Orchard Therapeutics’ Gene Therapy OTL-203 Stabilizes or Improves Sensory Symptoms in Patients With MPS-IH


Hearing function was found to be normal for 4 of the patients (50%) at their most recent follow-up.

Orchard Therapeutics’ OTL-203, an investigational hematopoietic stem cell (HSC) gene therapy intended to treat the Hurler subtype of mucopolysaccharidosis type I (MPS-IH), has stabilized or improved some ocular and auditory symptoms among patients treated in a proof-of-concept study between July 2018 and December 2019.1 The new results, which build upon safety data previously reported, were announced at the 30th Annual Congress of the European Society of Gene & Cell Therapy (ESGCT), held October 24-27 in Brussels, Belgium.

Among 8 patients who were treated with the gene therapy in the study, 5 patients (62.5%) showed an improvement in corneal clouding and 3 patients (37.5%) showed stabilization in corneal clouding. These findings are from the most recent follow-up for each patient, which ranges from 3.14 to 4.58 years posttreatment, and were assessed in comparison to baseline measurements. Furthermore, Orchard noted that photophobia and the other ophthalmological symptoms typically associated with the disease were absent from the patients after treatment with the gene therapy.

Hearing function was found to be normal for 4 of the patients (50%) at their most recent follow-up. Furthermore, after being treated with the gene therapy, none of the 8 patients have experienced severe hearing loss and none of the patients have needed any hearing loss intervention or use of hearing aids.

In light of the promising results seen so far, the company is planning to conduct a global registrational trial for OTL-203 that will seek to enroll 40 patients with MPS-IH in total. The randomized study, which will compare OTL-203 against standard-of-care treatment with allogeneic HSC transplant, is anticipated to begin enrollment activities at its first site before the end of 2023. Eventually, the study is expected to be active at 6 locations in the United States and Europe. Orchard received clearance of an investigational new drug application for this study from the FDA in January 2023.2

“These positive data presented at ESGCT add to the growing body of evidence underscoring the potential of a one-time HSC gene therapy to correct a range of disease manifestations not effectively addressed by the current standard of care,” Leslie Meltzer, PhD, the chief medical officer of Orchard Therapeutics, said in a statement. “The complications associated with MPS-IH involve multiple organ systems and have an adverse impact on patients’ quality of life. We continue to be encouraged by these results from our proof-of-concept study and look forward to initiating our global registrational trial later this year.”

OTL-203 consists of patients’ own CD34+ HSCs which have been modified ex vivo with a lentiviral vector that encodes IDUA, the disease-targeted gene.2,3 Efficacy and safety results from the non-randomized, single-center, proof-of-concept study, which treated patients exclusively at Ospedale San Raffaele in Milan, Italy, were previously reported in the New England Journal of Medicine (NEJM).3 According to a November 2021 press release summarizing the results of the study, at the most recent follow-up at that time, all participants demonstrated stable cognitive development, progressive acquisition of motor skills over time, progression along expected growth percentiles of healthy children, and longitudinal growth considered within the range of normal. In terms of safety, OTL-203 was generally well-tolerated with an overall survival rate of 100% at last available follow-up, and there were no cases of graft-versus-host disease.

“MPS-IH places an enormous burden on affected children, their families, and society,” Maria Ester Bernardo, PhD, the head of the pediatric bone marrow transplantation unit at San Raffaele Hospital in Milan and a senior author of the NEJM manuscript, said in a November 2021 statement.3 “Current treatment options are associated with significant limitations and do not adequately address some of the more severe manifestations of disease. Based on these preliminary first-in-human data, administration of a one-time HSC gene therapy designed to overexpress IDUA represents a potential step forward in the treatment landscape.”

1. Orchard Therapeutics Announces Presentation of Additional Positive Data from Proof-of-concept Study of OTL-203 in MPS-IH at ESGCT 2023. News release. Orchard Therapeutics. October 26, 2023. Accessed November 2, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-presentation-additional-positive
2. Orchard Therapeutics announces U.S. FDA clearance of IND application for OTL-203 in MPS-IH. News release. Orchard Therapeutics. January 5, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-us-fda-clearance-ind-application
3. Orchard Therapeutics announces New England Journal of Medicine publication of interim proof-of-concept study results of OTL-203 for Hurler syndrome. News release. Orchard Therapeutics. November 18, 2021. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-new-england-journal-medicine-0
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