multiple organ and organ functions, including pulmonary cardiovascular level and that. And so we based on the publication, some of reporting that at the when year, you see some improvement already, so we're very encouraged by that. But other parameters, for example, the hematological parameter, I will give us more opportunity to directly measure that change. For example, we talked about the correction in the media.

Baisong Mei: In our clinical trial, we monitor multiple organ and organ functions, including pulmonary, cardiovascular, liver, renal, and that.

Baisong Mei: So, based on the publication, some of the reporting that...

Baisong Mei: But other parameters, for example, the hematological parameter, will give us more opportunity to directly measure that change. For example, we're talking about the correction of anemia.

Baisong Mei: And then the third category is patient-reported outcome. And we are also very encouraged by the reports and being published in its field, then we will be able to see an end of the collective life change after the treatment. So we're looking forward to see the more data, and we are very excited to see that our data from all our patients are very consistent. Now we report 18 patient data. We see that the same direction and the same trajectory in terms of the patient data wise; we're very pleased. We're looking forward to share more data in the year.

Baisong Mei: And then the third category is patient report outcome, and we are also very encouraged by the reports and being published in this field that we will be able to see and end the

Baisong Mei: hope all of us in the New York Kabul area and all the other nations are joining us today the data from all of our patients.

Unknown Executive: Thanks very much, Phil. So I'll have Baisong talk about the differentiation and how we see that evolving, and then I will take your question on how we think about the size of the population.

Gilmore ONeill: Thanks very much, Bay Song, and then Phil, regard your next, your second question, which is around where do we think that the population size or orphan indication, where we're sort of focusing our initial for aid in vivo lines up for optimal ROI. A couple of things. First of all, the reason that we're actually focusing on rare orphan, the main reason obviously is that as we bring a new technology to patients, we want to actually maximize the probability of technical and regulatory success, while we at the field and agencies characterize and learn the long-term risk benefits associated with this technology.

Speaker Change: while we at the field and agencies characterize and learn the long-term risk benefits associated with this technology.

Gilmore ONeill: More importantly than when I turn or not, more importantly, but then I turn to market size. The market size to talk about is really based on patients, the patient numbers with indication versus the price, and obviously price would be determined by a number of factors including the amount saved by what we're talking about are potentially or largely curious of therapies with high potency. This is one of the things we're really excited about our technology: we're talking about using this technology not just because it's new and cool, but because it has the potential to deliver high potency, large effect sizes, and patients.

Phil Nadeau: And so when you actually consider those elements, our current estimates that a range of about four to 500 million is about the market size that would be meaningful and enable us to drive growth. And as we grow and evolve into treating larger populations as we build that safety characterization in a number of smaller orphan size parts. Congratulations. That's very helpful. Yeah, that's very helpful. Thank you.

Speaker Change: That's very helpful. Yeah, that's very helpful. Thank you.

Charanda Lai: I'll take our next question from Jay Olson with Oppenheimer. Your line is open. Hey, this is Charanda Lai for Jay. Thanks for taking the question. Just maybe on Renysel. By the time you filed at BLA, I'm just curious. Do you think the fall of in the adolescent cohort is long enough so the label may cover both? Adele and adolescent patients. Thank you. Thank you very much.

Speaker Change: Hey, this is John on the line for Jay. Thanks for taking the questions.

Speaker Change: This may be on a random show, by the time you've filed...

Speaker Change: BLA. I'm just curious, do you think the follow up in the adolescent cohort is long enough so the label may cover both adult and adolescent patients? Thank you.

Baisong Mei: I want to just recap; state your question because it was a little muffled on the line. I think you were asking, will the adolescent cohort be followed for long enough to be part of the label? And transmission of the band? Okay. Thank you. Yes, thanks, Chen. We are very pleased with the progress of the adolescent cohort. And we started the enrollment of this year. We are already completing enrollment in a matter of months. So very pleased with that. We certainly wanted to seek a broader indication of all age cohorts. And we already have alignment with FDA about to the clinical trial for all the age cohorts.

Speaker Change: Thanks very much, Jay. I want to just restate your question because it was a little muffled on the line. I think you were asking, will the adolescent cohort be followed for long enough to be part of the label?

Speaker Change: Baisong

Baisong Mei: Yeah, yeah, thanks. Thanks for the question. And as we stated before, in the clinical trial, we're looking at three categories of evidence about differentiation, including hematological parameters, organ function, and patient-reported outcome, and then in terms of timing of those endpoints and when we see the change. And so for end-organ function, you specifically mentioned that it is a relatively new field. But fortunately, we already see more publications in the allogeneic transplant for treating sickle cell disease.

