RARE Daily

FDA Grants Fast Track Designation to Orchard for OTL-203 in Hurler Syndrome

December 1, 2023

Rare Daily Staff

The U.S. Food and Drug Administration has granted Fast Track designation to Orchard Therapeutics’ investigational hematopoietic stem cell gene therapy OTL-203 for the treatment of the Hurler subtype of mucopolysaccharidosis type I.

Fast Track designation is intended to expedite the development of promising medicines that address serious medical needs. Therapeutic candidates that receive Fast Track designation may be eligible for enhanced interactions with the FDA, including potentially quicker submission and review timelines.

MPS-I is a rare, inherited neurometabolic disease caused by a deficiency of the alpha-L-iduronidase (IDUA) lysosomal enzyme resulting in the accumulation of glycosaminoglycans (GAGs) in multiple organs, including the eyes, ears, heart, as well as the musculoskeletal and central nervous systems. It is estimated to occur globally in 1 in 100,000 live births. Approximately 60 percent of children born with MPS-I have the most severe subtype, MPS-IH, also called Hurler syndrome, and rarely live past the age of 10 when untreated. Current treatment options for MPS-IH include allogeneic hematopoietic stem cell transplant (HSCT) and chronic enzyme replacement therapy, both of which have significant limitations.

OTL-203 uses a modified virus to insert a functional copy of the IDUA gene into a patient’s cells. OTL-203 is being developed in partnership with the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. OTL-203 has previously received Rare Pediatric Disease designation from the FDA and Priority Medicines (PRIME) designation from the European Medicines Agency.

“We are encouraged that OTL-203 has been granted Fast Track designation because new treatment options are urgently needed for children with MPS-IH, as the current standard of care is associated with significant morbidity and mortality,” said Leslie Meltzer, chief medical officer at Orchard.

In an ongoing single-center proof-of-concept study, eight patients diagnosed with MPS-IH were treated at Ospedale San Raffaele in Milan, Italy with investigational OTL-203 between July 2018 and December 2019. Interim results published in The New England Journal of Medicine showed all patients had stable cognitive performance post-treatment. In addition, all participants had progressed along expected growth percentiles of healthy children and exhibited longitudinal growth that was considered within the normal range adjusted for age and gender. In subsequent follow-up, study investigators have observed continued cognitive development and evidence of continued growth within normal range and improvements in skeletal health with a median follow-up of 3.78 years (range: 3.14 to 4.58 years) as of May 2023.

Throughout the proof-of-concept study, treatment with OTL-203 has been generally well-tolerated with a safety profile consistent with the selected conditioning regimen. The viral vector integration profile was consistent with other lentiviral-based HSC gene therapy studies, and all participants had a stable and highly polyclonal repertoire. Anti-alpha-L-iduronidase (IDUA) antibodies present prior to gene therapy as a result of enzyme replacement therapy were not seen in any patient within two months following treatment. In addition, enzyme replacement therapy was discontinued at least three weeks prior to any patient receiving gene therapy treatment, and no patients have re-started enzyme replacement therapy post-treatment.

Following the promising results observed in the PoC study, Orchard Therapeutics is initiating a multi-center, randomized, active controlled clinical trial designed to evaluate the efficacy and safety of OTL-203 in patients with MPS-IH compared to standard of care with allogeneic HSCT. A total of 40 patients with a confirmed diagnosis of MPS-IH who meet the study inclusion criteria will be randomized 1:1 to receive either OTL-203 or allogeneic HSCT. The study is powered to demonstrate superiority of OTL-203 over HSCT.

The primary endpoint, which will be measured at two years post-treatment, comprises a composite of clinically meaningful outcomes, including death, the need for rescue transplant, treatment failure, immunological complications, as well as severe cognitive and/or growth impairment. Secondary endpoints include biochemical markers, additional clinical assessments, as well as safety and tolerability. The company expects to activate up to six sites in the United States and Europe.

Photo: Leslie Meltzer, chief medical officer at Orchard

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