Q4 2025 REGENXBIO Inc Earnings Call

March 5, 2026

Speaker #1: Thank you for standing by, and welcome to REGENXBIO's fourth quarter and year-end 2025 earnings conference call. At this time, all participants are in a listen-only mode.

Operator: Thank you for standing by. Welcome to REGENXBIO's Q4 and year-end 2025 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. To remove yourself from the queue, you may press star one one again. I would now like to hand the call over to Patrick Christmas, Chief Legal Officer of REGENXBIO. Please go ahead.

Speaker #1: After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press *11 on your telephone.

Speaker #1: To remove yourself from the queue, you may press *11 again. I would now like to hand the call over to Patrick Christmas, Chief Legal Officer of REGENXBIO.

Speaker #1: Please go ahead.

Speaker #2: Good morning, and thank you for joining us today. Earlier this morning, REGENXBIO released financial and operating results for the fourth quarter and year ending December 31, 2025.

Patrick Christmas: Good morning, thank you for joining us today. Earlier this morning, REGENXBIO released financial and operating results for Q4 and year ending 31 December 2025. The press release is available on our website at www.regenxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties.

Speaker #2: The press release is available on our website at www.regenxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook, in addition to regulatory and product development plans.

Speaker #2: These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted, and can be identified by words such as expect, plan, will, may, anticipate, believe, should, or intend, or by similar expressions.

Speaker #2: Any such forward-looking statements are not guarantees of future performance, and involve certain risks and uncertainties. These risks are described in the risk factors and the management's discussion and analysis section of REGENXBIO's annual report on Form 10-K for the full year ended December 31, 2025, and comparable risk factors section of REGENXBIO's quarterly reports on Form 10-Q, which will be on file with the Securities and Exchange Commission and available in the SEC's website.

Patrick Christmas: These risks are described in the Risk Factors and the Management's Discussion and Analysis section of REGENXBIO's annual report on Form 10-K for the full year ended 31 December 2025, and comparable Risk Factors section of REGENXBIO's quarterly reports on Form 10-Q, which will be on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, 5 March 2026, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise. Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company.

Speaker #2: Any information we provide on this conference call is provided only as of the date of this call, March 5, 2026, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise.

Speaker #2: Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project the financial position or operating results of the company.

Speaker #2: Actual results may differ materially. I'll now turn the call to Curran Simpson, President and CEO of REGENXBIO. Curran?

Patrick Christmas: Actual results may differ materially. I'll now turn the call to Curran Simpson, President and CEO of REGENXBIO. Curran.

Speaker #3: Thank you, Patrick. Good morning, everyone, and thank you for joining our call today. 2026 is set to be a pivotal year for REGENXBIO. With great focus on advancing our late-stage pipeline in 2025, we enter the year with near-term top-line Phase 3 readouts and ongoing commercial readiness activities in Duchenne muscular dystrophy and wet AMD.

Curran M. Simpson: Thank you, Patrick. Good morning, everyone, thank you for joining our call today. 2026 is set to be a pivotal year for REGENXBIO. With great focus on advancing our late-stage pipeline in 2025, we enter the year with near-term top-line phase 3 readouts and ongoing commercial readiness activities in Duchenne muscular dystrophy and wet AMD. Last but not least, we are also entering the pivotal phase IIb/III program named NAVIGATE for diabetic retinopathy being developed in collaboration with our eye care partner, AbbVie. Our clear focus on execution in 2025 has led to a robust set of important catalysts to transform REGENXBIO from a late-stage development organization to a commercial entity. Today, I am joined by Dr.

Curran Simpson: Thank you, Patrick. Good morning, everyone, thank you for joining our call today. 2026 is set to be a pivotal year for REGENXBIO. With great focus on advancing our late-stage pipeline in 2025, we enter the year with near-term top-line phase 3 readouts and ongoing commercial readiness activities in Duchenne muscular dystrophy and wet AMD. Last but not least, we are also entering the pivotal phase IIb/III program named NAVIGATE for diabetic retinopathy being developed in collaboration with our eye care partner, AbbVie. Our clear focus on execution in 2025 has led to a robust set of important catalysts to transform REGENXBIO from a late-stage development organization to a commercial entity. Today, I am joined by Dr.

Speaker #3: Last but not least, we are also entering the pivotal Phase 2B/3 program named NAVIGATE. For diabetic retinopathy being developed, in collaboration with our eye care partner AbbVie.

Speaker #3: Our clear focus on execution in 2025 has led to a robust set of important catalysts to transform REGENXBIO from a late-stage development organization to a commercial entity.

Speaker #3: Today, I am joined by Dr. Stephen Pakola, our Chief Medical Officer, who will walk through the ongoing clinical advancement of our programs, and Mitch Chan, our Chief Financial Officer, to provide our financial updates.

Curran M. Simpson: Steve Pakola, our Chief Medical Officer, who will walk through the ongoing clinical advancement of our programs, and Mitchell Chan, our Chief Financial Officer, to provide our financial updates. With that, let me start with RGX-202, our late-stage Duchenne program. I'm pleased to report that momentum for RGX-202, our potential best-in-class gene therapy for Duchenne, remains strong. We completed dosing in our pivotal study last fall and are seeing robust enrollment in our confirmatory trial, reflecting continued enthusiasm from the Duchenne community. Our growing clinical data set, including the 18-month phase 1/2 NSAA results shared in January, demonstrate meaningful differentiation from the known natural history of Duchenne across multiple validated measures. Combined with a favorable safety and biomarker profile to date, we believe RGX-202 has the potential to deliver durable, clinically meaningful benefit.

Curran Simpson: Steve Pakola, our Chief Medical Officer, who will walk through the ongoing clinical advancement of our programs, and Mitchell Chan, our Chief Financial Officer, to provide our financial updates. With that, let me start with RGX-202, our late-stage Duchenne program. I'm pleased to report that momentum for RGX-202, our potential best-in-class gene therapy for Duchenne, remains strong. We completed dosing in our pivotal study last fall and are seeing robust enrollment in our confirmatory trial, reflecting continued enthusiasm from the Duchenne community. Our growing clinical data set, including the 18-month phase 1/2 NSAA results shared in January, demonstrate meaningful differentiation from the known natural history of Duchenne across multiple validated measures. Combined with a favorable safety and biomarker profile to date, we believe RGX-202 has the potential to deliver durable, clinically meaningful benefit.

Speaker #3: With that, let me start with RGX 202, our late-stage Duchenne program. I'm pleased to report that momentum for RGX 202, our potential best-in-class gene therapy for Duchenne, remains strong.

Speaker #3: We completed dosing in our pivotal study last fall and are seeing robust enrollment in our confirmatory trial, reflecting continued enthusiasm from the community. Our growing clinical dataset, including the 18-month Phase 1/2 NSAA results shared in January, demonstrates meaningful differentiation from the known natural history of Duchenne across multiple validated measures.

Speaker #3: Combined with a favorable safety and biomarker profile to date, we believe RGX 202 has the potential to deliver durable, clinically meaningful benefit. With less than 1% of the global Duchenne population having received an approved gene therapy, and no approved option for patients ages 1 to 3, the unmet need remains significant.

Curran M. Simpson: With less than 1% of the global Duchenne population having received an approved gene therapy and no approved option for patients ages 1 to 3, the unmet need remains significant. We look forward to sharing additional phase 1/2 data next week at the Muscular Dystrophy Association's annual meeting and top-line data from our pivotal study early in Q2 as we advance towards a BLA submission. We look forward to engaging with FDA mid-year to discuss our planned BLA submission using the accelerated approval pathway. We have FDA engagement planned ahead of the pre-BLA meeting and intend to support our primary microdystrophin endpoint with significant functional data, both in the pre-BLA meeting and at the time of submission.

Curran Simpson: With less than 1% of the global Duchenne population having received an approved gene therapy and no approved option for patients ages 1 to 3, the unmet need remains significant. We look forward to sharing additional phase 1/2 data next week at the Muscular Dystrophy Association's annual meeting and top-line data from our pivotal study early in Q2 as we advance towards a BLA submission. We look forward to engaging with FDA mid-year to discuss our planned BLA submission using the accelerated approval pathway. We have FDA engagement planned ahead of the pre-BLA meeting and intend to support our primary microdystrophin endpoint with significant functional data, both in the pre-BLA meeting and at the time of submission.

Speaker #3: We look forward to sharing additional Phase 1-2 data next week at the muscular dystrophy association's annual meeting and top-line data from our pivotal study early in the second quarter, as we advance towards a BLA submission.

Speaker #3: We look forward to engaging with FDA mid-year to discuss our planned BLA submission using the accelerated approval pathway. We have FDA engagement planned ahead of the pre-BLA meeting, and intend to support our primary microdystrophin endpoint with significant functional data both in the pre-BLA meeting and at the time of submission.

Speaker #3: By the fall of 2026, we will have 12-month functional data on the majority of pivotal trial patients. In addition, with the enrollment momentum in our confirmatory study, our safety database continues to expand.

Curran M. Simpson: By the fall of 2026, we will have 12 months functional data on the majority of pivotal trial patients. With the enrollment momentum in our confirmatory study, our safety database continues to expand. In our retinal disease programs, our partnership with AbbVie continues to progress. Top line data for subretinal Surrovac in wet AMD are expected in Q4 this year. ATMOSPHERE and ASCENT represent the largest global gene therapy program in this indication, and if approved, Surrovac would be the first gene therapy for wet AMD. I'm also pleased to share that site activation plans are also underway in the NAVIGATE pivotal study in diabetic retinopathy, with first patient dosing expected next quarter, triggering a $100 million milestone from AbbVie. Turning to our MPS programs.

Curran Simpson: By the fall of 2026, we will have 12 months functional data on the majority of pivotal trial patients. With the enrollment momentum in our confirmatory study, our safety database continues to expand. In our retinal disease programs, our partnership with AbbVie continues to progress. Top line data for subretinal Surrovac in wet AMD are expected in Q4 this year. ATMOSPHERE and ASCENT represent the largest global gene therapy program in this indication, and if approved, Surrovac would be the first gene therapy for wet AMD. I'm also pleased to share that site activation plans are also underway in the NAVIGATE pivotal study in diabetic retinopathy, with first patient dosing expected next quarter, triggering a $100 million milestone from AbbVie. Turning to our MPS programs.

Speaker #3: In our retinal disease programs, our partnership with AbbVie continues to progress. Top-line data for subretinal, SUREVEC, in wet AMD are expected in Q4 this year.

Speaker #3: ATMOSPHERE and DESCENT represent the largest global gene therapy program in this indication, and if approved, SUREVEC would be the first gene therapy for wet AMD.

Speaker #3: I'm also pleased to share that site activation plans are also underway in the NAVIGATE pivotal study in diabetic retinopathy, with first patient dosing expected next quarter.

Speaker #3: Triggering a $100 million milestone from AbbVie. Finally, turning to our MPS programs. Since receiving the CRL for RGX-121 two weeks ago, we have also received the clinical hold letters for both RGX-111 and RGX-121.

Curran M. Simpson: Since receiving the CRL for RGX-121 2 weeks ago, we have also received the clinical hold letters for both RGX-111 and RGX-121. We believe that the requirements to remove the holds are addressable and in fact had already been in the process of addressing them. We continue to work on the CRL response and working towards a Type A meeting with the goal of resubmitting the BLA. We remain committed to the MPS community and the Hunter syndrome patients waiting for a treatment for this devastating disease. As we enter 2026, our focus is clear execute against our key milestones and bring the hope for transformative gene therapies closer to patients in need. With that, I'll turn it over to Steve.

Curran Simpson: Since receiving the CRL for RGX-121 2 weeks ago, we have also received the clinical hold letters for both RGX-111 and RGX-121. We believe that the requirements to remove the holds are addressable and in fact had already been in the process of addressing them. We continue to work on the CRL response and working towards a Type A meeting with the goal of resubmitting the BLA. We remain committed to the MPS community and the Hunter syndrome patients waiting for a treatment for this devastating disease. As we enter 2026, our focus is clear execute against our key milestones and bring the hope for transformative gene therapies closer to patients in need. With that, I'll turn it over to Steve.

Speaker #3: We believe that the requirements to remove the holds are addressable, and, in fact, had already been in the process of addressing them. We continue to work on the CRL response and are working towards a Type A meeting, with the goal of resubmitting the BLA.

Speaker #3: We remain committed to the MPS community and the Hunter syndrome patients waiting for a treatment for this devastating disease. As we enter 2026, our focus is clear: execute against our key milestones and bring the hope for transformative gene therapies closer to patients in need.

Speaker #3: With that, I'll turn it over to Steve.

Speaker #4: Thank you, Curran. I'll start with the RGX 202 program. For the treatment of Duchenne. As Curran mentioned, we are incredibly excited that enrollment in the affinity Duchenne pivotal trial completed in October 2025.

Steve Pakola: Thank you, Kern. I'll start with the RGX-202 program for the treatment of Duchenne. As Kern mentioned, we are incredibly excited that enrollment in the AFFINITY DUCHENNE pivotal trial completed in October 2025. As a reminder, this study enrolled ambulatory patients aged 1 and older and is the most advanced clinical stage gene therapy program for Duchenne. RGX-202 has demonstrated a highly differentiated safety and efficacy profile with consistent, robust microdystrophin expression in the phase I/II study. This includes the positive NSAA data we disclosed in January. As Kern referenced, the 7.4 average improvement compared to the recognized CTAP model observed at 18 months is striking. These results are generally consistent with the October 2025 data, showing all patients exceeded their expected functional outcomes when compared to CTAP as well as matched external controls at 12 months.