Speaker Change: So we're very pleased with that. We certainly wanted to seek for a broader indication of all age cohorts, and we already have alignment with FDA about the clinical trial for all the age cohorts. So that's what we're very much looking forward to that.

Baisong Mei: So that's why we are very much looking forward to that. Okay. Thank you so much. Thank you.

Baisong Mei: They have presented encouraging data that after allogeneic transplantation, you can see end-organ function improvement, including cardiovascular, central nervous system, and so on and so forth. In our clinical trial, we monitor multiple end-organ functions, including pulmonary, cardiovascular, liver, renal, and that. And so based on the publication, some are reporting that in one year, they see some improvement already. So we are very encouraged by that. But other parameters, for example, the hematological parameter, will give us more opportunity to directly measure that change. For example, we're talking about the correction in the liver.

Speaker Change: Okay, thank you so much.

Yian Zhu: We'll take our next question from Yian Zhu with Wells Fargo Securities. Your line is open. Oh, great. Thanks for taking our questions.

Baisong Mei: And then the third category is patient-reported outcome. And we are also very encouraged by the reports and articles published in this field that we will be able to see the quality of life change after the treatment. So we're looking forward to seeing more data, and we are very excited to see that the data from all our patients is very consistent. Now we report 18 patient data. We see that the same direction and the same trajectory in terms of patient data-wise. We're looking forward to sharing more data with you.

Yian Zhu: So for the in legal program, are you trying to upregulate the gene, the disease causing gene itself? Or are you trying to upregulate a different gene to compensate for the loss of the disease-calling gene? In other words, are we talking about a hapline insufficiency type of indication? Or are we talking about recessive gene, recessive gene defect here?

Speaker Change: So for the In Vivo program,

Speaker Change: Are you trying to upregulate the disease-causing gene itself, or are you trying to upregulate a different gene to compensate for the loss of the disease-causing gene? In other words...

Speaker Change: Are we talking about a haploinsufficiency type of indication?

Yian Zhu: I can barely wanted to ask about any updated timing for the CAFC patent dispute process. Thank you. Thanks very much, Yian Zhu.

Speaker Change: Secondarily, I wanted to ask about any updated timing for the CAFC patent dispute process. Thank you.

Unknown Executive: Thanks very much, Baisong. And then, Phil, with regard to your second question, which is around where do we think that a population size for an orphan indication, where we're sort of focusing our initial foray in vivo, lines up for optimal ROI? A couple of things. First of all, the reason that we're actually focusing on rare orphans, the main reason, obviously, is that as we bring new technology to patients, we want to actually maximize the probability of technical and regulatory success.

Unknown Executive: While, you know, we in the field and agencies characterize and learn the long-term risk benefits associated with this technology. More importantly, then, when I turn, or not more importantly, but then I turn to market size, the market size we talk about is really based on patients, the patient numbers with indication versus price. And obviously, price will be determined by a number of factors, including the amount saved by what we're talking about are potentially or largely curative therapies with high potency.

Linda Burkly: So, with the first question, I'm going to start by saying that you have actually described sort of, you've actually nailed both elements of the upregular strategy, but I let Linda just expand on that. And then I'll restate the second question, and we'll address that. Yeah. Thanks very much for your question. So the two scenarios that you described, like both are possible approaches, when you can imagine in a loss of function, homeless areas, recessive state, upregulating a pathway gene, second compensate for the loss of the mutated gene. So, that that's the case with the renicell example, where beta globin in TDT is there's no expression of beta globin, or in sickle cells of these, it's a deleterious mutation, and so it's not functioning properly.

Speaker Change: Thanks very much Yanan. So with the first question, I'm going to start by saying that you have actually described

Speaker Change: You've actually nailed both elements of the operating strategy, but I'll let Linda just expand on that, and then I'll restate the second question, and we'll address that. Yeah, thanks very much for your question. So the two scenarios that you described, like both are possible approaches. One can imagine

Linda Burkly: in loss of function, homozygous recessive state, upregulating a pathway gene that can compensate for the loss of the mutated gene. So that's the case with the Renacel example where beta globin in TDT is, there's no expression of beta globin or in sickle cell disease, it's a deleterious mutation and so it's not functioning properly and we upregulate gamma globin to compensate in both of those cases. One can also imagine a scenario of haploinsufficiency where you have

Linda Burkly: And we upregulate gamma globin to compensate in both of those cases. One can also imagine a scenario of hapline sufficiency, where you have one allele has a mutation pathogenic mutation, but there's a wild type of allele that can be upregulated to compensate for the loss of function of the mutated allele. So either scenario is a potential target. for us.

