A First In Human, Single Arm, Open Label Phase 1/2 Study Evaluating ECUR-506 in Neonatal OTC Deficiency: Initial Observations
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Gene Therapy
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Secondary Categories:
- Gene Therapy
Introduction:
Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder resulting in impaired ureagenesis and hyperammonemia. Severe neonatal onset OTCD typically presents in the first 48-72 hours of life with progressive encephalopathy. Clinical sequelae may include feeding difficulties, lethargy, respiratory distress, seizures, coma, and development delay among survivors. Management may include renal replacement therapy acutely, and nitrogen scavengers and protein restriction both acutely and long-term. Orthotopic liver transplantation is the only curative option.
ECUR-506 is a liver-directed, investigational gene editing product being developed for the treatment of neonatal onset OTCD. Administered as a single intravenous dose, ECUR-506 is comprised of a mixture of AAV vectors encoding either a meganuclease, M2PCSK9, for targeted editing of the human PCSK9 gene, or a codon-optimized human OTC donor gene at a ratio of 1:3, respectively. Dual vector administration is designed to guide OTC transgene integration into the hepatocyte genome. While traditional gene addition is associated with episomal dilution in dividing tissues, genome integration is expected to result in the distribution of the integrated donor gene to daughter cells, thereby producing a more durable response when targeting rapidly dividing tissues, which may prove particularly beneficial in children.
Methods:
OTC-HOPE (NCT06255782) is a 24-week, first in human, single arm, Phase 1/2, open-label, global, multi-center trial designed to assess the safety and efficacy of ECUR-506 in male participants with genetically confirmed neonatal onset OTCD who are <9 months of age and 3.5 kg to 10 kg at the time of dosing. Dose levels were informed by nonclinical studies. The initial dose level was effective in a murine model of OTCD. Subsequent doses will be based on an assessment of the totality of the safety and efficacy data accumulating in the trial. Study participants will be included in a long-term 14.5-year follow-up study. Herein, clinical and biomarker data of the first study participant at 4 months post-treatment are described, as of 16 October 2024.
Results:
The first study participant experienced two hyperammonemic crises by 3.5 months of age and subsequently underwent ECUR-506 (1.3 x 1013 GC/kg) infusion at 6.5 months of age. The infusion was well-tolerated and through 4 months post-treatment the participant has remained asymptomatic and has experienced no hyperammonemic events. At 4 weeks post-infusion, the participant experienced asymptomatic transaminitis which resolved within 4 weeks of the initiation of immunosuppressive therapy. All other safety labs have been generally unremarkable to date, and the participant has demonstrated age-appropriate growth (~75th percentile for weight). For the initial 8 weeks following ECUR-506 administration, the participant was managed with nitrogen scavenger and protein restriction. During this time, fasting plasma ammonia remained normal and serum blood urea nitrogen increased. Reductions in plasma glutamine levels prompted the weaning of scavenger therapy, which was discontinued 12 weeks post ECUR-506 administration. Protein allowance has subsequently been liberalized, plasma ammonia and glutamine levels have remained within the normal range, and the participant remains off scavenger medications.
Conclusion:
These data represent the initial 4-month experience of the first infant dosed via an in-vivo AAV-mediated gene editing therapy. These encouraging preliminary safety and efficacy findings support the continuation of the study in a devastating disease with limited treatment options.
Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder resulting in impaired ureagenesis and hyperammonemia. Severe neonatal onset OTCD typically presents in the first 48-72 hours of life with progressive encephalopathy. Clinical sequelae may include feeding difficulties, lethargy, respiratory distress, seizures, coma, and development delay among survivors. Management may include renal replacement therapy acutely, and nitrogen scavengers and protein restriction both acutely and long-term. Orthotopic liver transplantation is the only curative option.
ECUR-506 is a liver-directed, investigational gene editing product being developed for the treatment of neonatal onset OTCD. Administered as a single intravenous dose, ECUR-506 is comprised of a mixture of AAV vectors encoding either a meganuclease, M2PCSK9, for targeted editing of the human PCSK9 gene, or a codon-optimized human OTC donor gene at a ratio of 1:3, respectively. Dual vector administration is designed to guide OTC transgene integration into the hepatocyte genome. While traditional gene addition is associated with episomal dilution in dividing tissues, genome integration is expected to result in the distribution of the integrated donor gene to daughter cells, thereby producing a more durable response when targeting rapidly dividing tissues, which may prove particularly beneficial in children.
Methods:
OTC-HOPE (NCT06255782) is a 24-week, first in human, single arm, Phase 1/2, open-label, global, multi-center trial designed to assess the safety and efficacy of ECUR-506 in male participants with genetically confirmed neonatal onset OTCD who are <9 months of age and 3.5 kg to 10 kg at the time of dosing. Dose levels were informed by nonclinical studies. The initial dose level was effective in a murine model of OTCD. Subsequent doses will be based on an assessment of the totality of the safety and efficacy data accumulating in the trial. Study participants will be included in a long-term 14.5-year follow-up study. Herein, clinical and biomarker data of the first study participant at 4 months post-treatment are described, as of 16 October 2024.
Results:
The first study participant experienced two hyperammonemic crises by 3.5 months of age and subsequently underwent ECUR-506 (1.3 x 1013 GC/kg) infusion at 6.5 months of age. The infusion was well-tolerated and through 4 months post-treatment the participant has remained asymptomatic and has experienced no hyperammonemic events. At 4 weeks post-infusion, the participant experienced asymptomatic transaminitis which resolved within 4 weeks of the initiation of immunosuppressive therapy. All other safety labs have been generally unremarkable to date, and the participant has demonstrated age-appropriate growth (~75th percentile for weight). For the initial 8 weeks following ECUR-506 administration, the participant was managed with nitrogen scavenger and protein restriction. During this time, fasting plasma ammonia remained normal and serum blood urea nitrogen increased. Reductions in plasma glutamine levels prompted the weaning of scavenger therapy, which was discontinued 12 weeks post ECUR-506 administration. Protein allowance has subsequently been liberalized, plasma ammonia and glutamine levels have remained within the normal range, and the participant remains off scavenger medications.
Conclusion:
These data represent the initial 4-month experience of the first infant dosed via an in-vivo AAV-mediated gene editing therapy. These encouraging preliminary safety and efficacy findings support the continuation of the study in a devastating disease with limited treatment options.