PHILADELPHIA, PA — iECURE’s experimental gene-editing therapy reduced the annualized rate of life-threatening metabolic crises by 74% in the low-dose cohort of an early-stage trial in infants with severe ornithine transcarbamylase deficiency, providing initial clinical evidence of metabolic benefit as the company completes dosing across three dose levels.
The Philadelphia-based biotechnology company presented updated Phase 1/2 OTC-HOPE trial results last week at the Society for the Study of Inborn Errors of Metabolism annual symposium in Helsinki, Finland.
Among three participants receiving the lowest dose of ECUR-506, the annualized rate of hyperammonemic crises fell 74% compared with pretreatment rates, a statistically significant reduction with a p-value of 0.01. The broader rate of hyperammonemic events declined 57%, with a p-value of 0.02.
Hyperammonemic crises are acute episodes in which elevated ammonia levels are accompanied by neurological symptoms. They can result in hospitalization, permanent neurological injury or death.
The updated 74% reduction compares with a previously reported 65% decline. iECURE attributed the change to identification of an additional crisis in one participant’s pretreatment medical history following further review.
The clinical responses varied among the three low-dose participants. One patient, whose peak ammonia level at initial presentation was 840 micromoles per liter, achieved what the company characterized as a complete clinical response and stopped both ammonia-scavenger medication and protein restriction.
The other two participants had initial peak ammonia levels of at least 1,600 micromoles per liter. Both showed measures consistent with reduced disease burden, according to iECURE, including one who discontinued one of two ammonia-scavenger medications.
The variation suggests underlying disease severity may affect how much OTC enzyme activity must be restored to achieve metabolic stability, according to the company and study investigators.
“The safety, editing and clinical data generated to date are helping us better understand the relationship between underlying disease severity and the level of enzyme restoration that may be needed to achieve metabolic correction,” said Julien Baruteau, an investigator in OTC-HOPE and professor at University College London Great Ormond Street Institute of Child Health.
ECUR-506 is designed to insert a functional copy of the OTC gene into the PCSK9 locus of liver cells, with the goal of restoring production of the deficient enzyme. The therapy uses two adeno-associated virus vectors, including one carrying an ARCUS® nuclease licensed from Precision BioSciences (Nasdaq: DTIL).
Liver biopsies conducted 24 weeks after treatment in two of the three low-dose participants showed evidence of targeted hepatic editing, iECURE reported. The family of the third participant didn’t consent to a biopsy.
The company also observed reductions in serum PCSK9 levels across the low-dose cohort, which it described as additional evidence consistent with editing at the targeted locus. Biopsy analyses for the intermediate- and high-dose cohorts are pending.
Nine participants have now received ECUR-506, with three each treated at low, intermediate and high doses. Phase 1/2 dosing has been completed, while participant evaluations remain underway.
As of July 28, iECURE characterized ECUR-506 as generally well tolerated across the three cohorts, with no unexpected treatment-related safety events. No thrombotic microangiopathy or infusion reactions were reported.
Transient Grade 2 or Grade 3 transaminitis, without symptoms and without a dose-dependent pattern, occurred in seven of eight participants and resolved with reactive immunosuppression, according to the company. Another participant received preventive corticosteroids after treatment under the study protocol.
One participant died after experiencing hypoxemic respiratory failure. Investigators determined the death was unrelated to ECUR-506 and attributed it to progression of the underlying OTC deficiency and resulting complications, iECURE reported.
“With nine participants now treated, we are encouraged by the safety profile observed to date and the clinical and editing data emerging from the study,” Chief Medical Officer Gabe Cohn said.
OTC deficiency is a rare genetic disorder caused by deficiency of a liver enzyme needed to remove ammonia from the bloodstream. The neonatal form can emerge shortly after birth and progress from poor feeding, vomiting and lethargy to seizures, coma and other life-threatening complications.
Existing management includes protein restriction and ammonia-scavenger drugs, which can control ammonia levels but don’t eliminate the risk of metabolic crises.
OTC-HOPE is a first-in-human study enrolling male infants with genetically confirmed severe neonatal-onset OTC deficiency who are no older than seven months at screening. It is evaluating the safety, tolerability and efficacy of a single intravenous administration of ECUR-506, along with biological, developmental and quality-of-life measures.
Participants undergo six months of follow-up in the main study before entering a 14.5-year long-term follow-up protocol.
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