Speaker #4: As a reminder, this study enrolled ambulatory patients aged 1 and older and is the most advanced clinical-stage gene therapy program for Duchenne. RGX 202 has demonstrated a highly differentiated safety and efficacy profile with consistent robust microdystrophin study.

Speaker #4: This includes the positive NSAA data we disclosed in January. As Curran referenced, the 7.4 average improvement compared to the recognized CTAP model observed at 18 months is striking.

Speaker #4: These results are generally consistent with the October 2025 data showing all patients succeeded their outcomes when compared to CTAP, as well as matched external controls at 12 months.

Speaker #4: It's important to note the majority of these patients were eight years and older at dosing, an age when functional decline is expected, making these functional outcomes even more impressive.

Steve Pakola: It's important to note the majority of these patients were 8 years and older at dosing, an age when functional decline is expected, making these functional outcomes even more impressive. The Duchenne patient and physician communities continue to recognize the excellent safety profile of RGX-202 to date. As reported in the phase I/II study, we have seen no SAEs or AESIs, including no thrombocytopenia or liver injury. We attribute this to our proactive immune suppression regimen, our novel construct, and our field-leading product purity with more than 80% full capsids. We are very pleased with how these differentiated elements enable us to deliver 202 at a 2e14 dose and maximize the potential for efficacy without compromising safety. Next week at MDA, we are thrilled to share additional new phase I/II data on podium, including functional and safety outcomes.

Speaker #4: The Duchenne patient and physician communities continue to recognize the excellent safety profile of RGX 202 to date. As reported in the Phase 1-2 study, we have seen no SAEs or AESIs including no thrombocytopenia or liver injury.

Speaker #4: We attribute this to our proactive immune suppression regimen; our novel construct; and our field-leading product purity. With more than 80% full capsids. We are very pleased with how these differentiated elements enable us to deliver.

Speaker #4: 202 at a 2E14 dose, and maximize the potential for efficacy without compromising safety. Next week at MDA, we are thrilled to share additional new Phase 1/2 data on podium, including functional and safety outcomes.

Speaker #4: With this momentum in our pivotal study and results to date in the Phase 1-2 study, we look forward to sharing top-line data from the pivotal study in early second quarter this year.

Steve Pakola: With this momentum in our pivotal study and results to date in the phase 1/2 study, we look forward to sharing top-line data from the pivotal study in early Q2 this year. Turning now to our Surrovac franchise, which is advancing one-time treatment for wet AMD and diabetic retinopathy, or DR. Enrollment is complete in ATMOSPHERE and ASCENT, our two large pivotal studies intended to support global regulatory submissions for subretinal wet AMD starting next year. The data from the subretinal program have been excellent, with durable outcomes reported through 4 years in the phase 1/2 trial. Additionally, Surrovac recipients in the fellow eye bilateral dosing study demonstrated a 93% reduction in annualized anti-VEGF injection need at 12 months, with 60% of recipients remaining injection-free through that timeframe. We look forward to sharing top-line results from ATMOSPHERE and ASCENT with AbbVie in Q4.

Speaker #4: Turning now to our SUREVEC franchise, which is advancing one-time treatment for wet AMD and diabetic retinopathy, or DR. Enrollment is complete in atmosphere and ascent are two large pivotal studies intended to support global regulatory submissions for subretinal wet AMD starting next year.

Speaker #4: The data from the subretinal program have been excellent, with durable outcomes reported through four years in the Phase 1/2 trial. Additionally, SUREVEC recipients in the fellow eye bilateral dosing study demonstrated a 93% reduction in annualized anti-VEGF injection need at 12 months.

Speaker #4: With 60% of recipients remaining injection-free, through that timeframe, we look forward to sharing top-line results from atmosphere and ascent with AbbVie in Q4. We are very excited to be advancing SUREVEC into pivotal stage for DR using in-office suprachoroidal delivery with AbbVie.

Steve Pakola: We are very excited to be advancing ABBV-RGX-314 into pivotal stage for DR using in-office suprachoroidal delivery with AbbVie. This progressive vision-threatening disease is a public health priority globally. It remains a leading cause of vision loss among working age adults in the US, a one-time treatment could change the way this disease is treated for millions of people. Site activation activities are underway in the Phase IIb/III NAVIGATE trial. This is a double masked sham injection control trial evaluating ABBV-RGX-314 at 1e12, which is the same as DL3 in the Phase II ALTITUDE trial. The Phase IIb portion of the study will enroll 136 patients with non-proliferative DR or NPDR. The primary endpoint is 2-step or greater improvement on the diabetic retinopathy severity scale, or DRSS, at one year.

Speaker #4: This progressive, vision-threatening disease is a public health priority globally. It remains a leading cause of vision loss among working-age adults in the US, and a one-time treatment could change the way this disease is treated for millions of people.

Speaker #4: Site activation, activities are underway in the Phase 2B, 3 NAVIGATE trial. This is a double-masked sham injection control trial evaluating SUREVEC at 1E12, which is the same as dose level 3 in the Phase 2 altitude trial.

Speaker #4: The Phase 2b portion of the study will enroll 136 patients with non-proliferative diabetic retinopathy, or NPDR. The primary endpoint is a two-step or greater improvement on the Diabetic Retinopathy Severity Scale over one year.

Speaker #4: As a reminder, in the Phase 2 ALTITUDE trial, at two years post-treatment with dose level 3 and short-course prophylactic topical steroids, no intraocular inflammation was observed.

Steve Pakola: As a reminder, in the Phase II ALTITUDE trial, at 2 years post-treatment with DL3 and short course prophylactic topical steroids, no intraocular inflammation was observed. The majority of subjects achieved DRSS improvement, with 50% achieving at least a 2-step improvement without any additional DR treatment. Survivac at DL3 also reduced the risk of disease progression, demonstrating a greater than 70% risk reduction in vision-threatening complications compared to historical control. As Karan mentioned, we are working towards addressing the clinical holds for RGX-111 and RGX-121. In the interim, we have received the final genetic analysis from the SAE in the RGX-111 study. The analysis of the resected tumor was conducted by an independent third-party lab, and as we reported, detected an AAV vector genome integration event associated with overexpression of a proto-oncogene PLAG1.

Speaker #4: The majority of subjects achieved DRSS improvement, with 50% achieving at least a two-step improvement without any additional DR treatment. SUREVEC at dose level 3 also reduced the risk of disease progression, demonstrating a greater than 70% risk reduction in vision-threatening complications compared to historical control.

Speaker #4: As Curran mentioned, we are working towards addressing the clinical holds for 111 and 121, and in the interim, we have received the final genetic analysis from the SAE in the RGX 111 study.

Speaker #4: The analysis of the resected tumor was conducted by an independent third-party lab, and, as we reported, detected an AAV vector genome integration event associated with overexpression of a proto-oncogene, PLAG-1.

Speaker #4: Clonal integration of AAV vector elements into the PLAG1 gene was detected in the tumor tissue. Analyses supported classification as a PLAG1 family neuroepithelial tumor and are consistent with the hypothesis that AAV vector integration at the PLAG1 site contributed to tumor formation.

Steve Pakola: Clonal integration of AAV vector elements into the PLAG1 gene was detected in the tumor tissue. Analysis supported classification as a PLAG1 family neuroepithelial tumor and are consistent with the hypothesis that AAV vector integration at the PLAG1 site contributed to tumor formation. Of note, this participant had a background of factors that could have contributed to risk of oncogenic transformation. This child underwent an unsuccessful stem cell transplant at 4 months of age with loss of donor chimerism, and he received chemotherapeutics that may have contributed to DNA damage. Notably, the report concludes, based on formal neuropsychological testing and developmental pediatrician assessment, that the patient's neurocognitive development is above average, which indicates mitigation of MPS I disease. We anticipate the analysis will be published in a peer review journal this year, and we are pleased that the patient continues to do well.

Speaker #4: Of note, this participant had a background of factors that could have contributed to the risk of oncogenic transformation. This child underwent an unsuccessful stem cell transplant at four months of age, with loss of donor chimerism, and received chemotherapeutics that may have contributed to DNA damage.

Speaker #4: Notably, the report concludes, based on formal neuropsychological testing and developmental pediatrician assessment, that the patient's neurocognitive development is above average. Which indicates mitigation of MPS-1 disease.

Speaker #4: We anticipate the analysis will be published in a peer-reviewed journal this year, and we are pleased that the patient continues to do well. Finally, I’d like to express my sincere gratitude to all the patients, families, clinicians, site staff, and patient advocacy representatives who have supported these trials.

Steve Pakola: Finally, I'd like to express my sincere gratitude to all the patients, families, clinicians, site staff, and patient advocacy representatives who have supported these trials. With that, I'll turn the call over to Mitch to review our financial guidance. Mitch?

Speaker #4: With that, I'll turn the call over to Mitch to review our financial guidance. Mitch?

Speaker #1: Thank you, Steve. And good morning, everyone. REGENXBIO ended the quarter on December 31, 2025, with cash equivalents and marketable securities of $241 million, compared to $245 million as of December 31, 2024.

Mitchell Chan: Thank you, Steve, and good morning, everyone. REGENXBIO ended Q4 on 31 December 2025 with cash equivalent and marketable securities of $241 million, compared to $245 million as of 31 December 2024. This year-end figure reflects the $110 million upfront payment from Nippon Shinyaku in Q1 2025 and the $145 million in net proceeds received from the royalty monetization with HealthCare Royalty Partners in Q2 2025, offset by cash used to fund operating activities through the year. We continue to invest in de-risking our late-stage program in 2025.

Mitch Chan: Thank you, Steve, and good morning, everyone. REGENXBIO ended Q4 on 31 December 2025 with cash equivalent and marketable securities of $241 million, compared to $245 million as of 31 December 2024. This year-end figure reflects the $110 million upfront payment from Nippon Shinyaku in Q1 2025 and the $145 million in net proceeds received from the royalty monetization with HealthCare Royalty Partners in Q2 2025, offset by cash used to fund operating activities through the year. We continue to invest in de-risking our late-stage program in 2025.

Speaker #1: This year, the end figure reflects the $110 million upfront payment from Nippon Shinyaku in the first quarter of 2025 and the $145 million in net proceeds received from the royalty monetization with Healthcare Royalty Partners in the second quarter of 2025, offset by cash used to fund operating activities through the year.

Speaker #1: We continue to invest in de-risking our late-stage program in 2025. R&D expenses were $228 million for the year ended December 31, 2025, compared to $209 million in 2024, with much of this cost going to pivotal trial execution and manufacturing of RGX-202 and SUREVEC.

Mitchell Chan: R&D expenses were $228 million for the year ended 31 December 2025, compared to $209 million in 2024, with much of this cost going to pivotal trial execution and manufacturing of RGX-202 and Survac. We also continue to bring meaningful revenue to REGENXBIO in 2025, with total annual revenue being $170 million. This includes the upfront license revenue under our Nippon Shinyaku collaboration, as well as an increase in royalty revenue for Zolgensma and Evrysdi, both of which are included in our royalty monetization agreement with HealthCare Royalty. We expect the 31 December cash balance reported today to fund our operations into early 2027.

Mitch Chan: R&D expenses were $228 million for the year ended 31 December 2025, compared to $209 million in 2024, with much of this cost going to pivotal trial execution and manufacturing of RGX-202 and Survac. We also continue to bring meaningful revenue to REGENXBIO in 2025, with total annual revenue being $170 million. This includes the upfront license revenue under our Nippon Shinyaku collaboration, as well as an increase in royalty revenue for Zolgensma and Evrysdi, both of which are included in our royalty monetization agreement with HealthCare Royalty. We expect the 31 December cash balance reported today to fund our operations into early 2027.

Speaker #1: We also continue to bring meaningful revenue to REGENXBIO in 2025, with total annual revenue being $170 million. This includes the upfront license revenue under our Nippon Shinyaku collaboration, as well as an increase in royalty revenue for Zolgensma and Iphysma.

Speaker #1: Both of which are included in our Royalty Monetization agreement with Healthcare Royalty. We expect the December 31st cash balance reported today to fund our operations into early 2027.

Speaker #1: This cash runway guidance does not include the $100 million development milestone we expect to receive from AVI upon first patient dose in the NAVIGATE study or any additional funds from the May 2025 Healthcare Royalty Agreement, which together could extend our runway into the second half of 2027.

Mitchell Chan: This cash runway guidance does not include the $100 million development milestone we expect to receive from AbbVie upon first patient dose in the NAVIGATE study or any additional funds from the May 2025 healthcare royalty agreement, which together could extend our runway into the second half of 2027. This guidance also does not include any future revenue from our MPS programs. In all, we find ourselves in a strong position to leverage multiple funding options as we advance towards multiple product launches. With that, I will turn the call back to Curran to provide final thoughts.

