Rare Daily Staff

Orchard Therapeutics said initial results from a clinical trial of a frozen formulation of OTL-200 suggests its as effective as a fresh formulation of its experimental gene therapy in development for the treatment of metachromatic leukodystrophy, a rare and life-threatening metabolic disorder.

Metachromatic leukodystrophy (MLD) is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, the gallbladder, kidneys, and spleen. Over time, the nervous system is damaged and patients with MLD will experience neurological problems such as motor, behavioral, and cognitive regression, and severe spasticity and seizures, finding it more and more difficult to move, talk, swallow, eat and see. In its most severe forms, patients will not survive beyond their first decade of life. Currently, there are no effective treatments for MLD.

OTL-200 is an ex vivo, autologous, hematopoietic stem cell-based gene therapy being studied for the treatment of MLD. Orchard acquired OTL-200 from GlaxoSmithKline in April 2018, and it originated from a pioneering collaboration between GSK and the San Raffaele-Telethon Institute for Gene Therapy in Milan.

The initial data show that cellular engraftment with OTL-200 using a frozen formulation is similar to that observed using a fresh formulation with the longest patient having 12 months of follow-up since treatment. The data are featured in a poster session at the European Society of Gene & Cell Therapy Annual Congress in Barcelona, Spain.

These data compare the initial results of OTL-200 in the first four MLD patients treated using a frozen formulation to a previously presented integrated analysis of 29 patients treated with a fresh formulation that demonstrated meaningful clinical outcomes.

Hematopoietic stem cells are collected, purified and transduced in the same way for both formulations. For the cryopreserved formulation, following transduction, the gene-corrected cells are placed in a specific medium that allows them to be stably frozen. After successful testing and release, the cryopreserved cells are shipped to the site of care where they are thawed and administered to patients who have received conditioning.

“If approved, a cryopreserved formulation of OTL-200 would more readily facilitate global commercialization and patient access efforts, which are key elements in our mission to deliver potentially curative therapies to patients suffering from often-deadly rare diseases,” said Mark Rothera, president and chief executive officer of Orchard. “With over 40 patients now treated using a cryopreserved formulation across our pipeline of six clinical-stage programs, we are confident our approach is supported by a robust set of evidence.”

At the time of the analysis, four early-onset MLD patients (two late infantile and two early juvenile) have been treated with the cryopreserved formulation of OTL-200. All patients are alive and were followed for a minimum of one month, with the longest follow-up out to 12 months in the first patient treated. The age at the time of treatment ranged from seven months to 42 months.

The initial results in four patients receiving the frozen formulation demonstrated stable levels of engraftment of gene-corrected cells were within the range observed in patients treated with the fresh formulation. Engraftment of gene-corrected cells in all patients receiving the cryopreserved formulation was seen one month after treatment and remained stable throughout the length of follow-up for each patient.

Reconstitution of arylsulfatase-A enzyme activity in the peripheral blood and cerebrospinal fluid to normal or supra-normal levels is consistent with results seen in patients treated with the fresh formulation at the same timepoints.

The emerging safety profile of the frozen formulation is consistent with the safety profile observed in the fresh formulation. No treatment related adverse events or signs of oncogenic transformation have been reported in the patients receiving the cryopreserved formulation as of the date of the analysis.

Preliminary evidence also suggests that the first patient treated with the cryopreserved formulation has acquired motor capabilities consistent with the physiologically progressive acquisition of new motor skills observed in healthy children. At the time of the 12-month assessment, the patient had surpassed the expected age of disease onset based on an older untreated sibling, while attaining age-appropriate motor development.            

Orchard said it remains on track to submit a marketing authorization application in Europe for MLD in the first half of 2020, as well as a biologics licensing application in the United States approximately one year later.

Photo: Mark Rothera, president and chief executive officer of Orchard

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