Ornithine Transcarbamylase Deficiency Gene Therapy Gets FDA Orphan Drug Designation


BGT-OTCD is being developed in a collaboration between Bloomsbury Genetic Therapies and University College London.

Bloomsbury Genetic Therapies’ BGT-OTCD, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat ornithine transcarbamylase deficiency (OTCD), has received an orphan drug designation (ODD) from the FDA.1

BGT-OTCD, which is delivered via a single intravenous injection and utilizes the AAV-LK03 vector, with high specificity for the cells of the liver, is being developed in a collaboration between Bloomsbury and University College London (UCL). UCL submitted a clinical trial application to the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) in December 2022 that was later cleared by the MHRA in May 2023.2,3 UCL is planning to carry out a phase 1/2 clinical trial, called HORACE (NCT05092685).1 Bloomsbury and UCL anticipate that HORACE, which will seek to recruit children with OTCD in the UK, will begin enrolling patients within the third quarter of this year.

“Ornithine transcarbamylase deficiency is a rare genetic disorder that is characterized by complete or partial lack of the OTC enzyme which causes too much ammonia to accumulate in the body,” Anupam Chakrapani, a consultant in metabolic medicine at Great Ormond Street Hospital and the trial’s principal investigator, said in a May 2023 statement.3 “People with this disease suffer from symptoms including vomiting, impaired voluntary movement and progressive lethargy, which can all progress to brain damage, coma or death if left untreated. The capsid used in this investigational AAV gene therapy, AAV-LK03, was selected for its enhanced ability to transduce human hepatocytes, and in particular periportal hepatocytes where the urea cycle preferentially takes place. We hope the trial will show that BGT-OTCD could provide sustained curative effect following a single administration even in children with a growing liver.”

Bloomsbury has noted that in preclinical research, BGT-OTCD underwent comprehensive evaluations of safety and biodistribution and showed curative potential.2 According to the clinicaltrials.gov page, the therapy is expected to have potential as a “bridge-to-transplant" for liver transplantation, the only currently approved curative option for OTCD. Liver transplantations are limited in availability, come with the need for lifelong immunosuppression and arginine supplementation, and carry a substantial risk for serious and life-threatening complications.1 As such, it is anticipated that BGT-OTCD could enable children with OTCD to grow in a more metabolically stable condition and sustain less long-term damage until liver transplantation becomes a viable option.

“Having already received an ODD from the European Medicine Agency (EMA) and the rare pediatric disease designation from the FDA for BGT-OTCD, we now look forward to leveraging the benefits that this new designation brings, including the provision of post-approval market exclusivity in the US” Adrien Lemoine, MSc, the co-founder and chief executive officer of Bloomsbury, said in an August 9, 2023, statement.1

BGT-OTCD is Bloomsbury’s lead gene therapy program, but the company has a pipeline of gene therapy products for other rare disease indications currently in preclinical development. BGT-DTDS, an investigational AAV vector-based gene therapy intended to treat dopamine transporter deficiency syndrome, has also received ODDs from both the FDA and EMA and rare pediatric disease designation from the FDA.5 On March 1, 2023, the company held a scientific advice meeting with the UK’s MHRA in order to confirm that the preclinical research conducted to date on BGT-DTDS is sufficient for the initiation of a clinical trial for the therapy.6 As a result of the meeting, in which the MHRA gave an opinion supportive of clinical trial initiation, the company plans to submit a combined clinical trial and ethics committee application to the MHRA in 2024 for a phase 1/2/3 registrational trial. Bloomsbury is also exploring the potential of BGT-DTDS to treat Parkinson disease and has additional preclinical stage gene therapy programs for Niemann-Pick disease type C and infantile neuroaxonal dystrophy.7

1. Bloomsbury Genetic Therapies receives orphan drug designation from the U.S. FDA for BGT-OTCD for the treatment of ornithine transcarbamylase deficiency (OTCD). News release. Bloomsbury Genetic Therapies Limited. August 9, 2023. Accessed August 18, 2023. https://bloomsburygtx.com/bloomsbury-genetic-therapies-receives-orphan-drug-designation-from-the-u-s-fda-for-bgt-otcd-for-the-treatment-of-ornithine-transcarbamylase-deficiency-otcd/
2. Bloomsbury Genetic Therapies announces CTA filing for a phase I/II study for its lead gene therapy program. News release. Bloomsbury Genetic Therapies Limited. December 7, 2022. Accessed August 18, 2023. https://bloomsburygtx.com/bloomsbury-genetic-therapies-announces-cta-filing-for-a-phase-i-ii-study-for-its-lead-gene-therapy-program/
3. Bloomsbury Genetic Therapies announces clinical trial application accepted by U.K. regulatory agency to initiate phase 1/2 gene therapy trial of BGT-OTCD for the treatment of ornithine transcarbamylase deficiency (OTCD). News release. Bloomsbury Genetic Therapies Limited. December 7, 2022. Accessed August 18, 2023. https://bloomsburygtx.com/bloomsbury-genetic-therapies-announces-clinical-trial-application-accepted-by-u-k-regulatory-agency-to-initiate-phase-1-2-gene-therapy-trial-of-bgt-otcd-for-the-treatment-of-ornithine-transcarbamylas/
5. Bloomsbury Genetic Therapies receives rare paediatric disease designation from the U.S. FDA for BGT-DTDS for the treatment of dopamine transporter deficiency syndrome (DTDS). News release. Bloomsbury Genetic Therapies Limited. May 3, 2023. Accessed August 18, 2023. https://bloomsburygtx.com/bloomsbury-receives-rare-paediatric-disease-designation-from-the-u-s-fda-for-bgt-dtds-for-the-treatment-of-dopamine-transporter-deficiency-syndrome-dtds/
6. Bloomsbury genetic therapies completes successful scientific advice meeting with the MHRA regarding its BGT-DTDS program. News release. Bloomsbury Genetic Therapies Limited. April 26, 2023. Accessed August 18, 2023. https://bloomsburygtx.com/bloomsbury-genetic-therapies-completes-successful-scientific-advice-meeting-with-the-mhra-regarding-its-bgt-dtds-program/
7. Pipeline. Bloomsbury Genetic Therapies. Website. Accessed August 18, 2023. https://bloomsburygtx.com/pipeline/
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