Mitch Chan: This cash runway guidance does not include the $100 million development milestone we expect to receive from AbbVie upon first patient dose in the NAVIGATE study or any additional funds from the May 2025 healthcare royalty agreement, which together could extend our runway into the second half of 2027. This guidance also does not include any future revenue from our MPS programs. In all, we find ourselves in a strong position to leverage multiple funding options as we advance towards multiple product launches. With that, I will turn the call back to Curran to provide final thoughts.

Speaker #1: This guidance also does not include any future revenue from our MPS programs. In all, we find ourselves in a strong position to leverage multiple funding options as we advance towards multiple product launches.

Speaker #1: With that, I will turn the call back to Curran to provide final thoughts.

Speaker #2: Thank you, today, our strong execution has positioned us for an exciting and transformational year ahead as we share pivotal readouts and look to enhance the treatment landscape in Duchenne, Wet AMD, and diabetic retinopathy.

Curran M. Simpson: Thank you, Mitch. As you heard today, our strong execution has positioned us for an exciting and transformational year ahead as we share pivotal readouts and look to enhance the treatment landscape in Duchenne, wet AMD, and diabetic retinopathy, representing large indications and commercial opportunities. Our investment in in-house manufacturing and co-development with world-class partners keep us in a strong position as we approach commercialization. Last week, we joined the rare disease community in recognizing Rare Disease Day, and I'd like to take a moment to acknowledge these patients, families, and community leaders. We know they are counting on us to deliver innovative new medicines, and we greatly appreciate the support they've shown us, particularly on our rare programs recently. Their needs are significant and urgent, and we are inspired by their commitment to raise awareness and give voice to the critical need for new therapies.

Curran Simpson: Thank you, Mitch. As you heard today, our strong execution has positioned us for an exciting and transformational year ahead as we share pivotal readouts and look to enhance the treatment landscape in Duchenne, wet AMD, and diabetic retinopathy, representing large indications and commercial opportunities. Our investment in in-house manufacturing and co-development with world-class partners keep us in a strong position as we approach commercialization. Last week, we joined the rare disease community in recognizing Rare Disease Day, and I'd like to take a moment to acknowledge these patients, families, and community leaders. We know they are counting on us to deliver innovative new medicines, and we greatly appreciate the support they've shown us, particularly on our rare programs recently. Their needs are significant and urgent, and we are inspired by their commitment to raise awareness and give voice to the critical need for new therapies.

Speaker #2: Representing large indications and commercial opportunities. Our investment in in-house manufacturing and co-development with world-class partners keep us in a strong position as we approach commercialization.

Speaker #2: Last week, we joined the rare disease community in recognizing rare disease day, and I'd like to take a moment to acknowledge these patients, families, and community leaders.

Speaker #2: We know they are counting on us to deliver innovative new medicines, and we greatly appreciate the support they've shown us, particularly on our rare programs recently.

Speaker #2: Their needs are significant and urgent. And we are inspired by their commitment to raise awareness and give voice to the critical need for new therapies.

Speaker #2: With that, I'll turn the call over for questions. Operator?

Curran M. Simpson: With that, I'll turn the call over for questions. Operator?

Curran Simpson: With that, I'll turn the call over for questions. Operator?

Speaker #3: Thank you. As a reminder, to ask a question, you will need to press *11 on your telephone. To remove yourself from the queue, you may press *11 again.

Operator: Thank you. As a reminder, to ask a question, you will need to press star one one on your telephone. To remove yourself from the queue, you may press star one one again. We ask that you please limit yourself to one question and one follow-up to allow everyone the opportunity to participate. Please stand by while we compile the Q&A roster. Our first question comes from the line of Mani Foroohar of Leerink Partners. Please go ahead, Manny.

Speaker #3: We ask that you please limit yourself to one question and one follow-up to allow everyone the opportunity to participate. Please stand by while we compile the Q&A roster.

Speaker #3: Our first question comes from the line of Manny Forahar, a Believrink partner. Please go ahead, Manny.

Speaker #4: Hey, guys. Thanks for taking the question. So, as we get closer to data and regulatory clarity in terms of your submission around DMD, obviously there's a lot of debate and concern around whether a controlled trial, or whether an appropriate control arm, could be—obviously, those are both Sarepta and Solid have seen that in the confirmatory and pivotal studies, respectively.

Mani Foroohar: Hey, guys. Thanks for taking the question. As we get closer to data and regulatory clarity in terms of submission around DMD, obviously, there's a lot of debate and concern around whether a controlled trial or an appropriate control arm could be. Obviously, both Sarepta and Solid Biosciences have seen that in the confirmatory and pivotal studies respectively. What gives you confidence on your path to accelerated approval and on the design of your confirmatory study, which is a little bit different than both of those competitors?

Speaker #4: What gives you confidence on your path to a slow rate of approval and on the design of your confirmatory study, which is a little bit different than both of those competitors?

Curran M. Simpson: Thanks, Mani. I think there's a number of aspects to that that give us confidence. I think number 1, the fact that the protocol was prospectively reviewed by FDA. We received comments on the design of the study and the stats plan around comparison to external controls. We feel like we have. And none of that's changed. We haven't altered the pivotal protocol through execution. I think the second pillar of that is there's not a narrow difference between the results we're seeing on functional outcomes versus natural history comparatives, and this is, you know, matching many patients against the patient treated.

Speaker #2: Thanks, Manny. I think there's a number of aspects to that that give us confidence. I think, number one, the fact that the protocol was prospectively reviewed by FDA.

Curran Simpson: Thanks, Mani. I think there's a number of aspects to that that give us confidence. I think number 1, the fact that the protocol was prospectively reviewed by FDA. We received comments on the design of the study and the stats plan around comparison to external controls. We feel like we have. And none of that's changed. We haven't altered the pivotal protocol through execution. I think the second pillar of that is there's not a narrow difference between the results we're seeing on functional outcomes versus natural history comparatives, and this is, you know, matching many patients against the patient treated.

Speaker #2: We received comments on the design of the study and the stats plan around comparison to external controls. So we feel like we altered the pivotal protocol through execution. I think the second pillar of that is there's not a narrow difference between the results we're seeing on functional outcomes versus natural history comparatives.

Speaker #2: And this is matching many patients against the patient treated. So I think that the fact that we have such compelling data specifically in the older patients where they're typically in a declined phase, I feel will sort of trump the concept of a placebo arm, which we don't think is ethical.

Curran M. Simpson: I think that the fact that we have such compelling data, specifically in the older patients where they're typically in a decline phase, I feel will sort of trump the concept of a placebo arm, which we don't think is ethical. I think the other aspects of how that relates to the confirmatory study, the confirmatory study was included in the original protocol as in addition to the pivotal design. Again, that was reviewed by FDA. We're really pleased with how the enrollment is going there. One thing that enrolling as quickly as we have on the confirmatory study does in a positive way is increases the number of safety exposures that we have at the time of filing. We're talking about roughly 50 total rather than the 30 that were in the pivotal group.

Curran Simpson: I think that the fact that we have such compelling data, specifically in the older patients where they're typically in a decline phase, I feel will sort of trump the concept of a placebo arm, which we don't think is ethical. I think the other aspects of how that relates to the confirmatory study, the confirmatory study was included in the original protocol as in addition to the pivotal design. Again, that was reviewed by FDA. We're really pleased with how the enrollment is going there. One thing that enrolling as quickly as we have on the confirmatory study does in a positive way is increases the number of safety exposures that we have at the time of filing. We're talking about roughly 50 total rather than the 30 that were in the pivotal group.

Speaker #2: And I think the other aspects of how that relates to the confirmatory study—the confirmatory study was included in the original protocol as, in addition to the pivotal design.

Speaker #2: So again, that was reviewed by the FDA. We're really pleased with how the enrollment is going there. And one thing that enrolling as quickly as we have on the confirmatory study does in a positive way is increase the number of safety exposures that we have at the time of filing.

Speaker #2: We're talking about roughly 50 total rather than the 30 that were in the pivotal group. So a broader safety database at the time of review, which will be very helpful because in our end-of-phase two meeting, one of the things that we heard as a ticket to accelerated approval was similar efficacy but improved safety.

Curran M. Simpson: A broader safety database at the time of review, which will be very helpful because in our end of Phase II meeting, one of the things that we heard as a ticket to accelerated approval was similar efficacy but improved safety, and that was pre black box warning for ELEVIDYS. I think we are in an even stronger position now, around our data set, and we look forward to discussing that with FDA in our pre-BLA meeting.

Curran Simpson: A broader safety database at the time of review, which will be very helpful because in our end of Phase II meeting, one of the things that we heard as a ticket to accelerated approval was similar efficacy but improved safety, and that was pre black box warning for ELEVIDYS. I think we are in an even stronger position now, around our data set, and we look forward to discussing that with FDA in our pre-BLA meeting.

Speaker #2: And that was pre-Black Box warning for elevators. So I think we are in an even stronger position now around our dataset and we look forward to discussing that with FDA in our pre-BLA meeting.

Speaker #4: That's helpful. And as a clarifying question, when you talked about reaching alignment, submitting the protocol, including the confirmatory study protocol, can you give a sense of when that happened and if those interactions were with FDA and Sever under the current leadership or under the prior leadership proceeding Dr. Sprasada-Makari?

Mani Foroohar: That's helpful. As a clarifying question, when you talked about reaching alignment, submitting the protocol, including the confirmatory study protocol, can you give a sense of when that happened and if those interactions were with FDA and CBER under the current leadership or under the prior leadership preceding Dr. Sosada McCarty?

Speaker #2: Yeah, I can comment on the latter part of the question. It was just— it was under the prior leadership. This was roughly 2024 that these discussions took place.

Curran M. Simpson: Yeah, I can comment on the latter part of the question. It was under the prior leadership. This was roughly 2024 that these discussions took place. I would say, the review team that we spoke to and that this was reviewed by is pretty largely intact from what we can tell to date. Steve, if you wanna discuss just the prospective nature of the data plan.

Curran Simpson: Yeah, I can comment on the latter part of the question. It was under the prior leadership. This was roughly 2024 that these discussions took place. I would say, the review team that we spoke to and that this was reviewed by is pretty largely intact from what we can tell to date. Steve, if you wanna discuss just the prospective nature of the data plan.

Speaker #2: But I would say the review team that we spoke to and that this was reviewed by is pretty largely intact from what we can tell to date.

Speaker #2: Steve, if you want to discuss just the prospective nature of the data plan?

Speaker #4: Sure, thanks for the questions, Manny. So, highlighting what Curran mentioned—the importance of prospective design—this was all set as of those discussions that Curran met.

Steve Pakola: Sure. Thanks for the questions, Manny. You know, highlighting what Curran mentioned, the importance of prospective design. This was all set as of those discussions that Curran met. For example, the primary, this is accelerated approval, so we were very clear in our design of the primary being microdystrophin. We were also very clear in the secondary functional endpoints that we were looking at and the methodology for assessing that. This isn't a case where midstream we changed something or we looked at data and adjusted how we were looking at the data.

Speaker #4: So for example, the primary, this is accelerated approval. So we were very clear in our design of the primary being microdistrophin. We were also very clear in the secondary functional endpoints that we were looking at and the methodology for assessing that.

Speaker #4: So this isn't a case where midstream we change something or we looked at data and adjusted how we were looking at the data.

Curran M. Simpson: Monty, one thing I would add, in general is, you know, we understand the environment and, you know, where people are trying to assess FDA’s position. From the very beginning of the study, we knew about the controversy around microdystrophin as a biomarker, reasonably capable of predicting clinical benefit or functional benefit. I think that’s why in the way we’ve designed the study and in the way we’re approaching FDA, we’re maximizing the functional data that we bring to the review. I think that’s an incredibly important aspect of how we’re approaching this, because we feel like the functional data really supports the improved biomarker data that we have over current therapy.

Speaker #2: And Manny, one thing I would add in general is we understand the environment and where people are trying to assess FDA's position. From the very beginning of the study, we knew about the controversy around microdystrophin as a biomarker reasonably capable of predicting clinical benefit or functional benefit.

Curran Simpson: Monty, one thing I would add, in general is, you know, we understand the environment and, you know, where people are trying to assess FDA’s position. From the very beginning of the study, we knew about the controversy around microdystrophin as a biomarker, reasonably capable of predicting clinical benefit or functional benefit. I think that’s why in the way we’ve designed the study and in the way we’re approaching FDA, we’re maximizing the functional data that we bring to the review. I think that’s an incredibly important aspect of how we’re approaching this, because we feel like the functional data really supports the improved biomarker data that we have over current therapy.

Speaker #2: And I think that's why, in the way we've designed the study and in the way we're approaching the FDA, we're maximizing the functional data that we bring to the review.

Speaker #2: And I think that's an incredibly important aspect of how we're approaching this, because we feel like the functional data really supports the improved biomarker data that we have over current therapy.

Judah Frommer: Okay. That's helpful.

Mani Foroohar: Okay. That's helpful.

Speaker #4: Okay. That's helpful.

Operator: Thank you. Our next question comes from the line of Judah Frommer of Morgan Stanley. Please go ahead, Judah.

Speaker #5: Thank you. Our next question comes from the line of Judah Frommer of Morgan Stanley. Please go ahead, Judah.

Speaker #6: Yeah, hi. Good morning, guys. Thanks for taking the question. Maybe just to follow up on 202 to start. If FDA does end up wanting potentially longer-duration follow-up, specifically for safety, and you go down the path of a traditional approval, what would that entail?

