Study of LNP.UCD.ABE in Patients With Urea Cycle Disorders

Master Protocol for a Phase I/II Open-label Safety and Efficacy Study of LNP.UCD.ABE, a Lipid Nanoparticle-delivered Base Editing Therapy, in Patients With Urea Cycle Disorders Due to Variants Amenable to Corrective Editing by LNP.UCD.ABE

This is a single-site Phase 1/2 open-label umbrella clinical trial designed to evaluate the safety, tolerability, and efficacy of a single intravenous dose of LNP.UCD.ABE in 5 pediatric subjects with severe infantile-onset UCDs. This is a master clinical protocol in which subjects with a variant in a urea cycle disorder (UCD) gene (CPS1, OTC, ASS1, ASL, ARG, NAGS, or SLC25A15) that is demonstrated to be amenable to corrective editing by an adenine base editor (ABE) would be eligible for enrollment.

Humans ingest protein to support growth and the synthesis of a number of key macromolecules. Nitrogen waste generated from protein catabolism is converted to ammonia, which under normal physiologic conditions is converted to urea via the urea cycle. Urea is then excreted in urine to maintain whole-body nitrogen homeostasis. Loss of function of any of the six enzymes of the urea cycle-encoded by CPS1 (carbamoyl phosphate synthetase 1), OTC (ornithine transcarbamylase), ASS1 (argininosuccinate synthetase), ASL (argininosuccinate lyase), ARG (arginase), and NAGS (N-acetylglutamate synthetase)-results in a urea cycle disorder (UCD). In addition loss of the ornithine transporter, ORNT1 (encoded by SLC25A15), can also lead to disease.

Severe UCD patients typically present as neonates and have a profound decrease in function in any one of the six enzymes of the urea cycle or a lack of function of the ornithine transporter that carries urea cycle intermediates. This results in toxic accumulation of ammonia in the blood and accumulation of specific urea cycle amino acids that aid in diagnoses and therapeutic monitoring. Patients are at risk of developing extremely elevated blood ammonia levels (hyperammonemia) that can lead acutely to coma and death and chronically to profound neurologic dysfunction.

LNP.UCD.ABE is an investigational in vivo gene editing product proposed for the treatment of hyperammonemia in patients under 5 years of age with deficiencies in enzymes or a related transporter of the urea cycle who are homozygous or compound heterozygous for a pathogenic variant in any UCD gene, including CPS1, OTC, ASS1, ASL, ARG, NAGS, and SLC25A15, that can be efficiently corrected by an adenine base editor (ABE).

Each subject will have a personalized variant-specific LNP.UCD.ABE developed and evaluated during the Screening period, which may last up to 8 months. Subjects will eligible for a lead in period to establish a stable diet. After the subject's drug is developed and lead in has been completed, the subject will be administered LNP.UCD.ABE via a single intravenous infusion. After LNP.UCD.ABE administration, participants will be followed for safety and efficacy for 52 weeks.

Inclusion Criteria:

1. Diagnosis of a severe urea cycle disorder, in the judgement of the investigators.

2. Molecular testing demonstrating homozygosity or compound heterozygosity for a disease-causing mutation in CPS1 that is targeted by a variant-specific version of the LNP.UCD.ABE drug product.

3. Current or historical biochemical testing consistent with a urea cycle disorder

4. At least one of the subject's alleles must be amenable to base editing by LNP.UCD.ABE, as assessed in vitro

5. A history of an ammonia level of ≥400 μmol/L prior to age 12 months, unless a diagnosis was made prenatally and care was initiated immediately after birth

   • If the patient is taking a nitrogen scavenger medication, their ammonia level may currently be in the normal range
   • If the patient is diagnosed prenatally, then personal history, family history, or analysis of mutations should indicate a high likelihood of a severe UCD.

6. Subjects more than 8 weeks from the initial diagnosis of a UCD must have demonstrated:

   • a persistent need for dietary protein restriction and chronic administration of a nitrogen scavenger medication, AND / OR
   • a recurrent hyperammonemic event AND / OR
   • a history of a hyperammonemia-induced seizure

7. Weight >3.5 kg at the time of screening

8. Legal guardian(s) capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

1. Abnormal liver function, electrolyte, coagulation, or blood count laboratory values thought not attributable to the underlying urea cycle disorder;
2. Demonstrated need for urgent liver transplantation due to liver failure, in the opinion of the investigators;
3. Participation in a prior gene therapy trial or participation in a trial of an investigational product in the last 12 months;
4. History of liver transplantation;
5. Any other diseases or conditions that the investigators would consider to pose unacceptable risk to the subject;
6. Inability or unwillingness to comply with the visit schedule and study assessments;
7. Any genetic variation in the causative urea cycle disorder gene that, in the opinion of the investigators, may decrease the potential efficacy of the drug product;
8. History of severe hypersensitivity or anaphylaxis to polyethylene glycol (PEG)-containing products, such as PEG-containing vaccines or laxatives