Orchard Therapeutics announced multiple clinical and preclinical updates from its portfolio of investigational hematopoietic stem cell (HSC) gene therapies in neurometabolic and neurodegenerative disorders. The data are being featured in several oral presentations at the ongoing 26th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Los Angeles. OTL-203 (MPS-IH) Skeletal Data Summary: The oral presentation showcased new skeletal data for all eight proof-of-concept trial patients with a median follow-up of 3.78 years, ranging from 3.14 to 4.58 years, compared to a median of two years reported in the November 2021New England Journal of Medicine publication.

As previously reported, all eight participants achieved the primary endpoint of supraphysiologic blood alpha-L-iduronidase (IDUA) activity. Growth velocity, cognition and motor function post-treatment were collected as secondary and exploratory endpoints. At baseline, most patients presented with severe joint range of motion impairment, severe acetabular (hip) dysplasia and varying degrees of dorso-lumbar kyphosis.

Treatment with OTL-203 was generally well tolerated and demonstrated extensive metabolic correction over four years after treatment. All patients showed sustained engraftment of gene-corrected cells with blood IDUA activity reaching supraphysiologic levels after treatment and normal or near-normal substrate levels maintained at last follow-up. Persistent IDUA activity and substrate reduction in the cerebrospinal fluid were also seen as of last follow-up, and all patients were able to remain off treatment with enzyme replacement therapy.

In addition: All patients exhibited longitudinal growth within expected reference ranges of healthy children according to age and gender, with a median height gain greater than that observed in an external cohort of HSCT patients at three years of follow-up; A clinically measurable reduction in both sitting and standing kyphosis was observed in the majority of patients. MRI spine score showed a general stabilization in all patients with no relevant signs of progression in dorso-lumbar kyphosis, vertebrae deformity and dens alterations; All patients progressively acquired fine and gross motor skills; Improvements in joint range of motion were seen compared to pre-treatment in shoulder flexion, shoulder abduction and hip and knee extension angles as compared with an external cohort of HSCT patients. The current standard of care for MPS-IH is allogeneic hematopoietic stem cell transplant (HSCT), which does not adequately address the growth and skeletal manifestations of the disease, among other clinical outcomes.

Orchard plans to initiate a global 40 patient, registrational, randomized controlled trial compared to standard of care in the second half of 2023.