Judah Frommer: Yeah. Hi. Good morning, guys. Thanks for taking the question. Maybe just a follow-up on RGX-202 to start. If FDA does end up wanting potentially, you know, longer duration follow-ups specifically for safety and you go down the path of a traditional approval, what would that entail? What would the confirmatory trial's role be in that scenario? Then just on the Hunter syndrome program, there's an approval decision coming up for Denali. What would you hope to learn from that program as you go back to FDA to discuss RGX-121 with them? Thanks.

Speaker #6: What would the confirmatory trial's role be in that scenario? And then just on the Hunter's program, there's an approval decision coming up for Denali.

Speaker #6: What would you hope to learn from that program as you go back to FDA to discuss 1-2-1 with them?

Speaker #2: Sure. Hi, Judah. I think on if FDA expects longer-term functional data the time points I would keep in mind is we completed enrollment of the pivotal study end of October, last year.

Curran M. Simpson: Sure. Hi, Judah. I think on if FDA expects longer-term functional data, the time points I would keep in mind is we completed enrollment of the pivotal study end of October last year. At that point, this year, we'll have 12-month data on the full pivotal dataset. Of course, there's time for QC of the data and then incorporating that into a filing. It's a near-term event that we would have functional data on the full pivotal dataset. If you consider that maybe there's a larger sample size required, the fact that we immediately went into enrollment of the confirmatory study, just keeps working towards more data as we go through the year. I feel like there's no discontinuity between our pivotal and our confirmatory dataset.

Curran Simpson: Sure. Hi, Judah. I think on if FDA expects longer-term functional data, the time points I would keep in mind is we completed enrollment of the pivotal study end of October last year. At that point, this year, we'll have 12-month data on the full pivotal dataset. Of course, there's time for QC of the data and then incorporating that into a filing. It's a near-term event that we would have functional data on the full pivotal dataset. If you consider that maybe there's a larger sample size required, the fact that we immediately went into enrollment of the confirmatory study, just keeps working towards more data as we go through the year. I feel like there's no discontinuity between our pivotal and our confirmatory dataset.

Speaker #2: So, at that point this year, we'll have 12-month data on the full pivotal dataset. And then, of course, there's time for QC of the data, and then incorporating that into a filing.

Speaker #2: But it's a near-term event that we would have functional event functional data on the full pivotal dataset. And then if you consider that maybe there's a larger sample size required, the fact that we immediately went into enrollment of the confirmatory study just keeps working towards more data as we go through the year.

Speaker #2: So I feel like there's no discontinuity between our pivotal and our confirmatory dataset. But we feel like the data we've seen in the phase one, two is already strikingly different from natural history.

Curran M. Simpson: We feel like the data we've seen in the phase I/II is already strikingly different from natural history, and so more is not always better in that case, given the unmet need that we're seeing, the prevalent market continuing to grow. We feel like we're in a good place, notwithstanding as well the safety profile that we're showing. You know, we have investigators clamoring for something where they don't have to worry post-treatment of, you know, these events that have been seen in high-dose AAV. On the outcomes for RGX-121, we certainly will pay a lot of attention to Denali's PDUFA decision, and in particular, the fact that part of that submission and significant element of that submission is heparan sulfate-based biomarker.

Curran Simpson: We feel like the data we've seen in the phase I/II is already strikingly different from natural history, and so more is not always better in that case, given the unmet need that we're seeing, the prevalent market continuing to grow. We feel like we're in a good place, notwithstanding as well the safety profile that we're showing. You know, we have investigators clamoring for something where they don't have to worry post-treatment of, you know, these events that have been seen in high-dose AAV. On the outcomes for RGX-121, we certainly will pay a lot of attention to Denali's PDUFA decision, and in particular, the fact that part of that submission and significant element of that submission is heparan sulfate-based biomarker.

Speaker #2: And so more is not always better in that case given the unmet need that we're seeing. The prevalent market continuing to grow. So we feel like we're in a good place notwithstanding as well the safety profile that we're showing.

Speaker #2: We have investigators clamoring for something where they don't have to worry post-treatment about these events that have been seen in high-dose AAV. On the outcomes for 121, we will certainly pay a lot of attention to Denali's PDUFA decision.

Speaker #2: And in particular, the fact that part of that submission—and a significant element of that submission—is a heparan sulfate-based biomarker. If you go on ChatGPT and pull up D2S6, it clearly says that it's a subcomponent of heparan sulfate.

Curran M. Simpson: If you go on ChatGPT and pull up D2S6, it clearly says that it's a subcomponent of heparan sulfate. We see them as the same. In the event that FDA continues to not necessarily see them the same, but endorses heparan sulfate, we'll be in a great position with our data to pivot to that if that's what's necessary. We feel really strongly that our dataset using D2S6 shows really good biomarker reduction, very consistent across patients who we know are neuronopathic from external reviews. We look forward to the Type A, but I think to your point, it will be helpful to see decisions on Ultragenyx's program and Denali's program to see how that may or may not affect ours.

Curran Simpson: If you go on ChatGPT and pull up D2S6, it clearly says that it's a subcomponent of heparan sulfate. We see them as the same. In the event that FDA continues to not necessarily see them the same, but endorses heparan sulfate, we'll be in a great position with our data to pivot to that if that's what's necessary. We feel really strongly that our dataset using D2S6 shows really good biomarker reduction, very consistent across patients who we know are neuronopathic from external reviews. We look forward to the Type A, but I think to your point, it will be helpful to see decisions on Ultragenyx's program and Denali's program to see how that may or may not affect ours.

Speaker #2: So, we see them as the same. But in the event that FDA continues to not necessarily see them the same, but endorses heparin sulfate, we'll be in a great position with our data to pivot to that if that's what's necessary.

Speaker #2: But we feel really strongly that our dataset using D2S6 shows really good biomarker reduction, very consistent across patients, who we know are neuronopathic from external reviews.

Speaker #2: And so we look forward to the type A. But I think to your point, it will be helpful to see decisions on ultragenics program and Denali's program to see how that may or may not affect ours.

Speaker #6: Do you have those heparin sulfate assays, if it's a relatively simple addition to the submission?

Judah Frommer: Do you have those heparan sulfate assays if it's a relatively simple addition to the submission?

Speaker #2: We do.

Curran M. Simpson: We do.

Curran Simpson: We do.

Speaker #6: Thanks.

Judah Frommer: Thanks.

Speaker #5: Thank you. Our next question comes from the line of Annabelle Samimi of Stifel. Your line is open, Annabelle.

Operator: Thank you. Our next question comes from the line of Annabel Samimy of Stifel. Your line is open, Annabel.

Judah Frommer: Hi. Thanks for taking my question. I'm gonna be original and ask about 314. I noticed that you were moving forward with DL3, and I, and I know also that you had agreed with AbbVie to conduct a phase II trial to test the higher dose, but you are going with DL3. I guess the question is, why is it not going straight into a phase III? Does the phase II/III also count as part of that pivotal? I'm just curious about what you found with DL4 that made you go with DL3, and what does this mean for wet AMD? Thanks.

Annabel Samimy: Hi. Thanks for taking my question. I'm gonna be original and ask about 314. I noticed that you were moving forward with DL3, and I, and I know also that you had agreed with AbbVie to conduct a phase II trial to test the higher dose, but you are going with DL3. I guess the question is, why is it not going straight into a phase III? Does the phase II/III also count as part of that pivotal? I'm just curious about what you found with DL4 that made you go with DL3, and what does this mean for wet AMD? Thanks.

Speaker #7: Hi. Thanks for taking my question. I'm going to be original and ask about 314. So I noticed that you were moving forward with dose level three and I know also that you had agreed with Abby to conduct a phase two trial to test the higher dose, but you are going with dose level three.

Speaker #7: So I guess the question is, why is it not going straight into a phase three? Does the phase two, three also count as part of that pivotal?

Speaker #7: And just curious about what you found with DL4 that made you go with DL3 and what does this mean for what AMD? Thanks.

Speaker #2: Great. Thanks, Annabelle. And I'll comment a bit on the trial and what's coming and Steve can comment a little bit on the dose selection.

Curran M. Simpson: Great. Thanks, Annabel. I'll comment a bit on the trial and what's coming, and Steve can comment a little bit on the dose selection. Keep in mind for the phase 2 studies on diabetic retinopathies, relatively small sample size, but strikingly good results in terms of what we were seeing on 2-step improvement, et cetera, that we've published. The goal really of the Phase IIb as it stands now is just to expand that data set to a higher number of patients and confirm that result. It's sequenced to be off an interim look and then directly into a larger pivotal study. I think that's just prudent risk management as we develop the program and move forward.

Curran Simpson: Great. Thanks, Annabel. I'll comment a bit on the trial and what's coming, and Steve can comment a little bit on the dose selection. Keep in mind for the phase 2 studies on diabetic retinopathies, relatively small sample size, but strikingly good results in terms of what we were seeing on 2-step improvement, et cetera, that we've published. The goal really of the Phase IIb as it stands now is just to expand that data set to a higher number of patients and confirm that result. It's sequenced to be off an interim look and then directly into a larger pivotal study. I think that's just prudent risk management as we develop the program and move forward.

Speaker #2: Keep in mind for the phase two studies, on diabetic retinopathies, relatively small sample size. But strikingly good results in terms of what we were seeing on two-step improvement, etc., that we've published.

Speaker #2: The goal really of the phase two be as it stands now is just to expand that dataset to a higher number of patients and confirm that result.

Speaker #2: But it's sequenced to be, often, interim look and then directly into a larger pivotal study. And I think that's just prudent risk management as we develop the program and move forward.

Curran M. Simpson: The patients that are treated in the phase IIb will certainly contribute to the safety database that will be created for DR. They are helpful in some ways managing the size of the pivotals that we have to run. Now, I'll let Steve talk a little bit about the dose selection.

Curran Simpson: The patients that are treated in the phase IIb will certainly contribute to the safety database that will be created for DR. They are helpful in some ways managing the size of the pivotals that we have to run. Now, I'll let Steve talk a little bit about the dose selection.

Speaker #2: The patients that are treated in the Phase 2b will certainly contribute to the safety database that will be created for DR, so they are helpful in some ways in managing the size of the pivotals that we have to run.

Speaker #2: Now, I'll let Steve talk a little bit about the dose selection.

Speaker #6: Sure. First, Annabelle, thanks for raising certainly one of our big priorities, which is DR given what a massive unmet need that is where we certainly believe a one-time treatment is really what's needed for this disease to make the ultimate impact.

Steve Pakola: Sure. First, Annabel, thanks for raising, certainly one of our big priorities, which is DR, given what a massive unmet need that is, where we certainly believe a one-time treatment is really what's needed for this disease to make the ultimate impact. The other thing I'd say is on the dose selection and the Phase IIb/III concept is it's a real validation of not only our commitment, but also AbbVie's to embark on a Phase IIb, III program. As any program, we do, the dose escalation to really look at safety and efficacy. I think one of the aspects was with the time that we took to evaluate dose level one, dose level two, dose level three, the longer we looked, the more compelling dose level three became.

Speaker #6: And the other thing I'd say is on the dose selection and the phase two B three concept is it's a real validation of not only our commitment, but also Abby's to embark on a phase two B three program.

Speaker #6: So as any program, we do the dose escalation to really look at safety and efficacy. I think one of the aspects was with the time that we took to evaluate dose level one, dose level two, dose level three, the longer we look, the more compelling dose level three became.

Speaker #6: And it really reached a point of pretty remarkable results where we were definitely hitting our target product profile. Where the durability to actually see 50% of patients not only be stable, but actually have at least a two-step improvement in diabetic retinopathy was really quite compelling.

Steve Pakola: It really reached a point of pretty remarkable results where we were definitely hitting our target product profile, where the durability to actually see 50% of patients not only be stable, but actually have at least a 2-step improvement in diabetic retinopathy was really quite compelling. I think clinically, even more meaningful for clinicians is the fact that there was a dramatic reduction in vision-threatening complications, over 70% compared to what you'd anticipate without treatment based on natural history data. I think this constellation was really what drove the decision for us and AbbVie, if you're already at your target product profile, and meaningfully with short course topical steroids, 0 cases of IOI, which is really the big sensitivity in the retina community when it comes to safety. We really had what we needed to go forward.

Speaker #6: And I think clinically, even more meaningful for clinicians is the fact that there was a dramatic reduction in vision-threatening complications over 70% compared to what you'd anticipate without treatment based on natural history data.

Speaker #6: So I think this constellation was really what drove the decision for us and Abby, if you're already at your target product profile, and meaningfully with a short course topical steroids zero cases of IOI, which is really the big sensitivity in the retina community when it comes to safety.

Speaker #6: We really had what we needed to go forward. And once you hit your target product profile and you're really frankly plateauing in terms of the results that you'd anticipate, and you're seeing durability, that made it a clear decision for us and Abby to move forward.

Steve Pakola: You know, once you hit your target product profile and you're really frankly plateauing in terms of the results that you'd anticipate, and you're seeing durability, that made it a clear decision for us and AbbVie to move forward.

[Analyst] (Bank of America): Just to follow up. Like, I know that you're exploring DL4 and wet AMD. Are you not going to move forward with that one, given the profile for DL3? I guess I'm just trying to understand, if there's any safety question with DL4.

