Company Overview - Lexeo Therapeutics is a cardiac genetic medicines company focused on utilizing AAV gene therapy to address genetic cardiovascular diseases with high unmet needs [2] - The company's most advanced program targets Friedreich's ataxia, showing significant impacts on both cardiac and neurologic aspects of the disease [2] Treatment Efficacy - The gene therapy has resulted in all patients with abnormal heart mass returning to the normal range, indicating a positive effect on cardiac pathology [2] - Improvement in neurologic disease symptoms has been observed, with effect sizes on neurologic scales comparable to those of commercially approved therapies [2] Future Developments - Lexeo Therapeutics plans to move its Friedreich's ataxia program into a registrational study within the year, aiming to establish a new standard of care for this high unmet need disease [3]

Core Insights - uniQure N.V. announced updated preliminary safety and exploratory efficacy data from its Phase 1/2a trial of AMT-191 for Fabry disease, presented at the WORLDSymposium in San Diego, California [1] Trial Data - AMT-191 is an investigational AAV gene therapy for Fabry disease, a rare X-linked lysosomal disorder characterized by excessive lipid deposition in tissues [2] - As of January 8, 2026, all 11 patients in three dose cohorts (6×10^13 gc/kg, 4×10^13 gc/kg, and 2×10^13 gc/kg) showed elevated α-galactosidase A (α-Gal A) activity, which is crucial as deficiency leads to GB3 buildup and Fabry disease [2] Efficacy Observations - Dose-dependent increases in α-Gal A activity were noted, ranging from 0.34- to 82.2-fold at the lowest dose, 1.6- to 312.52-fold at the mid dose, and 27.7- to 223.7-fold at the highest dose [3] - These increases were durable, with follow-up periods ranging from over a year in the high-dose cohort to four months in the mid-dose cohort [3] Patient Outcomes - Six out of 11 patients were withdrawn from enzyme replacement therapy (ERT) after meeting criteria including elevated α-Gal A activity [4] Safety Profile - Stable plasma lyso-Gb3 levels were maintained across all dose cohorts, regardless of ERT status, indicating a manageable safety profile for AMT-191 [5] - No Serious Adverse Events (SAEs) related to AMT-191 were observed at the 4×10^13 gc/kg and 2×10^13 gc/kg doses, although two patients at the 4×10^13 gc/kg dose experienced asymptomatic Grade 3 liver enzyme elevations [5] Dose-Limiting Toxicity - The two liver enzyme elevation cases were confirmed as dose-limiting toxicity, leading to a pause in additional dosing in the mid- and high-dose cohorts pending further evaluation [6] - Both patients responded to corticosteroid therapy and are under follow-up [6] Additional Observations - At the 6×10^13 gc/kg dose, five previously reported SAEs occurred, including two unrelated (stroke, diplopia) and two related (chest pain, increased troponin) to AMT-191, along with one possibly related SAE (leptomeningeal enhancement) [7] - One patient at this dose experienced an asymptomatic Grade 3 liver enzyme elevation that resolved with corticosteroid therapy [7] Market Reaction - Following the announcement, uniQure shares increased by 6.10% to $26.01 [8]

Core Viewpoint - Ultragenyx Pharmaceutical Inc. has resubmitted its Biologics License Application (BLA) for UX111, a gene therapy for Sanfilippo syndrome type A, to the FDA, aiming for accelerated approval based on new long-term clinical data demonstrating positive effects over 8.5 years [2][3][5]. Group 1: Product and Clinical Data - UX111 (rebisufligene etisparvovec) is an AAV9 gene therapy in Phase 1/2/3 development targeting Sanfilippo syndrome type A, a rare and fatal lysosomal storage disease with no approved treatment [6]. - The resubmitted BLA includes comprehensive responses to previous FDA observations and additional long-term clinical data, which support an intermediate clinical endpoint for accelerated approval [3][4]. - Updated clinical data show a durable treatment effect across multiple biomarkers and maintain an acceptable safety profile, with detailed updates to be presented at WORLDSymposium™ 2026 [4]. Group 2: Regulatory Process and Timeline - The FDA granted Priority Review for the UX111 BLA in February 2025, with a Prescription Drug User Fee Act (PDUFA) action date expected within a month of resubmission [5]. - The company anticipates a review period of up to six months from the resubmission date, with a PDUFA date expected in the third quarter of 2026 [5]. Group 3: Disease Background - Sanfilippo syndrome type A (MPS IIIA) is characterized by rapid neurodegeneration, with onset in early childhood, leading to cognitive, language, and motor decline, and has a median life expectancy of 15 years [7]. - The disease affects approximately 3,000 to 5,000 patients in commercially accessible geographies and is caused by biallelic pathogenic variants in the SGSH gene, leading to a deficiency in the sulfamidase enzyme [7][8]. Group 4: Company Overview - Ultragenyx is focused on developing novel therapies for serious rare and ultra-rare genetic diseases, with a diverse portfolio aimed at addressing high unmet medical needs [9]. - The company is led by a management team experienced in rare disease therapeutics, emphasizing time- and cost-efficient drug development [10].

