avalotcagene ontaparvovec (DTX301) / Ultragenyx - LARVOL DELTA

Cross-reactive Immunologic Material (CRIM) Analyses for AAV Gene Therapy (ASGCT 2025) - P1/2 | "For individuals with OTC enrolled in the DTX301 Phase 1/2 study (ClinicalTrials.gov Identifier: NCT02991144), 1 of 8 participants with available data was characterized as CRIM-medium risk due to a hemizygous splicing mutation predicted to cause absence of a portion of ornithine transcarbamylase protein. For individuals with GSDIa enrolled in the DTX401 Phase 1/2 study (ClinicalTrials.gov Identifier: NCT03517085), two of 12 participants were characterized as CRIM-high risk and three of 12 were characterized as CRIM-medium risk due to homozygous or compound heterozygous mutations predicted to result in truncation or absence of glucose-6-phosphatase protein...As more people consider taking AAV gene therapy, understanding the impact of CRIM more comprehensively will help guide discussions to optimize these potentially transformative treatments. Disease Focus of Abstract:Rare Diseases"

Gene therapy • Gene Therapies • Immunology • Rare Diseases • CD4 • CD8 • HLA-B • HLA-C

Durable Efficacy and Safety of DTX301: Long-term Follow Up (LTFU) of a Phase 1/2 Trial in Adults with Ornithine Transcarbamylase Deficiency (OTCD (ASGCT 2025) - P1/2, P3 | "DTX301 continues to show manageable safety and durable improvements in clinical responses. The Phase 3 trial (NCT05345171) is currently evaluating DTX301 in adults and children ≥12 years of age. Disease Focus of Abstract:Inborn Errors in Metabolism"

Clinical • P1/2 data • CNS Disorders • Genetic Disorders • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Vascular Neurology

The Seropositivity Dilemma for AAV Gene Therapy (ASGCT 2025) - "To explore the impact of seropositivity further, we characterized the total binding antibody titers in individuals with Ornithine Transcarbamylase Deficiency (OTC), Glycogen Storage Disease type Ia (GSDIa) and Wilson Disease (WD), as these are the populations that are under investigation for DTX301, DTX401 and UX701 AAV gene therapies, respectively. These data support further investigation into more frequent AAV TAb testing and will inform discussions about the possibility of dosing low TAb+ individuals in future AAV GT trials. Disease Focus of Abstract:Rare Diseases"

Gene therapy • Gene Therapies • Hepatology • Metabolic Disorders • Movement Disorders • Rare Diseases

Clinical Study of DTX301 AAV- Mediated Gene Transfer for Ornithine Transcarbamylase(OTC) Deficiency (clinicaltrials.gov) - P3 | N=50 | Active, not recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Recruiting ➔ Active, not recruiting

Enrollment closed • Gene Therapies • Genetic Disorders

Clinical Study of DTX301 AAV- Mediated Gene Transfer for Ornithine Transcarbamylase(OTC) Deficiency (clinicaltrials.gov) - P3 | N=50 | Recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Trial primary completion date: Dec 2024 ➔ Mar 2025

Trial primary completion date • Gene Therapies • Genetic Disorders

DESIGN OF A PHASE 3 STUDY OF AAV-MEDIATED GENE TRANSFER OF ORNITHINE TRANSCARBAMYLASE (OTC) IN PATIENTS WITH LATE-ONSET OTC DEFICIENCY (SSIEM 2024) - P3 | "Discussion/Conclusion This phase 3 study aims to determine efficacy and confirm safety of DTX301 by monitoring changes in clinical response and disease management, health outcomes, cognitive state, hyperammonemic crises, biochemical analytes, and immune response. Palavras-chave : OTC, gene therapy, clinical trial, phase 3"

Clinical • P3 data • CNS Disorders • Gene Therapies • Genetic Disorders • Vascular Neurology

LONG-TERM FOLLOW UP (LTFU) OF A PHASE 1/2 TRIAL OF DTX301 IN ADULTS WITH LATE-ONSET ORNITHINE TRANSCARBAMYLASE DEFICIENCY (OTCD) (SSIEM 2024) - P1/2, P3 | "DTX301 continues to show manageable safety and durable efficacy. The randomized, placebo-controlled Phase 3 trial (NCT05345171) is currently enrolling adults and children >12 years of age."