Speaker #7: Just to follow up, I know that you're exploring DL4 and what AMD are you not going to move forward with that one given the profile for DL3?

Annabel Samimy: Just to follow up. Like, I know that you're exploring DL4 and wet AMD. Are you not going to move forward with that one, given the profile for DL3? I guess I'm just trying to understand, if there's any safety question with DL4.

Speaker #7: I guess I'm just trying to understand if there's any safety question with DL4.

Steve Pakola: Yeah. wet AMD is just a trickier indication in terms of reading the tea leaves and looking for a signal in terms of efficacy compared to DR, where there's no other treatment and you're really looking at pretty binary assessment of things like actual improvement in DR. I think it's just more straightforward to make a decision on DR as compared to wet AMD. We and AbbVie are continuing to evaluate the data.

Speaker #6: what AMD is just a trickier indication in terms of reading the tea leaves and looking for a signal. In terms of efficacy compared to DR, where there's no other treatment and you're really looking at pretty binary assessment of things like actual improvement in DR. So I think it's just more straightforward to make a decision on DR as compared to what AMD.

Speaker #6: So we and Abby are continuing to evaluate the data you.

[Analyst] (Bank of America): Okay. Thank you.

Annabel Samimy: Okay. Thank you.

Operator: Thank you. Our next question comes from the line of Alec Stranahan of Bank of America. Please go ahead, Alec.

Speaker #5: Thank you. Our next question. Comes from the line of Alex Stranahan, a Bank of America. Please go ahead, Alex.

Alec Stranahan: Hey, guys. Thanks for taking our questions. Two from me as well. I guess first is on the functional data. Could you just remind us how much of this you'll be providing the top line? I guess how many patients you expect you'll have at that point for the 12-month functional data. Just on MPS I'm curious how the neoplasm in the MPS I patient maybe shifts the benefit risk discussion with the FDA, and I guess what kind of mitigation measures you're considering here, given it sounds to be AAV related. Thank you.

Speaker #4: Hey, guys. Thanks for taking our questions. Two from me as well. I guess first is, how much of this you'll be providing the top line?

Speaker #4: I guess how many patients you expect you'll have at that point for the 12-month functional data? And then just on MPS-1, curious how the neoplasm in the MPS-1 patient maybe shifts the benefit-risk discussion with the FDA and I guess what kind of mitigation measures you're considering here given it sounds to be AAV-related.

Speaker #4: Thank you.

Speaker #2: Yeah. Thanks, Alex. I can speak a bit on the top line data plans. So I think as we've previously discussed, we will have obviously safety data update on the full cohort, which is NF30.

Curran M. Simpson: Thanks, Alex. I can speak a bit on the top-line data plans. I think as we've previously discussed, we will have, obviously, a safety data update on the full cohort, which is N of 30. We'll have biomarker top-line data for the primary endpoint for the full pivotal data set as well. In terms of functional data, we haven't set a specific time for the release of the top-line data, so it's a little bit in flux, but I'd set an expectation of roughly seven or so patients at 12 months for functional data.

Curran Simpson: Thanks, Alex. I can speak a bit on the top-line data plans. I think as we've previously discussed, we will have, obviously, a safety data update on the full cohort, which is N of 30. We'll have biomarker top-line data for the primary endpoint for the full pivotal data set as well. In terms of functional data, we haven't set a specific time for the release of the top-line data, so it's a little bit in flux, but I'd set an expectation of roughly seven or so patients at 12 months for functional data.

Speaker #2: We'll have biomarker top line data for the primary endpoint for the full pivotal dataset as well. In terms of functional data, we haven't set a specific time for the release of the top line data.

Speaker #2: So it's a little bit in flux, but I'd set an expectation of roughly seven or so patients at 12 months for functional data and then, of course, throughout the remainder of the year we'll consider updating that as additional data comes in.

Curran M. Simpson: Of course, throughout the remainder of the year, we'll consider updating that as additional data comes in. Historically, we did report some 9-month data early in the phase 1, 2 studies. We're gonna try to avoid that because that really doesn't work well with most of our natural history comparisons that we would like to make. On top of it, we just feel 9 months is too early to judge sort of stability of effect on function. As we go past 12 months, then I think we get to a meaningful level of functional data, and they're well past the removal of the immune suppression agents.

Curran Simpson: Of course, throughout the remainder of the year, we'll consider updating that as additional data comes in. Historically, we did report some 9-month data early in the phase 1, 2 studies. We're gonna try to avoid that because that really doesn't work well with most of our natural history comparisons that we would like to make. On top of it, we just feel 9 months is too early to judge sort of stability of effect on function. As we go past 12 months, then I think we get to a meaningful level of functional data, and they're well past the removal of the immune suppression agents.

Speaker #2: Historically, we did report some nine-month data. Early in the phase one two studies, and I think we're going to try to avoid that because that really doesn't work well with most of our natural history comparisons that we would like to make.

Speaker #2: And I think on top of it, we just feel nine months is too early to judge sort of stability of effect on function but as we go past 12 months, then I think we get to a meaningful level of functional data and they're well past the removal of the immune suppression agents.

Steve Pakola: I can.

Speaker #4: And I can jump in as well. Alex, on the MPS-1 neoplasm. So you, of course, hit the nail on the head of, well, what does this mean in terms of the overall benefit-risk?

Steve Pakola: I can.

Curran M. Simpson: Go on. Yeah.

Curran Simpson: Go on. Yeah.

Steve Pakola: jump in as well, Alec, on the MPS I neoplasm. You of course hit the nail on the head of, well, what does this mean in terms of the overall benefit risk? Our view and what we hear from clinicians as well is that on one hand you have the risk of a rare event such as tumor, which isn't completely unanticipated given the fact that we know that integration can happen with AAVs. In fact, it's even included in AAV gene therapy labels for that reason, the potential risk. Fortunately, it does seem to be a very rare event. We have over 6,000 patients treated with AAVs of different sorts by different sponsors. Here's a case where an integration happened at a proto-oncogene.

Speaker #4: And our view and what we hear from clinicians as well is that on one hand, you have the risk of a rare event such as tumor, which isn't completely unanticipated given the fact that we know that integration can happen with AAVs.

Speaker #4: And in fact, it's even included in AAV gene therapy labels for that reason—the potential risk. So fortunately, it does seem to be a very rare event.

Speaker #4: We have over 6,000 patients treated with AAVs of different sorts by different sponsors. And here's a case where an integration happened at a proto-oncogene.

Speaker #4: So the clinical community, if we raise this with an investigator and KOLs in the space, almost instinctively their first response is, okay, there's a rare risk of a tumor versus 100% risk of inexorable decline and irreversible brain damage.

Steve Pakola: The clinical community, if we raise this with investigators and KOLs in the space, almost instinctively their first response is, Okay, there's a rare risk of a tumor versus a 100% risk of inexorable decline and irreversible brain damage. It really comes down to that context for this devastating disease with such unmet need that the clinicians, it hasn't changed their view of the favorable benefit risk. From our view going forward, as far as mitigations that you raised, just as in this patient, we can look at MRI, periodic MRI. We've already looked at that in the other patients, not only in the RGX-111 program, but also RGX-121 and not seen any other evidence. Of course, full disclosure and investigator brochure and informed consent.

Speaker #4: So it really comes down to that context for this devastating disease with such unmet need, that the clinicians—it hasn't changed their view of the favorable benefit-risk.

Speaker #4: So from our view, going forward, as far as mitigations that you raised, just as in this patient, we can look at MRI periodic MRI.

Speaker #4: We've already looked at that in the other patients, not only in the 111 program, but also 121, and not seen any other evidence. And of course, full disclosure in the investigator brochure and informed consent, and with that knowledge, clinicians and the patient families are able to make that assessment about benefit-risk.

Steve Pakola: With that knowledge, clinicians and the patient families are able to make that assessment about benefit risk.

Speaker #4: Got it. Very helpful. Thank you.

Eduardo Gurgel: Got it. Very helpful. Thank you.

Alec Stranahan: Got it. Very helpful. Thank you.

Speaker #5: Thank you. Our next question. Comes from the line of Paul Choi of Goldman Paul.

Operator: Thank you. Our next question comes from the line of Paul Choi of Goldman Sachs. Please go ahead, Paul.

Speaker #7: Hi. Thank you and good morning. Thank you for taking our questions. I have two on RGX202, please. First, with regard to the data you'll have next week at MDA, can you just clarify what patient numbers you'll have and additional duration of follow-up, or should we just think of or will it just be additional details on the 18-month data that you previously presented?

Paul Choi: Hi. Thank you and good morning. Thank you for taking our questions. I have 2 on RGX-202, please. First, with regard to the data you'll have next week at MDA, can you just clarify what patient numbers you'll have and additional duration of follow-up? Or will it just be additional details on the 18-month data that you previously presented? My second question is, you've in your press release talk about the functional data to date in the context of a CTAP analysis. Can you comment on whether in terms of your FDA interactions, there's alignment on using these kinds of analyses versus sort of conventional North Star analysis? Any clarity there on the FDA's acceptance of those that evaluation framework would be helpful.

Speaker #7: And my second question is, you've in your press release talk about the functional data to date in the context of a CTAP analysis. Can you comment on whether the in terms of your FDA interactions, there's alignment on using these kinds of analyses versus sort of conventional North Star analysis?

Speaker #7: Any clarity there on the FDA's acceptance of those that evaluation framework would be helpful? Thank you.

Paul Choi: Thank you.

Speaker #2: Thanks, Paul. I think because the MDA manuscript is in deep editing mode with Steve, I'll let Steve cover the expectations for MDA. Next week.

Curran M. Simpson: Thanks, Paul. I think because the MDA manuscript is in deep editing mode with Steve, I will let Steve cover the expectations for MDA next week. It will be, I think, a pretty substantial update, maybe the last update, if you will, in terms of Phase I, II data as we transfer over to our pivotal program. Steve, maybe you want to comment on what to expect.

Curran Simpson: Thanks, Paul. I think because the MDA manuscript is in deep editing mode with Steve, I will let Steve cover the expectations for MDA next week. It will be, I think, a pretty substantial update, maybe the last update, if you will, in terms of Phase I, II data as we transfer over to our pivotal program. Steve, maybe you want to comment on what to expect.

Speaker #2: But it will be, I think, a. Pretty substantial update maybe the last update if you will in terms of phase one two data as we transfer over to our pivotal program.

Speaker #2: But Steve, maybe you want to comment on what to expect.

Steve Pakola: Sure. All patients with the primary endpoint, I think is obviously a key aspect for what we'd anticipate. We're almost there actually in what we've disclosed before. I think function, the key thing is more patients and longer follow-up. We're really excited about the fact that we've already disclosed previously last year and early this year, several different cuts of functional data where we're really happy with what we've seen at Dose Level 1 and Dose Level 2, even out to 18 months with Dose Level 2 for the CTAP. It's just really a great chance to keep building on that base of functional data. The consideration on the different ways of looking at function and what to compare to CTAP, I think it's important to note that the program doesn't hinge on CTAP.

Speaker #4: Sure. So all patients with the primary endpoint, I think, is obviously a key aspect for what we'd anticipate we're almost there actually in what we've disclosed before.

Speaker #4: I think function, the key thing is more patients and longer follow-up. We're really excited about the fact that we've already disclosed previously last year and early this year several different cuts of functional data where we're really happy with what we've seen at dose level one and dose level two.

Speaker #4: Even out to 18 months with dose level two for the CTAP. So it's just really a great chance to keep building on that base of functional data.

Speaker #4: The consideration on the different ways of looking at function and what to compare it to, CTAP, I think it's important to note that the program doesn't hinge on CTAP.

Steve Pakola: It's really a supportive analysis. Our view is the totality of the data is important that in looking at control data from external databases, it's very comforting and very validating if different ways of looking at it, you see very consistent results. That's what we've seen to date. Certainly our primary approach from a functional basis, and this is what we've pre-specified as well is the traditional approach separate from CTAP, where that includes as well the propensity score weighting. I think that's gonna give audiences also a sense to see how the results are looking compared to what one would anticipate based on prior analysis. We're gonna be looking at all this, and I think you can anticipate seeing several different ways of looking at comparison to expected trajectory without treatment.

Speaker #4: It's really a supportive analysis so our view is the totality of the data is important that in looking at controlled data, from external databases, it's very comforting and very validating if different ways of looking at it, you see very consistent results.

Speaker #4: And that's what we've seen to date. But certainly our primary approach from a functional basis, and this is what we've pre-specified as well, is the traditional approach separate from CTAP where that includes as well the propensity score weighting.

Speaker #4: So I think that's going to give audiences also a sense to see how the results are looking compared to what one would anticipate based on prior analysis.

Speaker #4: So we're going to be looking at all this, and I think you can anticipate seeing several different ways of looking at comparison to expected trajectory without treatment.

Curran M. Simpson: I think one thing I'd add on MDA is, we have a poster that will accompany the podium presentation. We haven't talked a lot about benefit to cardiac in Duchenne. Part of the reason for that is that we expect those type of outcomes to be much more long term in terms of seeing that in a clinical setting. What we're providing at MDA is a preclinical model of specifically showing the differentiation of our construct using the C-terminus in potentially preventing cardiac sort of deterioration, if you will. Just something to have a look at, as part of the total data set, some additional preclinical data that we think really supports what we've known from our preclinical work, where we saw good biodistribution in the mdx model in cardiac muscle.