Company Overview - REGENXBIO is experiencing a transformational year, having a legacy of approximately 15 years in AAV gene therapy, initially focusing on out-licensing products like Zolgensma derived from its original intellectual property and technology [2] - In the last 8 to 10 years, the company has shifted towards developing new programs internally [2] Technology and Development - The company utilizes NAV technology, which includes over 100 vectors within the NAV family, and has five licensees primarily using AAV8 and AAV9 [3] - REGENXBIO has dosed over 5,000 patients with its technology over the years, indicating a significant level of experience and application in the field [3]

Summary of Regenxbio FY Conference Call (January 14, 2026) Company Overview - **Company**: Regenxbio (NasdaqGS: RGNX) - **Key Speakers**: Curran Simpson (CEO), Mitch Chan (CFO), Dr. Steve Pakola (CMO) [1] Industry and Technology - **Industry**: Gene Therapy - **Technology**: AAV (Adeno-Associated Virus) gene therapy with over 5,000 patients dosed [2][3] - **Focus**: Development of new capsids to enhance therapeutic efficacy and safety [5] Core Points and Arguments Pipeline and Product Development - **BLA Review**: The company has a Biologics License Application (BLA) under review for the Hunter program, with a PDUFA date of February 8, 2026 [8][22]. - **Late-Stage Programs**: Top-line readouts expected for two late-stage programs: Duchenne program (RGX-202) in Q2 2026 and wet AMD program (RGX-314) with AbbVie later in 2026 [4][8]. - **Duchenne Program**: Aiming to provide functional benefits to children with Duchenne muscular dystrophy, with pivotal data showing significant improvements in patient outcomes [10][11][19]. - **Wet AMD Program**: RGX-314 is positioned as a potential first non-rare gene therapy approved, with significant commercial readiness efforts in collaboration with AbbVie [9][25]. Manufacturing and Scalability - **Manufacturing Capabilities**: The company has advanced manufacturing processes, capable of producing 2,500 doses per year for RGX-202 and up to 350,000 doses for RGX-314 [28][29]. - **Quality Control**: Achieved an 80% full capsid level in batches, which is critical for safety and efficacy [29]. Safety and Efficacy - **Immune Suppression Regimen**: A proactive immune suppression strategy has been implemented to enhance safety and efficacy, allowing for higher dosing without significant adverse effects [36][37]. - **Clinical Outcomes**: Positive safety profiles and functional benefits observed in patients, with significant improvements in NSAA scores [19][17]. Additional Important Content - **Global Expansion**: Plans for expanding clinical studies outside the U.S. to address broader patient needs [21][39]. - **Partnerships**: Collaboration with AbbVie for the wet AMD program, leveraging their existing sales force and expertise in ophthalmology [43][44]. - **Market Potential**: The company is targeting significant unmet needs in rare diseases and chronic retinal diseases, with a focus on long-term patient outcomes and reducing treatment burdens [31][27]. Conclusion - **Future Outlook**: Regenxbio is positioned for a transformative year with multiple late-stage catalysts, a strong manufacturing base, and a commitment to patient-centric outcomes in gene therapy [31].

Core Viewpoint - Sanofi's SAR446268 has received fast track designation from the FDA for treating non-congenital myotonic dystrophy type 1, highlighting the urgency and potential of this gene therapy in addressing an unmet medical need [1][7]. Group 1: Product Development - SAR446268 utilizes a vectorized RNA interference approach to silence DMPK expression, aiming to reduce toxic RNA foci and restore normal muscle function [2]. - The therapy is currently in a first-in-human phase 1-2 study to assess safety, tolerability, and efficacy, with patient enrollment expected to begin in late 2025 [3]. - Sanofi has received orphan designations for SAR446268 in both the US and EU, indicating its potential significance in treating rare diseases [3]. Group 2: Disease Overview - Myotonic dystrophy type 1 (DM1) is a rare genetic disorder affecting approximately 1 in 2,300 people globally, characterized by progressive muscle weakness and various systemic effects [4]. - The condition is caused by mutations in the DMPK gene and has no currently approved treatments, emphasizing the importance of SAR446268 [4][7]. Group 3: Company Profile - Sanofi is an R&D driven biopharma company focused on improving lives through innovative medicines and vaccines, with a commitment to addressing urgent healthcare challenges [5].