Oneill: One allele has a mutation, a pathogenic mutation, but there's a wild-type allele that can be upregulated to compensate for the loss of function of the mutated allele.

Oneill: So either scenario is a potential target for us.

Gilmore ONeill: Thank you very much, Linda.

Unknown Executive: I mean, this is what we want. One of the things we're really excited about our technology is that we're talking about using this technology, not just because it's new and cool, but because it has the potential to deliver high potency, large effect sizes in patients. And so, when you consider those elements, you know, our current estimates that a range of about 400 to 500 million is about the market size that would be meaningful and enable us to, you know, drive growth. And as we grow and evolve into treating larger populations, as we build that safety characterization in a number of smaller orphan-sized populations.

Eric Lucera: And I think Yanan, you asked a second question about updates on the CAC timings. Obviously, the oral presentations occurred in the last quarter in May. And we anticipated decision probably for the end of the year.

Speaker Change: Thank you very much Linda and I think Yanan you asked a second question about update on the CAFC timings. Obviously the oral presentations occurred in the last quarter in May and we anticipate a decision probably before the end of the year.

Gilmore ONeill: May I just want to say, I was just wondering if I could translate haplo insufficiency into late terms for those who might not have done molecular biology or genetics. By haplow insufficiency, everyone carries two copies; most copies, two copies of a gene. And the context of haploinsufficiency, one gene is not functioning, which results in a reduction in the total dose of protein that's available to the person, resulting in disease, so-called insufficiency, for haploinsufficiency. And the strategy that Linda is describing, that we're pursuing to manage that, is that you drive up expression of the normal copy to actually approach or get to the same dose of overall protein that would be required for normal health.

Unknown Executive: That's very helpful. Yeah, that's very helpful. Thank you. Thank you.

Operator: We'll take our next question from Jay Olson with Oppenheimer. Your line is open. Hey, this is Sean on the line for Jay. Thanks for taking the questions.

Unknown Executive: Thank you. We'll take our next question from Jay Olson with Oppenheimer Airline.

Unknown Executive: Thanks very much. I just want to just restate your question because I was a little muffled on the line. I think you were asking was, will the adolescent cohort be followed for long enough to be part of the label? and Joe Shindelar.

Unknown Executive: Thank you. Yeah, that's great. Thank you. Yeah, thanks, Chen.

Unknown Executive: We are very pleased with the progress of the adolescent cohort. And we started enrollment this year, and we already completed enrollment in a matter of months. So we're very pleased with that. We certainly wanted to seek a broader indication for all age cohorts. And we already have alignment with FDA about the clinical trial for all the age cohorts. So that's what we're very much looking forward to.

Operator: Thank you. We'll take our next question from Yian Zhu with Wells Fargo Securities. Your line is open.

Unknown Executive: For the in vivo program, are you trying to upregulate the disease-causing gene itself, or are you trying to upregulate a different gene to compensate for the loss of the disease-causing gene? In other words, are we talking about a haploinsufficiency type of indication, or are we talking about a recessive gene defect here? Secondarily, I wanted to ask about any updated timing for the CAFC patent dispute process. Thank you.

Speaker Change: Everyone carries two copies.

Unknown Executive: Thanks very much, Yanan. So with the first question, I'm going to start by saying that you have actually described, you've actually nailed both elements of the Operating Strategy, but I'll let Linda just expand on that. And then I'll restate the second question, and we'll address that. Yeah, thanks very much for your question.

Linda Burkly: So the two scenarios that you described are both possible approaches. One can imagine in a loss of function, homozygous recessive state, upregulating a pathway gene that can compensate for the loss of the mutated gene. So that's the case with the Renacel example, where in TDT, there's no expression of beta-globin, or in sickle cell disease, it's a deleterious mutation, and so it's not functioning properly. And we upregulate gamma-globin to compensate in both of those cases.

Gilmore ONeill: That was helpful. Great. Thanks, O'Neill, and thanks, Linda.

Nick: Thank you.

Unknown Executive: Thank you very much, Linda. And I think Yanan asked a second question about an update on the CAFC timings. Obviously, the oral presentations occurred in the last quarter of May, and we anticipate a decision probably before the end of the year. It managed to work. Thank you.