Curran Simpson: I think one thing I'd add on MDA is, we have a poster that will accompany the podium presentation. We haven't talked a lot about benefit to cardiac in Duchenne. Part of the reason for that is that we expect those type of outcomes to be much more long term in terms of seeing that in a clinical setting. What we're providing at MDA is a preclinical model of specifically showing the differentiation of our construct using the C-terminus in potentially preventing cardiac sort of deterioration, if you will. Just something to have a look at, as part of the total data set, some additional preclinical data that we think really supports what we've known from our preclinical work, where we saw good biodistribution in the mdx model in cardiac muscle.

Speaker #2: I think one thing I'd add on MDA is we have a poster that will accompany the podium presentation we haven't talked a lot about benefit to cardiac in Duchenne.

Speaker #2: And part of the reason for that is that we expect those type of outcomes to be much more long-term in terms of seeing that in a clinical setting.

Speaker #2: So what we're providing at MDA is a preclinical model of specifically showing the differentiation of our construct using the C-terminus in potentially preventing cardiac, sort of, deterioration, if you will.

Speaker #2: So just something to have a look at as part of the total data set some additional preclinical data that we think really supports what we've known from our preclinical work where we saw good biodistribution in the MDX model in cardiac muscle.

Curran M. Simpson: Stay tuned there.

Curran Simpson: Stay tuned there.

Speaker #2: So stay tuned there.

Steve Pakola: Great. The other key thing is continued safety. The earlier question about how much long-term safety. Each update is not just the functional, but a chance to show continued differentiation on safety.

Speaker #5: Great.

Speaker #4: And the other key thing is continued safety. So the earlier question about how much long-term safety. So each update is not just the functional, but a chance to show continued differentiation on safety.

Operator: Thank you. Our next question comes from the line of Luca Issi of RBC. Please go ahead, Luca.

Speaker #5: Thank you. Our next question comes from the line of Luca Issi of RBC. Please go ahead, Luca.

Luca Issi: Well, great. Thanks so much for taking my question. Maybe Steve, any update on safety for DMD? You know, you obviously have a very strong scientific hypothesis around Sarilumab and eculizumab and, you know, MT to capture ratio, et cetera. You know, we've seen obviously more setbacks for Denali on the safety side from, you know, Pfizer and Sarepta than we would've liked. I guess, what percentage of your patients have ALT and AST elevations at this point? How are the kinetics of those curves in term of both like peak and area under curve compared to Sarepta and Pfizer? Again, I don't think we've seen those curves before, so any context there will be much appreciated. Maybe quickly, Steve, also on the CRLs for MPS II, the dubs now public.

Speaker #6: Well, great. Thanks so much for taking my question. Maybe Steve, any update on safety for DMD? You obviously have a very strong scientific hypothesis around serolimus and eculizumab and the MT2 capsid ratio, etc.

Speaker #6: But we've seen, obviously, more setbacks for this field on the safety side from Pfizer and Sarepta than we would have liked. So I guess, what percentage of your patients have ALT and AST elevations at this point?

Speaker #6: And how are the kinetics of those curves in terms of both peak and area under the curve compared to Sarepta and Pfizer? Again, I don't think we've seen those curves before.

Speaker #6: So any context there would be much appreciated. And then maybe quickly, Steve, also on the CRL for MTS2, that's obviously now public. Why do you measure heparin sulfate at baseline versus after therapy using two different routes of access?

Luca Issi: Why do you measure heparan sulfate at baseline versus after therapy using 2 different routes of access? I think the CRL notes that you used ICV at baseline versus spinal tap after therapy, which obviously created some variability. We're just curious for why you decided to do that. Thanks so much.

Speaker #6: I think the CRL notes that you use ICV at baseline versus spinal tap after therapy, which obviously created some variability. So we're just curious for why you decided to do that.

Speaker #6: Thanks so much.

Steve Pakola: Sure. On the safety aspect, you know, there's several reasons why we anticipated having a differentiated safety profile, the higher purity, the specific construct, and our immune modulation regimen. I think a key factor is we haven't changed our immune modulation at all since the beginning of the study. I think that gives comfort in how to analyze the type of safety data that we're seeing. phase I/II, we continue to see no cases of liver injury. It's 13 patients, but 0 out of 13 is clearly different from existing therapy where that rate is 40%. You know, we look forward to showing some more details on that from the phase I/II study at MDA as well.

Speaker #4: Sure. So on the safety aspect, there's several reasons why we anticipated having a differentiated safety profile, the higher purity, the specific construct, and our immune modulation regimen.

Speaker #4: And I think a key our immune modulation at all since the beginning of the study. So I think that gives comfort in how to analyze the type of safety data that we're seeing.

Speaker #4: Phase one, two, we continue to see no cases of the liver injury. So it's 13 patients, but 0 out of 13 is clearly different from existing therapy where that rate is 40%.

Speaker #4: So we'll look forward to showing some more details on that from the phase one, two study at MDA as well. Also on thrombocytopenia, no cases of thrombocytopenia as well, which is one of the key complement-mediated signals of complement activation.

Steve Pakola: Also on thrombocytopenia, no cases of thrombocytopenia as well, which is one of the key complement mediated signals of complement activation that could signal potential risk for other more serious events. You know, we continue to see the differentiation that we'd like to see and look forward to showing, you know, more data going forward. Of course, we'll have the top line results in the first half of Q2, which, you know, will be another cut for you to get more comfort on the data. On to the CRL, there was, yes, some comment about the potential impact of route of taking the sample. There was consistency actually in the vast majority of patients utilizing the same approach.

Speaker #4: That could signal potential risk for other more serious events. So we continue to see the differentiation that we'd like to see. And look forward to showing more data going forward.

Speaker #4: And of course, we'll have the top-line results in the first half of the second quarter, which will be another cut for you to get more comfort on the data.

Speaker #4: So onto the CRL, there was, yes, some comment about the potential impact of route of taking the sample there was consistency, actually, in the vast majority of patients that utilizing the same approach.

Steve Pakola: We actually have the benefit of screening and baseline measurement where we have total consistency of ability to match like for like or apples to apples in terms of the same method of sampling. We see really the same results in terms of change from baseline. That will be part of our response. You know, showing that analysis more clearly and more upfront so that they can get comfort around that difference. Thanks so much, guys.

Speaker #4: We actually have the benefit of screening and baseline measurement where we have total consistency of ability to match like-for-like or apples-to-apples in terms of the same method of sampling.

Speaker #4: And we see really the same results in terms of change from baseline. So that will be part of our response, of doing—showing that analysis more clearly and more upfront so that they can get comfort around that difference.

Speaker #6: Got it. Thanks so much, guys.

Operator: Thank you. Our next question comes from the line of Brian Skorney of Baird. Please go ahead, Brian.

Speaker #5: Thank you. Our next question, comes from the line of Brian Scorney of Baird. Please go ahead, Brian.

Brian Skorney: Hey, good morning team. A couple of questions for me. Maybe going back to some of the questions around the Delta two aspects of unit discussion on the Hunter application. There's a lot of talk about it in the CRL, and I think references, this was a discussion point in the mid and late cycle review meetings. I guess at any point were measures of regular heparan sulfate discussed and submitted in the application process? It seems like something that could have been addressed during the review. Can you share what the sH data look like in the CSF and the other organs with us? Then on DMD, given what you've been through in the Hunter review, what sort of dynamics and questions are you looking to have answered in the pre-BLA meeting with the agency?

Speaker #4: Hey, good morning, team. A couple of questions for me. Maybe going back to some of the questions around the Delta-2 aspects of unit discussion on the Hunter application.

Speaker #4: There's a lot of talk about it in the CRL, and I think references this as a discussion point in the mid and late cycle review meetings.

Speaker #4: I guess at any point where measures of regular heparin and sulfate discussed and submitted in the application process, it seems like something that could have been addressed.

Speaker #4: During the review, can you share what the SAH data look like in the CS app and the other organs with us? And then on DMD, given what you've been through in the Hunter review, what sort of dynamics and questions are you looking to have answered in the pre-DLA meeting with the agency?

Brian Skorney: You know, I guess the bottom line is does anything coming out of your BLA meeting matter if it isn't coming directly from Steve Pakola?

Speaker #4: And I guess the bottom line is, does anything coming out of your BLA meeting matter if it isn't coming directly from the NIPR sub?

Curran M. Simpson: Thanks for the question. I'll take the DMD one, and then I'll maybe have Steve talk through the heparan sulfate data, which we did provide limited heparan sulfate data during the review, but it was quite late in the review cycle. I think in terms of what are the outcomes we're looking for in the pre-BLA meeting, I think that's the point at which, if you recall all the way back to the original protocol and our end of phase 2 meeting, you know, one of the things that we discussed with FDA was correlation of the microdystrophin results to functional outcomes was something that was an expectation of FDA. Importantly, there was no specified number of patients of data that had to be provided to make that correlation.

Curran Simpson: Thanks for the question. I'll take the DMD one, and then I'll maybe have Steve talk through the heparan sulfate data, which we did provide limited heparan sulfate data during the review, but it was quite late in the review cycle. I think in terms of what are the outcomes we're looking for in the pre-BLA meeting, I think that's the point at which, if you recall all the way back to the original protocol and our end of phase 2 meeting, you know, one of the things that we discussed with FDA was correlation of the microdystrophin results to functional outcomes was something that was an expectation of FDA. Importantly, there was no specified number of patients of data that had to be provided to make that correlation.

Speaker #2: Thanks for the question. I'll take the DMD one, and then I maybe have Steve talk through the heparin sulfate data, which we did provide limited heparin sulfate data during the review, but it was review cycle.

Speaker #2: But I think, in terms of what are the outcomes we're looking for in the pre-BLA meeting, I think that's the point at which, if you recall all the way back to the original protocol and our end-of-Phase 2 meeting, one of the things that we discussed with FDA was correlation of the microdystrophin results to functional outcomes.

Speaker #2: It was something that was an expectation of FDA. Now, importantly, there was no specified number of patients of data that had to be provided to make that correlation.

Curran M. Simpson: I think that was something that everyone considered would be a review issue at the time. As we've seen in our phase I, II data, there's a very strong correlation that we're seeing to date all of our patients above the 10% threshold, and we're seeing the majority of patients having not just sustained function or lack of disease progression, but improvement in age groups where you wouldn't expect it. I think we have really compelling data, which at the time of the BLA discussion, pre-BLA discussion, I think will be very helpful hopefully to encourage, we're ready to file the BLA. The timing of the pre-BLA meeting is optimized now to provide sort of maximum functional data at the time of discussion.

Curran Simpson: I think that was something that everyone considered would be a review issue at the time. As we've seen in our phase I, II data, there's a very strong correlation that we're seeing to date all of our patients above the 10% threshold, and we're seeing the majority of patients having not just sustained function or lack of disease progression, but improvement in age groups where you wouldn't expect it. I think we have really compelling data, which at the time of the BLA discussion, pre-BLA discussion, I think will be very helpful hopefully to encourage, we're ready to file the BLA. The timing of the pre-BLA meeting is optimized now to provide sort of maximum functional data at the time of discussion.

Speaker #2: I think that was something that everyone considered would be a review issue at the time. I think as we've seen in our phase one, two data, there's a very strong correlation that we're seeing to date.

Speaker #2: All of our patients, above the 10% threshold, and we're seeing the majority of patients having not just sustained function, or lack of disease progression, but improvement in age groups where you wouldn't expect it.

Speaker #2: So I think we have really compelling data, which at the time of the BLA discussion, pre-BLA discussion, I think will be very helpful, hopefully to encourage we're ready to file the BLA. The timing of the pre-BLA meeting is optimized now to provide sort of maximum functional data at the time of discussion.

Curran M. Simpson: We have moved it out slightly, but it doesn't really alter, I think, the overall speed at which we can file, which we could file immediately after that meeting. Typically a pre-BLA meeting will incorporate feedback from FDA leadership. I think that's why that's an important event for us. Obviously ahead of that, we're going to do as much as we can informally outside of that process to assure ourselves of a positive outcome. Is that helpful? I'll let Steve talk about heparan sulfate a bit.

Curran Simpson: We have moved it out slightly, but it doesn't really alter, I think, the overall speed at which we can file, which we could file immediately after that meeting. Typically a pre-BLA meeting will incorporate feedback from FDA leadership. I think that's why that's an important event for us. Obviously ahead of that, we're going to do as much as we can informally outside of that process to assure ourselves of a positive outcome. Is that helpful? I'll let Steve talk about heparan sulfate a bit.

Speaker #2: So, we have moved it out slightly, but it doesn't really alter, I think, the overall speed at which we can file, which we could file immediately after that meeting.

Speaker #2: Typically, a pre-BLA meeting will incorporate feedback from FDA leadership. So, I think that's why that's an important event for us. And, obviously, ahead of that, we're going to do as much as we can informally, outside of that process, to assure ourselves of a positive outcome.

Speaker #2: Is that helpful? And then I'll let Steve talk about heparin sulfate a bit.

Brian Skorney: Yeah. Thank you. That's helpful.