Summary of Passage Bio (PASG) FY Conference Call - September 05, 2025 Company Overview - Passage Bio is a clinical stage genetic medicines company focused on neurodegenerative diseases, particularly frontotemporal dementia (FTD) [2][3] Core Program: PBFT02 - PBFT02 is the lead clinical program targeting frontotemporal dementia with the GRN mutation, addressing a significant unmet need as there are no approved disease-modifying therapies for this condition [2][4] - The target population includes approximately 18,000 patients with GRN mutation FTD and 21,000 with C9orf72 mutation FTD across the U.S. and Europe [3] Clinical Development and Milestones - The ongoing phase 1/2 study of PBFT02 is a multicenter international open-label dose exploration study, currently active in the U.S., Canada, Portugal, and Brazil [7] - Key upcoming milestones include seeking regulatory feedback on manufacturing comparability in Q4 2025 and reporting dose two data in the first half of 2026 [3][21] Mechanism of Action - PBFT02 utilizes AAV gene therapy to increase levels of progranulin, a protein crucial for CNS cell homeostasis, which is deficient in patients with GRN mutation FTD [4][5] - The administration route is intracisterna magna, allowing for broad CNS biodistribution and lower doses compared to systemic delivery [9][10] Clinical Data and Safety Profile - Initial cohorts have shown promising results, with dose one achieving an average of over 25 nanograms per ml of progranulin levels at 12 months, indicating robust and durable responses [15][18] - The safety profile includes three serious adverse events (SAEs) among eight treated patients, with a decision to implement prophylactic anticoagulation for future patients due to observed venous thromboembolic events [12][20] Biomarker Analysis - Plasma neurofilament levels, a marker of neurodegeneration, showed a significant reduction in treated patients compared to the expected annual increase of 29% in untreated patients, suggesting a potential slowing of disease progression [17][20] - The study is also tracking CSF progranulin levels and clinical dementia rating scales to assess treatment efficacy [9][11] Competitive Landscape - PBFT02 is positioned as a potentially best-in-class therapy, with higher and more durable progranulin levels compared to other therapies in development for FTD [18][19] - Market research indicates a preference for a one-time therapy over monthly treatments, particularly for patients with behavioral dementia [19] Future Directions - Plans to expand the clinical study to include FTD C9 patients, as raising progranulin may also benefit TDP-43 pathology seen in multiple neurodegenerative diseases [20][21] - The company has a cash balance of $58 million, providing a runway into Q1 2027 to continue patient treatment and data collection [22] Conclusion - Passage Bio is advancing its clinical program for PBFT02 with promising early data and a clear regulatory pathway, aiming to address significant unmet needs in neurodegenerative diseases [22]

Core Insights - REGENXBIO Inc. announced preclinical results showing that a microdystrophin gene therapy construct with the C-terminal (CT) domain provides improved functional benefits for patients with Duchenne Muscular Dystrophy compared to a construct without the CT domain [1][4][5] - RGX-202 is the only investigational microdystrophin gene therapy candidate that includes the CT domain, making it closest to naturally occurring dystrophin [2][8] Group 1: Research Findings - The preclinical study published in Molecular Therapy Methods and Clinical Development demonstrated that the microdystrophin with the CT domain was maintained at higher levels in transduced muscles and effectively recruited the dystrophin-associated protein complex to the muscle membrane [4][5] - The incorporation of the CT domain enhances the microdystrophin design, allowing for higher accumulation levels in muscle and potentially improving functional benefits [5][7] Group 2: Clinical Trial Insights - Interim results from the Phase I/II AFFINITY DUCHENNE trial indicated that RGX-202 showed consistent evidence of positively changing the disease trajectory in patients with Duchenne and had a favorable safety profile [5][6] - REGENXBIO is currently enrolling participants in the pivotal portion of the Phase I/II/III AFFINITY DUCHENNE trial and plans to submit a Biologics License Application (BLA) via the accelerated approval pathway in mid-2026 [6][9] Group 3: Company Overview - REGENXBIO is a biotechnology company focused on gene therapy, with a late-stage pipeline that includes RGX-202 for Duchenne, among other treatments for rare diseases [11] - The company has pioneered AAV gene therapy since its founding in 2009 and has treated thousands of patients with its AAV platform [11]