Clinical • P1/2 data • CNS Disorders • Genetic Disorders • Metabolic Disorders • Vascular Neurology

Long-Term Safety and Urea Cycle Function Following a Phase 1/2 Trial of DTX301 in Adults with Late-Onset Ornithine Transcarbamylase (OTC) Deficiency (ASGCT 2024) - P1/2, P3 | "DTX301 continues to show a manageable safety profile. Expected vector-induced effects were treated by corticosteroids and resolved. Patients tolerated corticosteroid regimens without metabolic decompensation."

Clinical • P1/2 data • CNS Disorders • Genetic Disorders • Hepatology • Metabolic Disorders • Vascular Neurology

Design of a Phase 3 study of AAV-mediated gene transfer of ornithine transcarbamylase (OTC) in patients with late-onset OTC deficiency (SIMD 2024) - P3 | "This ongoing phase 3 study aims to determine efficacy and confirm safety of DTX301 in patients ≥12 years old with late-onset OTCD by monitoring clinical outcomes, hyperammonemic crises, and biochemical analytes."

Clinical • P3 data • CNS Disorders • Gene Therapies • Genetic Disorders • Vascular Neurology

Long-term safety and efficacy of DTX301 in adults with late-onset ornithine transcarbamylase (OTC) deficiency: A Phase 1/2 trial (SIMD 2024) - P1/2, P3 | "DTX301 continues to show a manageable safety profile and encouraging evidence of durable efficacy with the longest treated complete responder exhibiting efficacy for over 5.5 years. Patients in this study will continue to be followed. The Phase 3 trial (NCT05345171) is currently recruiting."

Clinical • P1/2 data • Genetic Disorders • Metabolic Disorders

CAPtivate: Long Term Follow Up to Evaluate DTX301 in Adults With Late-Onset OTC Deficiency (clinicaltrials.gov) - P=N/A | N=11 | Active, not recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Trial completion date: Dec 2027 ➔ Dec 2029 | Trial primary completion date: Dec 2027 ➔ Dec 2029

Trial completion date • Trial primary completion date • Gene Therapies • Genetic Disorders

Long-term Safety and Efficacy of DTX301 in Adults with Late-Onset Ornithine Transcarbamylase (OTC) Deficiency: A Phase 1/2 Trial (SSIEM 2023) - P1/2, P3 | "DTX301 continues to show a manageable safety profile and encouraging evidence of durable efficacy with the longest treated complete responder exhibiting efficacy for over 5.5 years. Patients in this study will continue to be followed. The Phase 3 trial (NCT05345171) is currently recruiting."

Clinical • P1/2 data • Genetic Disorders • Metabolic Disorders

Long-Term Safety and Efficacy of DTX301 in Adults with Late-Onset Ornithine Transcarbamylase (OTC) Deficiency: A Phase 1/2 Trial (ASGCT 2023) - P1/2, P3 | "DTX301 continues to suggest a manageable safety profile and encouraging evidence of durable efficacy with the longest treated complete responder exhibiting efficacy for over 5 years. Patients in this study will continue to be followed. The Phase 3 trial (NCT05345171) is currently recruiting."

Clinical • P1/2 data • Genetic Disorders • Metabolic Disorders

CAPtivate: Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset Ornithine Transcarbamylase (OTC) Deficiency (clinicaltrials.gov) - P1/2 | N=16 | Completed | Sponsor: Ultragenyx Pharmaceutical Inc | N=11 ➔ 16

Enrollment change • Gene Therapies • Genetic Disorders

Clinical Study of DTX301 AAV- Mediated Gene Transfer for Ornithine Transcarbamylase(OTC) Deficiency (clinicaltrials.gov) - P3 | N=50 | Recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Initiation date: Sep 2022 ➔ Dec 2022

Trial initiation date • Gene Therapies • Genetic Disorders

Final safety and efficacy of a phase 1/2 trial of DTX301 in adults with late-onset ornithine transcarbamylase deficiency (OTCD) (ESGCT 2022) - No abstract available