Speaker #4: Yeah, thank you. That's helpful.

Steve Pakola: Yeah. Thanks. Thanks for the question, Brian. You know, to start off D2F6, it's important to note that biologically it's the substrate that directly would link to the enzyme that we're reconstituting with treatment. That's why prospectively, that's what we put forward throughout the program. We do measure heparan sulfate, and likewise we see, not surprisingly, a dramatic reduction in heparan sulfate. I guess similar to the earlier question about different routes of sampling, in our response to the CRL, we'll certainly lay out in greater detail our heparan sulfate results. The other thing is we really have an opportunity to clarify a lot of the factors, not just the biomarker. Function is another area where our clinicians are very positive about what they're seeing.

Speaker #2: Yeah, thanks for the question, Brian. So to start off, D2S6, it's important to note that biologically, it's the substrate that directly would link to the enzyme that we're reconstituting with treatment.

Speaker #2: So that's why prospectively, that's what we put forward throughout the program. We do measure heparin sulfate and likewise, we see not surprisingly a dramatic reduction in heparin sulfate.

Speaker #2: And I guess similar to the earlier question about different routes of sampling in our response to the CRL, we'll certainly lay out in greater detail our heparin sulfate results.

Speaker #2: The other thing is we really have an opportunity to clarify a lot of the factors, not just the biomarker and function is another area where our clinicians are very positive about what they're seeing.

Steve Pakola: As you'd expect, the longer the follow-up, the greater clarity you can anticipate seeing. We can certainly show longer term follow-up, which is one of the pathways that the FDA listed as a way to deal with the CRL.

Speaker #2: And as you'd expect, the longer the follow-up, the greater clarity you can anticipate seeing. So we can certainly show longer-term follow-up, which is one of the pathways that the FDA listed as a way to deal with the CRL.

Operator: Thank you. Our next question comes from Ellie Merle of Barclays. Ellie, your line is open.

Speaker #5: Thank you. Our next question. Comes from Ellie Murrell of Barclays. Ellie, your line is open.

Chad Jason: Hi, this is Chad Jason for Ellie. Thanks for taking our question. I think you mentioned you expect 12 months functional data from the majority, if not all of the pivotal patients in the fall of this year. How should we think of those data in context of the regulatory strategy? Could those be submitted as a supplement, and could that extend the review timeline?

[Analyst] (Barclays): Hi, this is Chad Jason for Ellie. Thanks for taking our question. I think you mentioned you expect 12 months functional data from the majority, if not all of the pivotal patients in the fall of this year. How should we think of those data in context of the regulatory strategy? Could those be submitted as a supplement, and could that extend the review timeline?

Speaker #6: Hi, this is Chetison for Ellie. Thanks for taking our question. I think you mentioned you expect 12-month functional data from the majority, if not all, of the pivotal patients.

Speaker #6: In the fall of this year, so how should we think of those data in context of the regulatory strategy? Could those be submitted as a supplement?

Speaker #6: And could that extend the review timeline?

Curran M. Simpson: That's a good question. I think that it will likely be a result of the discussion that we have at the pre-BLA meeting in terms of what level of functional data is required to submit. There's no point to submit early if we're going to get additional data requests. I think getting, you know, clarity on that with FDA will be very helpful. You know, we'll be in a position that we've already obviously completed our non-clinical work and that module's well along. We've completed substantially the in-manufacturing work related to the BLA, and that module will be ready quickly. I think to answer your question, the timing of the full filing for the BLA will be dependent on the clinical data and the functional data that we incorporate into it.

Curran Simpson: That's a good question. I think that it will likely be a result of the discussion that we have at the pre-BLA meeting in terms of what level of functional data is required to submit. There's no point to submit early if we're going to get additional data requests. I think getting, you know, clarity on that with FDA will be very helpful. You know, we'll be in a position that we've already obviously completed our non-clinical work and that module's well along. We've completed substantially the in-manufacturing work related to the BLA, and that module will be ready quickly. I think to answer your question, the timing of the full filing for the BLA will be dependent on the clinical data and the functional data that we incorporate into it.

Speaker #2: That's a good question. I think that we'll likely be a result of the discussion that we have at the pre-BLA meeting in terms of what level of functional data is required to submit.

Speaker #2: There's no point to submit early if we're going to get additional data requests. So I think getting clarity on that with FDA will be very helpful.

Speaker #2: We'll be in a position that we've already obviously completed our non-clinical work, and that module is well along. We've completed substantially the in-manufacturing work related to the BLA, and that module will be ready quickly.

Speaker #2: So I think the answer to your question, the timing of the full filing for the BLA will be dependent on the clinical data, and the functional data that we incorporate into it.

Curran M. Simpson: The chance to add it is a 120-day safety update that's part of a BLA submission. That has historically been very difficult to include additional clinical data beyond safety as part of it. I'm not confident that we would be able to add, at that point, more functional data. I think when we file, we want to be confident that that's acceptable with FDA.

Curran Simpson: The chance to add it is a 120-day safety update that's part of a BLA submission. That has historically been very difficult to include additional clinical data beyond safety as part of it. I'm not confident that we would be able to add, at that point, more functional data. I think when we file, we want to be confident that that's acceptable with FDA.

Speaker #2: The chance to add it is 120-day safety update that's part of a BLA submission. That has historically been very difficult to include additional clinical data beyond safety as part of it.

Speaker #2: So I'm not confident that we would be able to add at that point more functional data. So I think when we file, we want to be confident that that's acceptable with FDA.

Chad Jason: Okay. Just quickly on what the base case is. If you were fine requesting a pre-BLA in mid-2026, so how quickly after that should we expect an update? The actual BLA submission, is that still expected mid-2026?

[Analyst] (Barclays): Okay. Just quickly on what the base case is. If you were fine requesting a pre-BLA in mid-2026, so how quickly after that should we expect an update? The actual BLA submission, is that still expected mid-2026?

Speaker #6: Okay. And just quickly on what the base case is, I think you were fine requesting a pre-BLA in mid-26. So how quickly after that should we expect an update?

Speaker #6: And the actual BLA submission, is that still expected mid-26?

Curran M. Simpson: Yeah. The BLA submission could happen directly after the pre-BLA meeting. One of the topics in the pre-BLA meeting will be the timing of submission with FDA. I think post that meeting, we'll be in a good position to update on the overall filing timeline. Yes, it's possible that we can still file within 2026. That's really dependent on these ongoing discussions.

Curran Simpson: Yeah. The BLA submission could happen directly after the pre-BLA meeting. One of the topics in the pre-BLA meeting will be the timing of submission with FDA. I think post that meeting, we'll be in a good position to update on the overall filing timeline. Yes, it's possible that we can still file within 2026. That's really dependent on these ongoing discussions.

Speaker #2: Yes, the BLA submission could happen directly after the pre-BLA meeting. One of the topics in the pre-BLA meeting will be the timing of submission with the FDA.

Speaker #2: So I think post that meeting, we'll be in a good position to update on the overall filing timeline. But yes, it's possible that we can still file within 2026.

Speaker #2: That's really dependent on these ongoing discussions.

Chad Jason: Appreciate it. Thank you.

[Analyst] (Barclays): Appreciate it. Thank you.

Speaker #6: Appreciate it. Thank you.

Operator: Thank you. Our next question comes from the line of Daniil Gataulin of Chardan. Daniel, your line is open.

Speaker #5: Thank you. Our next question. Comes from the line of Donald Katulin of Shodan. Donald, your line is open.

Daniil Gataulin: All right. Yeah, good morning. Thank you guys for taking my question. On TM2, you mentioned a pre-BLA meeting in mid-2026, but also additional planned interactions in the first half. What is the agenda for those meetings? Secondly, what do you expect the regulatory path and timelines to look like for European approval?

Speaker #3: All right. Yeah, good morning. Thank you guys for taking my question. On Q2, you mentioned pre-BLA meeting in mid-26, but also additional plant interactions in the first half.

Speaker #3: What is the agenda for those meetings? And secondly, what do you expect the regulatory path and timelines to look like for European approval?

Curran M. Simpson: In terms of the regulatory interactions, we have planned meetings with FDA ahead of the pre-BLA meeting to get at some of the questions we've had today, around our data analysis methods. Some of which are new because we've been able to access additional natural history databases, and as Steve mentioned, and we've published additional CTAP data. Just trying to ensure that when we deliver our pre-BLA package, it's in line with FDA expectations. We haven't discussed the timing of those meetings, but they will be interspersed with things like top-line data and our pre-BLA meeting, as we go forward. The whole idea here is to de-risk the pre-BLA meeting with ongoing dialogue with FDA and ensure that we're fully aligned so that we have a high probability submission in terms of FDA acceptance.

Curran Simpson: In terms of the regulatory interactions, we have planned meetings with FDA ahead of the pre-BLA meeting to get at some of the questions we've had today, around our data analysis methods. Some of which are new because we've been able to access additional natural history databases, and as Steve mentioned, and we've published additional CTAP data. Just trying to ensure that when we deliver our pre-BLA package, it's in line with FDA expectations. We haven't discussed the timing of those meetings, but they will be interspersed with things like top-line data and our pre-BLA meeting, as we go forward. The whole idea here is to de-risk the pre-BLA meeting with ongoing dialogue with FDA and ensure that we're fully aligned so that we have a high probability submission in terms of FDA acceptance.

Speaker #2: In terms of the regulatory interactions, we have planned meetings with FDA ahead of the pre-BLA meeting to get at some of the questions we've had today.

Speaker #2: Around our data analysis methods, some of which are new because we've been able to access additional natural history databases and, as Steve mentioned, we've published additional CTAP data.

Speaker #2: So just trying to ensure that when we deliver our pre-BLA package, it's in line with FDA expectations. We haven't discussed the timing of those meetings, but they will be interspersed with things like top-line data, and our pre-BLA meeting as we go forward.

Speaker #2: So the whole idea here is to de-risk the pre-BLA meeting with ongoing dialogue with FDA and ensure that we're fully aligned so that we have a high probability submission in terms of FDA acceptance.

Curran M. Simpson: Again, that's why we continue to publish our functional data because that's what we think is the most compelling aspect of this on top of safety, is there's a huge unmet need in Duchenne, we see the prevalent population actually growing. We see a pretty narrow payer band in terms of patient ages that are being reimbursed, we expect there to be a lot of energy around additional therapies being made available. With our data, we think we have a compelling case to do that quickly. Is that helpful?

Curran Simpson: Again, that's why we continue to publish our functional data because that's what we think is the most compelling aspect of this on top of safety, is there's a huge unmet need in Duchenne, we see the prevalent population actually growing. We see a pretty narrow payer band in terms of patient ages that are being reimbursed, we expect there to be a lot of energy around additional therapies being made available. With our data, we think we have a compelling case to do that quickly. Is that helpful?

Speaker #2: And I think, again, that's why we continue to publish our functional data because that's what we think is the most compelling aspect of this on top of safety is there's a huge unmet need in Duchenne.

Speaker #2: And we see the prevalent population actually growing. We see a pretty narrow payer band in terms of patient ages that are being reimbursed. And so we expect there to be a lot of energy around additional therapies being made available.

Speaker #2: And with our data, we think we have a compelling case to do that quickly. Is that helpful?

Daniil Gataulin: It is. Thank you. With respect to the regulatory path and timelines for European approval?

Speaker #3: It is. Thank you. And with respect to the regulatory path and timelines for European approval?

Curran M. Simpson: For European approval, right now we're getting feedback on designs that include a placebo arm, which are feasible to run ex US. We don't have a specific timeline that we've put out in terms of when that study would start, but we'll be more specific about that post that official feedback from EMEA.

Curran Simpson: For European approval, right now we're getting feedback on designs that include a placebo arm, which are feasible to run ex US. We don't have a specific timeline that we've put out in terms of when that study would start, but we'll be more specific about that post that official feedback from EMEA.

Speaker #2: For European approval, right now, we're getting feedback on designs that include a placebo arm, which are feasible to run ex-US. We don't have a specific timeline that we've put out in terms of when that study would start.

Speaker #2: But we'll be more specific about that post that official feedback from EMEA.

Daniil Gataulin: Got it. Okay. All right. Thank you very much.

Speaker #3: Got it. Okay. All right. Thank you very much.

Curran M. Simpson: Thank you.

Curran Simpson: Thank you.

Speaker #2: Thank you.

Operator: Thank you. Our next question comes from the line of Bill Mann of Clear Street. Bill, your line is open.

Speaker #5: Thank you. Our of Bill Mahn of ClearStreet. Bill, your line is open.

Bill Mann: Good morning, and thank you. It seems that there's kind of a broad effort to read the 121 CRL and extrapolate that to 202. I was just hoping that you could point out specific points within the 121 CRL that you don't expect to, that you expect to differ in 202 and not keep it from approval.

Bill Maughan: Good morning, and thank you. It seems that there's kind of a broad effort to read the 121 CRL and extrapolate that to 202. I was just hoping that you could point out specific points within the 121 CRL that you don't expect to, that you expect to differ in 202 and not keep it from approval.

Speaker #4: Good morning and thank you. So it seems that there's kind of a broad effort to read the 121 CRL and extrapolate that to 202.

Speaker #4: So I was just hoping that you could point out specific points within the 121 CRL that you don't expect to that you expect to differ in 202 and not keep it from approval.