Nick: We'll take our next question from Steve. Steve, how's with Raymond James? Your line is open. Hi. Good morning, and thank you for the question. This is Nick on for Steve. Had a quick follow up to Lucas. First question actually.

Linda Burkly: One can also imagine a scenario of haploinsufficiency, where you have one allele with a mutation, a pathogenic mutation, but there's a wild-type allele that can be upregulated to compensate for the loss of function of the mutated allele. So either scenario is a potential target for us.

Nick: Are you able to speak to the importance in demand for fertility support in your own clinical trials experience for SCD? Also, curious if your thoughts on the potential market impact. If you're not able to provide the support, I want to prove. Thank you.

Unknown Executive: I was just wondering if I could translate haploinsufficiency into lay terms for those who might not have done molecular biology or genetics. By haploinsufficiency, everyone carries two copies. Most copies, two copies of a gene, and in the context of haploid insufficiency, one gene is not functioning, which results in a reduction in the total dose of protein that's available to the person, resulting in disease, the so-called insufficiency or haploid insufficiency. And the strategy that Linda is describing that we're pursuing to manage that is that you drive up expression of the normal copy to actually approach or get to the same dose of overall protein that would be required for normal health.

Baisong Mei: So, I'm going to split that question into two parts. I'm going to ask, based on to talk about our experience in our clinical trial, and then I'll have Karen to talk about the impact, and very importantly, how we anticipate, you know, mitigating or ensuring that that impact is not going to be there. Yeah, thank you for the question, Nick. We can go to trial setting. We do provide fertility support. Which is critical for patients, especially in the patient population, that it is important for them to have that support be able to go through the chemotherapy and conditioning process.

Unknown Executive: Great. Thanks, O'Neill, and thanks, Linda. Thank you. We'll take our next question from Steve Seedhouse with Raymond James. Your line is open. Hi, good morning, and thank you for the question. This is Nick on behalf of Steve.

Speaker Change: So I'm going to split that question into two parts. I'm going to ask Baisong to talk about our experience in our clinical trial, and then I'll have Caren to talk about the impact and very importantly, how we anticipate, you know, mitigating or ensuring that that impact is not going to be there.

Operator: Thank you. We'll take our next question from Steve Seedhouse with Raymond James. Your line is open.

Unknown Executive: So I'm going to split that question into two parts. I'm going to ask Baisong to talk about our experience in our clinical trial, and then I'll have Caren talk about the impact and, very importantly, how we anticipate, you know, mitigating or ensuring that that impact is not going to be there.

Caren Deardorf: You know, I want to let Karen to emphasize that importance of that in the commercial setting. Yeah, thanks. Thanks for the question. So, we do see this as a very important component of support to six patients in the context of the gene editing transplant. In terms of impacts on the market, what I will say is that for the Medicaid population within the CMMI model that we've all discussed and we hope and anticipate will get started sometime in 2025, there actually is a carve-out there so that within the model, which we don't know how many states will be included, but that does cover Medicaid patients and the fertility preservation is able to be included in that.

Speaker Change: I want to let Caren to emphasize the importance of that in a commercial setting.

Baisong Mei: Thank you for the question, Nick. In the clinical trial setting, we do provide fertility support, which is critical for patients, especially in this patient population, that it is important for them to have that support to be able to go through the chemotherapy and conditioning process. I want to let Caren emphasize the importance of that in the commercial setting.

Baisong Mei: Yeah, thanks. Thanks for the question. So we do see this as a very important component of support to six locations in the context of

Caren Deardorf: Yeah, thanks. Thanks for the question. So we do see this as a very important component of support to six locations in the context of gene editing transplantation. In terms of impact on the market, what I will say is that for the Medicaid population within the CMI model that we've all discussed, and we hope and anticipate will get started sometime in 2025. There actually is a curve out there so that within the model, which we don't know how many states will be included, but that does cover Medicaid patients, and fertility preservation is able to be included in that.

Caren Deardorf: And then in the commercial setting, it's fine. So the decision that HHS or the IG made does not affect commercial and also, again, CMMI, which we are encouraged and very hopeful that that will move quickly. And...

Caren Deardorf: And then, in the commercial setting, it is fine. So the decision that HHS or the IG made does not affect commercial and also, again, CMMI, which we are encouraged and very hopeful that that will move quickly. And I am hopeful that there will be enough pressure and enough parties that will move to eventually change this. So, by the time we're launching, I can't promise, but I don't anticipate it will be a huge market impact. And even in the coming years, I think that there are other opportunities for patients to be able to receive the gene editing therapies and the fertility preservation.