Clinical • P1/2 data • Genetic Disorders

Clinical Study of DTX301 AAV- Mediated Gene Transfer for Ornithine Transcarbamylase(OTC) Deficiency (clinicaltrials.gov) - P3 | N=50 | Recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Initiation date: May 2022 ➔ Sep 2022

Trial initiation date • Gene Therapies • Genetic Disorders

Safety and Efficacy of DTX301 in Adults with Late-onset Ornithine Transcarbamylase (OTC) Deficiency: A Phase 1/2 Trial (ASGCT 2022) - P1/2 | "DTX301 has shown promising results to date. Continued work is planned to study DTX301 as a potential new treatment for patients with OTC deficiency, and the Cohort 3 dose of 1.7x1013 GC/kg has been selected for study in a Phase 3 trial."

Clinical • P1/2 data • Genetic Disorders • Hypertension • Infectious Disease • Metabolic Disorders • Pain • Renal Disease

Clinical Study of DTX301 AAV- Mediated Gene Transfer for Ornithine Transcarbamylase(OTC) Deficiency (clinicaltrials.gov) - P3 | N=50 | Recruiting | Sponsor: Ultragenyx Pharmaceutical Inc

New P3 trial • Gene Therapies • Genetic Disorders

CAPtivate: Long Term Follow Up to Evaluate DTX301 in Adults With Late-Onset OTC Deficiency (clinicaltrials.gov) - P=N/A | N=11 | Active, not recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Enrolling by invitation ➔ Active, not recruiting | N=18 ➔ 11 | Trial completion date: Dec 2025 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2027

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Gene Therapies • Genetic Disorders

Prednisolone reduces the interferon response to AAV in cynomolgus macaques and may increase liver gene expression. (PubMed, Mol Ther Methods Clin Dev) - "DTX301, a non-replicating, recombinant self-complimentary adeno-associated virus vector serotype 8 (scAAV8)-encoding human ornithine transcarbamylase, is a promising gene therapy for ornithine transcarbamylase deficiency; however, the impact of sex and prophylactic immunosuppression on ornithine transcarbamylase gene therapy outcomes is not well characterized...These observations were not sustained upon immunosuppression withdrawal. Further studies may determine whether the observed effect can be prolonged."

Journal • Gene Therapies • Genetic Disorders • Metabolic Disorders

CAPtivate: Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset OTC Deficiency (clinicaltrials.gov) - P1/2; N=11; Completed; Sponsor: Ultragenyx Pharmaceutical Inc; Active, not recruiting ➔ Completed

Clinical • Trial completion • Gene Therapies • Genetic Disorders

[VIRTUAL] AAV8 gene therapy as a potential treatment for adults with lateonset ornithine transcarbamylase (OTC) deficiency: updated results from a phase 1/2 clinical trial (ESGCT 2021) - P1/2 | "DTX301 has shown promising results to date. Continued work is planned to study DTX301 as a potential new treatment for patients with OTC deficiency."

Clinical • P1/2 data • Gene Therapies • Metabolic Disorders

[VIRTUAL] Similar DTX301 (scAAV8OTC) Gene Therapy Outcomes in Female and Male Cynomolgus Macaques (ASGCT 2021) - "Prednisolone IS (1mg/kg/day) was administered 4 days before, and for 28 days following, DTX301 administration, and was tapered 25% by week from days 28 - 56. Few/weak ELISPOT responses were observed in the liver to the transgene peptide pools and none were observed in PBMCs. In summary, there were no apparent differences between female and males cynomolgous macaques in immunologic parameters or in DTX301 effectivity."

Gene Therapies • Hematological Disorders • Hepatology • Immunology • Metabolic Disorders • Transplantation • IFNG

[VIRTUAL] AAV8 Gene Therapy as a Potential Treatment in Adults with Late-Onset Ornithine Transcarbamylase (OTC) Deficiency: Updated Results from a Phase 1/2 Clinical Trial (ASGCT 2021) - P1/2 | "Data from CAPtivate indicate that DTX301 has an acceptable safety profile and may be a potential new therapy with long-term therapeutic benefit for patients with OTC deficiency. Follow‑up of all patients is ongoing and enrollment in cohort 4 is nearly complete."

Clinical • P1/2 data • Gene Therapies • Hepatology • Hypertension • Metabolic Disorders • Pain • Renal Disease