Curran M. Simpson: Yeah, it's a great question. I think there are some real clear differences between 121 and 202. Some of it goes back to the history of development for both programs. The 121 program really was based on a biomarker premise, meaning D2S6 being reasonably likely to predict clinical benefit. We felt like we had closed that loop in terms of the RMAT designation we got on the program in 2023. In the case of 121, sometimes you need several years of post-treatment follow-up for those patients to clearly state that they're deviating from natural acquisition of skills and cognitive improvement. Going into that filing, we didn't have the extent of clinical data supporting the biomarker that we do on 202.

Curran Simpson: Yeah, it's a great question. I think there are some real clear differences between 121 and 202. Some of it goes back to the history of development for both programs. The 121 program really was based on a biomarker premise, meaning D2S6 being reasonably likely to predict clinical benefit. We felt like we had closed that loop in terms of the RMAT designation we got on the program in 2023. In the case of 121, sometimes you need several years of post-treatment follow-up for those patients to clearly state that they're deviating from natural acquisition of skills and cognitive improvement. Going into that filing, we didn't have the extent of clinical data supporting the biomarker that we do on 202.

Speaker #2: Yeah, it's a great question. I think there are some real clear differences between 121 and 202. And some of it goes back to the history of development for both programs.

Speaker #2: The 121 program really was based on biomarker premise, meaning D2S6 being reasonably likely to predict clinical benefit. And we felt like we had closed that loop in terms of the RMET designation.

Speaker #2: We got on the program in 2023. In the case of 121, sometimes you need several years of post-treatment follow-up for those patients to clearly state that their deviating from natural acquisition of skills and cognitive improvement.

Speaker #2: And so going into that filing, we didn't have the extent of clinical data supporting the biomarker that we do on 202. So in Duchenne, thinking ahead on that and knowing that there was controversy around microdystrophin within FDA, we leaned in heavily on recruiting as quickly as we possibly could and also putting together the functional data to correspond directly with the biomarker data.

Curran M. Simpson: In Duchenne, thinking ahead on that and knowing that there was controversy around microdystrophin within FDA, we leaned in heavily on recruiting as quickly as we possibly could and also putting together the functional data to correspond directly with the biomarker data. We know going into the review process that we'll need both. That wasn't the case on RGX-121. We were really relying on the biomarker premise and that supporting data, but we only had, at the time of filing, 6 months of clinical data. In this case, for Duchenne, even going back to dose level one, we'll have beyond 2 years' worth of data showing durability of effect. For DL2, as we mentioned, several of our patients, maybe half the cohort, out past 12 months.

Curran Simpson: In Duchenne, thinking ahead on that and knowing that there was controversy around microdystrophin within FDA, we leaned in heavily on recruiting as quickly as we possibly could and also putting together the functional data to correspond directly with the biomarker data. We know going into the review process that we'll need both. That wasn't the case on RGX-121. We were really relying on the biomarker premise and that supporting data, but we only had, at the time of filing, 6 months of clinical data. In this case, for Duchenne, even going back to dose level one, we'll have beyond 2 years' worth of data showing durability of effect. For DL2, as we mentioned, several of our patients, maybe half the cohort, out past 12 months.

Speaker #2: And so we know going into the review process that we'll need both. So that wasn't the case on 121. We were really relying on the biomarker premise and that supporting data, but we only had at the time of filing six months of clinical data.

Speaker #2: In this case, for Duchenne, even going back to dose level one, we'll have beyond two years' worth of data. Showing durability of effect. And then for DL2, as we mentioned, several of our patients maybe half the cohort out past 12 months so a much different discussion with FDA that will be armed with clinical data showing correlation to what we think are very positive biomarker results that show benefit.

Curran M. Simpson: A much different discussion with FDA that we'll be armed with clinical data showing correlation to what we think are very positive biomarker results that show benefit. I think that that's probably the main difference between, as I see it, between how those programs will go and why we think two zero two will be, you know, more successful in providing that kind of data.

Curran Simpson: A much different discussion with FDA that we'll be armed with clinical data showing correlation to what we think are very positive biomarker results that show benefit. I think that that's probably the main difference between, as I see it, between how those programs will go and why we think two zero two will be, you know, more successful in providing that kind of data.

Speaker #2: So I think that's probably the main difference between as I see it between how those programs will go and why we think 202 will be more successful in providing that kind of data.

Steve Pakola: From the actual results, we also have the benefit of the safety differentiation again. I think also the greater your data is, the clearer you can believe that there's an actual difference. I think the 8 and older data in particular that Ken mentioned earlier, where patients are not just stable, they're actually improving. I think that goes into the delineation here as well, where that is definitely not something one would anticipate without treatment and even with existing therapy to have an actual improvement in those tough-to-treat older boys.

Speaker #4: And from the actual results that we also have the benefit of the safety differentiation again. And I think also the greater your data is, the clearer you can believe that there's an actual difference.

Speaker #4: So I think the 8 and older data in particular that Curran mentioned earlier where patients are improving. So I think that goes into the delineation here as well where that is definitely not something one would anticipate without treatment.

Speaker #4: And even with existing therapy to have an actual improvement in those tough-to-treat older boys. Great. And then I know Steve, you mentioned that 6,000 patients have now been treated with AAV in one form or another.

Bill Mann: I know, Steve, you mentioned that 6,000 patients have now been treated with AAV in one form or another. Is there a difference in the rate of AAV-associated neoplasms across different tissue types or serotypes or disease states?

Bill Maughan: I know, Steve, you mentioned that 6,000 patients have now been treated with AAV in one form or another. Is there a difference in the rate of AAV-associated neoplasms across different tissue types or serotypes or disease states?

Speaker #4: Is there a difference in the rate of AAV-associated neoplasms across different tissue types or serotypes or disease states?

Steve Pakola: From preclinical data and clinical data, there doesn't appear to be any particular difference between different serotypes in terms of the rate of integration. I think that's why across different programs that issue is raised, that there's the possibility that given that there is rare integration, that at some point you could have the integration basically go where you don't want it to go. But no, there's no real strong evidence of a particular predilection. Of course, you look at other factors, like where do you give the drug? What is the promoter different? What's the target tissue? And those are the aspects that give us a lot of comfort in terms of how this is really walled off from our other bigger opportunities of RGX-314 and RGX-202.

Speaker #2: Yeah. From preclinical data and clinical data, there doesn't appear to be any particular difference between different serotypes in terms of the rate of integration.

Speaker #2: So I think that's why across different programs that issue is raised, that there's the possibility that given that there is rare integration, that at some point, you could have the integration basically go where you don't want it to go.

Speaker #2: But no, there's no real strong evidence of a particular predilection. Of course, you look at other factors like where do you give the drug, is the promoter different, what's the target tissue.

Speaker #2: And those are the aspects that give us a lot of comfort in terms of how this is really walled off from our other bigger opportunities of 314 and 202.

Bill Mann: Great. Thank you.

Bill Maughan: Great. Thank you.

Speaker #4: Great. Thank you.

Operator: Thank you. Our next question comes from the line of Sean McCutcheon of Raymond James. Please go ahead, Sean.

Speaker #5: Thank you. Our next question comes from the line of Sean McCutcheon of Raymond James. Please go ahead, Sean.

Sean McCutcheon: Hey, guys. Thanks for the question. Now that you've announced the NAVIGATE, with the Phase IIb focusing on two-step DRSS improvement, how are you thinking about, if at all, the flexibility on that endpoint on binary or ordinal DRSS going into the Phase III, particularly as it relates to pulling out a benefit at one year versus the two-year timeframe where you saw the clearest benefit on two-step improvement at Dose Level 3 in ALTITUDE? Thanks.

Speaker #6: Hey, guys. Thanks for the question. Now that you've announced the Navigate with the phase 2B focusing on two-step DRSS improvement, how are you thinking about, if at all, the flexibility on that endpoint on binary or ordinal DRSS going into the phase 3, particularly as it relates to pulling out a benefit at one year versus the two-year timeframe where you saw the clearest benefit on two-step improvement at dose level 3 and altitude?

Speaker #6: Thanks.

Curran M. Simpson: I think I'll let Steve.

Curran Simpson: I think I'll let Steve.

Steve Pakola: Sure

Speaker #2: I think I'll let Steve shout at that. Thanks, Sean. Yeah, we're very pleased with the FDA's openness to looking at different types of endpoints and not just the traditional binary two-step improvement or two-step worsening and the precedent that's now out there.

Curran M. Simpson: take a shot at that.

Curran Simpson: take a shot at that.

Steve Pakola: Thanks, Sean. Yeah, we're very pleased with the FDA's openness to looking at different types of endpoints and not just the traditional binary, 2-step improvement or 2-step worsening and the precedent that's now out there. We and AbbVie decided to stick with the traditional 2-step change that's traditionally been used. I think you raise a great point, and it's one of the positives of the Phase IIb redesign that we have. Yes, we are starting with the at least 2-step improvement, but we have the flexibility to take into account that data to assess is it more sensitive or in another way, more power per number of patients that you have if you use an ordinal endpoint.

Speaker #2: We in AbbVie decided to stick with the traditional two-step change that's traditionally been used. But I think you raised a great point, and it's one of the positives of the phase 2B free design that we have.

Speaker #2: Yes, we are starting with at least two-step improvement, but we have the flexibility to take into account that data to assess is it more sensitive or another way more power per number of patients that you have if you use an ordinal endpoint.

Steve Pakola: I think it is reasonable to think that that may be the case because we're seeing benefit on both ends. We're seeing not only a higher rate of patients improving, but also critically a higher percent of patients who are not getting worse. An ordinal endpoint, when we look at things with AbbVie, is certainly an option.

Speaker #2: And I think it is reasonable to think that that may be the case because we're seeing benefit on both ends. We're seeing not only a higher rate of patients improving, but also critically, a higher percent of patients who are not getting worse.

Speaker #2: So an ordinal endpoint, when we look at things with AbbVie, may is certainly an option.

Operator: Thank you. Our next question comes from the line of Yi Chen of H.C. Wainwright & Co. Please go ahead, Yi.

Speaker #5: Thank you. Our next question. Comes from the line of Yee Chen. Of HC Wainwright. Please go ahead, Yee.

Eduardo Gurgel: Hi, this is Eduardo. One for you. I guess a quick question going back to 202. I'm curious if you've used the CTAP method to apply towards placebo arms in the ELEVIDYS study. Obviously, you know, one of the big gripes with the historical comparators that placebo arms don't necessarily track with them. I'm curious if you've actually used that method to see if you predict the placebo arms in these other randomized trials.

Eduardo Martinez-Montes: Hi, this is Eduardo. One for you. I guess a quick question going back to 202. I'm curious if you've used the CTAP method to apply towards placebo arms in the ELEVIDYS study. Obviously, you know, one of the big gripes with the historical comparators that placebo arms don't necessarily track with them. I'm curious if you've actually used that method to see if you predict the placebo arms in these other randomized trials.

Speaker #7: Hi. This is Eduardo, one for you. I guess a quick question going back to 202. I'm curious if you've used the CTAP method to apply elevatist study.

Speaker #7: Obviously, one of the big gripes with the historical comparator is that placebo arms don't necessarily track with them. So I'm curious if you've actually used that method to see if you predict the placebo arms in these other randomized trials.

Steve Pakola: Yeah. There, there's different studies out there, of course, and there is always the caveat you have to mention about cross-study comparisons and specifics that might be different. Certainly when we look at what's out there with ELEVIDIS in terms of CTAP or other models, particularly in the older boys, again, we do not see this evidence of older boys getting better versus just stabilization. A lot of the differentiation tends to be driven by the control data and approach. Again, I guess I'd circle back to it's important to look at CTAP, external matched control, and also the propensity score weighting. You know, I think when we have our next data updates, it's gonna be easier for the clinicians in the broader community to try to compare what's been seen previously.

Speaker #2: Yeah. So there's different studies out there, of course, and there is always the caveat you have to mention about cross-study comparisons and specifics that might be different.

Speaker #2: Certainly, when we look at what's out there with elevatists in terms of CTAP or other models, particularly in the older boys, again, we do not of older boys getting better.

Speaker #2: Versus just stabilization. So a lot of the differentiation tends to be driven by the control data and approach. But again, I guess I'd circle back to it's important to look at CTAP external matched control and also the propensity score weighting.

Speaker #2: So I think when we have our next data updates, it's going to be easier for the clinicians and the broader community to try to compare what's been seen previously.

Steve Pakola: Again, what we're seeing so far, if we continue to see that, we feel very confident about the differentiation by whichever method, that we'll be presenting.

Speaker #2: But again, what we're seeing so far, if we continue to see that, we feel very confident about the differentiation by whichever method that will be presenting.

Eduardo Gurgel: Got it. Thanks so much for answering the question.

Eduardo Martinez-Montes: Got it. Thanks so much for answering the question.

Speaker #4: Got it. Thanks so much for answering the question.

Operator: Thank you. Ladies and gentlemen, that does end the Q&A portion of our call and conclude today's conference call. Thank you for participating. You may now disconnect.

Speaker #5: Thank you. Ladies and gentlemen, that does end the Q&A portion of our call and conclude today's conference call. Thank you for participating. You may now disconnect.

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