Unknown Executive: I am hopeful that there will be enough pressure and enough parties that will move to eventually change this. So by the time we're launching, I can't promise, but I don't anticipate that there will be a huge market impact. And even in the coming years, I think that there will be other opportunities for patients to be able to receive gene editing therapies and fertility preservation.

Caren Deardorf: I am hopeful that there will be enough pressure and enough parties that will move to eventually change this. So by the time we're launching, I can't promise, but I don't anticipate it will be a huge market impact. And even in the coming years, I think that there are other opportunities for patients to be able to receive the gene editing therapies and the fertility preservation.

Caren Deardorf: Karen, it might be worth just pausing you for a second and just taking people through the acronyms and the sort of the structure of. Yeah, sorry. No, no, no, it's just, you know, what's in my mind. So CMS has a section; it's the CMMI model, which is created to be able to explore and launch pilot programs to patients, to different areas of need. There are numbers that have been done in oncology over the last years, and they created a specific cell and gene therapy program of which the sickle cell disease area was highlighted, and the program was initiated earlier this year, kicked off, and it is voluntary for both manufacturers and four states.

Unknown Executive: It might be worth just pausing for a second and just taking people through the acronyms and sort of the structure of yeah, sorry, no, no, just so you know what CMMI is. So, CMS has a section called the CMMI model, which is created to be able to

Caren Deardorf: So TBD on exactly, you know, who is involved in it, but the opportunity is there with a lot of funding for federal CMS through the CMMI model, to be able to negotiate with manufacturers on behalf of a lot of states. So it takes out some of that work and that variability. Again, it is a promising program that needs to be moved forward quickly, but within it, there was a waiver on the anti-kickback statute around providing the fertility preservation.

Caren Deardorf: states so TBD on exactly

Caren Deardorf: who is involved in it, but the opportunity is there with a lot of funding for federal CMS through the CMMI model to be able to negotiate with manufacturers on behalf of a lot of states. So it takes out some of that work and that variability. Again, it is a promising program that needs to be moved forward quickly, but within it,

Caren Deardorf: There was a waiver on the anti-kickback statute around providing the fertility preservation. So hopefully that gives a little bit better context.

Caren Deardorf: So hopefully that gives us a better context. Thanks very much, Karen. Thank you.

Operator: Thank you. We'll take our next question from Liisa Bayko with Evercore ISI. Your line is now open.

Speaker Change: Thanks very much, Caren.

Julie: We'll take our next question from Lisa Beko with Evercore ISI. Your line is now open. Hi, this is streaming on for Lisa. Thanks for taking our questions.

Speaker Change: Hi, this is Jingming, I'm for Liisa, thanks for taking our questions. So there's a large number of patients in the Middle East and can you please comment on how you plan to target this region? Do you plan to execute global launch yourself or will you need a partner considering the complexities? Thank you.

Caren Deardorf: So there's a large number of patients in the Middle East, and can you please comment on how you plan to target this region? Do you plan to execute global launch yourself, or will you need a partner considering the construct for these? Thank you. Thanks very much, Julie.

Unknown Executive: Thanks very much, Edwilling. I'm going to have Caren address that question. Yes, great. Thank you. And we agree that in the Middle East and elsewhere, there is a significant unmet need. As we've said and as was stated earlier, we continue to consider partnering for anything outside of the United States and any way that we can improve and accelerate access to therapies like Renacel to patients in need. So we continue to maintain that strategy, and we'll update it as appropriate. Thank you very much, Terence.

Caren Deardorf: I'm going to have Karen address that question. Great. Thank you. And we agree in the Middle East, and there are other geographies where there is a significant unmet need. As we've said, and as was stated earlier, we continue to consider partnering for anything outside of the United States, and any way that we can improve and accelerate access of therapies like Run a Cell to patients in need. So we continue to maintain that strategy, and we'll update that appropriately. Thank you very much, Karen. Thank you.

Speaker Change: of therapies like Renacel to patients in need. So we continue to maintain that strategy and we'll update as appropriate.

Speaker Change: Thank you very much, Karen.

Operator: Thank you. Ladies and gentlemen, this concludes today's call. Thank you once again for your participation. You may now disconnect.

Unknown Executive: Ladies and gentlemen, this concludes today's call. Thank you once again for your participation. You may now disconnect.

Speaker Change: Thank you. Ladies and gentlemen, this concludes today's call. Thank you once again for your participation. You may now disconnect.