PBFT02 Development and Preclinical Results - PBFT02 is an AAV gene therapy designed to deliver functional PGRN to the brain for the treatment of FTD-GRN [13] - In Grn-/- mice, AAV.hGRN vector ICV administration improved lysosomal function, reduced lipofuscin fluorescence in the thalamus, and reduced brain hexosaminidase activity [21, 23] - AAV1 was selected as the vector serotype due to superior hPGRN levels in CSF compared to AAV5 and AAVhu68 in NHPs [28, 29] - In Grn-/- mice, PBFT02 reduced lipofuscin deposition and neuroinflammation in the brain after intra-CSF delivery [34, 37] - ICM administration of PBFT02 enables PGRN delivery throughout the CNS [40] - In NHPs, PBFT02 dose-dependently increased PGRN in CSF up to day 14 [46, 48] - In NHPs, PBFT02 at Dose 1 resulted in approximately 10e4 GC/ug DNA throughout the brain [43] Clinical Trial (upliFT-D) and Safety - The upliFT-D trial is a global Phase 1/2 multi-center, open-label, dose-escalation study with PBFT02 [52, 55] - FTD-GRN Cohort 1 (n = 5) dosing is complete [56] - All four Cohort 1 participants who received a revised immunosuppression regimen had no SAEs or significant immune responses [57] - Cohort 1 interim data shows PBFT02 administration leads to robust and sustained increases in CSF PGRN [58]

Financial Data and Key Metrics Changes - REGENXBIO ended the quarter on March 31, 2025, with cash, cash equivalents, and marketable securities of $272 million, an increase from $245 million as of December 31, 2024, primarily driven by a $110 million upfront payment from the Nippon Shinyaku collaboration [24] - R&D expenses were $53 million for the quarter ended March 31, 2025, compared to $54.8 million for the same quarter in 2024, reflecting a decrease due to clinical trial expenses for RGX-314 and RGX-202 [25] Business Line Data and Key Metrics Changes - RGX-121, a potential first gene therapy for MPS II, is on track for potential FDA approval in the second half of 2025, with a BLA submitted under the accelerated approval pathway [8][9] - RGX-202, a next-generation candidate for Duchenne muscular dystrophy (DMD), has surpassed 50% enrollment in its pivotal study and is expected to submit a BLA in mid-2026 [10][11] - The retinal program, RGX-314, is advancing in two pivotal studies for wet AMD and is on track to be the first gene therapy on the market for this condition [12][19] Market Data and Key Metrics Changes - The DMD market is projected to have over half of the prevalent population untreated by 2027, highlighting a significant opportunity for RGX-202 [11] - The wet AMD and diabetic retinopathy markets represent large multibillion-dollar commercial opportunities, with RGX-314 positioned to serve as a meaningful alternative to current treatments [12][19] Company Strategy and Development Direction - The company is focused on transitioning to a commercial stage with in-house manufacturing capabilities and plans to secure non-dilutive funding [6][8] - A strategic partnership with Nippon Shinyaku aims to commercialize the neurodegenerative franchise, including RGX-121 and RGX-111 [9] - The company is preparing for commercial supply manufacturing of RGX-202 in anticipation of a 2027 launch [11][27] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the imminent acceptance of the BLA for RGX-121 and the positive trajectory of clinical programs [34][51] - The company is optimistic about the evolving regulatory landscape and the potential for accelerated approval pathways, particularly in light of recent developments in the industry [36][44] Other Important Information - The company has a robust cash runway expected to fund operations into the second half of 2026, with potential extensions through non-dilutive financing options [25][26] - The manufacturing innovation center in Rockville, Maryland, is capable of producing up to 2,500 doses of RGX-202 annually, ensuring readiness for market needs [11][12] Q&A Session Summary Question: Timing for the Hunter BLA - Management indicated that the BLA acceptance is imminent and they feel confident about the review process [34] Question: Competitor Insights and Regulatory Expectations - Management discussed the evolving expectations for accelerated approval in DMD, emphasizing the strength of their safety and functional data [36][44] Question: Changes in FDA Requirements - Management noted that there are no anticipated changes in the accelerated approval pathway and enrollment is on track [43][44] Question: Planning for Diabetic Retinopathy Phase III Trial - Management confirmed ongoing interactions with the FDA and that they are on track for first patient dosing this year [55] Question: Updates on DMD Functional Data - Management plans to release additional functional data in the first half of the year, focusing on dose level two patients [62][88] Question: Impact of Recent Pricing Announcements - Management stated it is too early to assess the impact of recent pricing discussions on their gene therapies [104]