Orchard Therapeutics Announces Additional Positive Data from Proof-of-Concept Study of OTL-203 in MPS-IH

Orchard Therapeutics recently announced a range of interim clinical outcomes, in addition to the previously reported neurological and skeletal results, from the company’s ongoing proof-of-concept (PoC) study of OTL-203, a hematopoietic stem cell (HSC) gene therapy in development for the treatment of the Hurler subtype of mucopolysaccharidosis type I (MPS-IH). The data were presented at the European Society of Gene and Cell Therapy (ESGCT) 30th Annual Congress in Brussels.

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 approximately 1 in 100,000 live births. Approximately 60% 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 (ERT), neither of which effectively address the broad range of clinical manifestations of the disease.

“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,” said Leslie Meltzer, PhD, Chief Medical Officer of Orchard Therapeutics. “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.”

In the single-center PoC 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.

At ESGCT, Dr. Maria Ester Bernardo, Clinical Coordinator, Pediatric Clinical Research Unit at San Raffaele Telethon-Institute for Gene Therapy (SR-TIGET) and the principal investigator of the PoC study, detailed the first findings on other treatment outcomes, including ocular (eye), and auditory (hearing) function. Results showed:

• Treatment with OTL-203 resulted in improvement (62.5% of patients; n=5/8) or stabilization (37.5% of patients; n=3/8) of corneal clouding at the time of last follow-up (ranging from 3.14-4.58 years) compared to baseline measured prior to administration with OTL-203.
  (Importantly, following treatment with OTL-203, no patients reported photophobia (light sensitivity), or any other ophthalmological symptoms typically associated with MPS-IH).
• At last follow-up, 50.0% of patients (n=4/8) showed normal hearing function, and none developed severe hearing loss. In addition, no treated patients have required a hearing aid or any intervention for hearing loss following administration with OTL-203 as of last follow-up.
• Follow-up to fully assess and characterize the potential impact of HSC gene therapy on ocular and auditory manifestations of MPS-IH is ongoing.

Summary of Previously Reported Safety Results

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

Global Registrational Trial Expected to Commence by Year-End

Following the promising results observed in the proof-of-concept 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 treatment, treatment failure, immunological complications, as well as severe cognitive and 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 US and Europe, the first of which is planned to open enrollment later this year.

Mucopolysaccharidosis type I (MPS-I) is a rare, inherited neurometabolic disease caused by a deficiency of the alpha-L-iduronidase (IDUA) lysosomal enzyme, which is required to break down sugar molecules called glycosaminoglycans (GAGs). The accumulation of GAGs across multiple organ systems results in multiple symptomatic manifestations of the disease including severe neurocognitive impairment, skeletal deformities, cardiovascular and pulmonary complications, impaired motor function, loss of hearing and corneal clouding. MPS-I occurs at an overall estimated frequency of one in every 100,000 live births. There are three subtypes of MPS-I. Approximately 60% of children born with MPS-I have the most severe subtype, called Hurler syndrome (MPS-IH), and rarely live past the age of 10 when untreated.

Treatment options for MPS-I include hematopoietic stem cell transplant and chronic enzyme replacement therapy, both of which have limitations, such as inadequate impact on some of the more severe manifestations of disease, as well as significant morbidity and mortality. At present, Newborn Screening (NBS) for MPS-I has been established in multiple geographies, including the US and Europe.

OTL-203 is an investigational hematopoietic stem cell gene therapy being developed for the treatment of MPS-IH. It 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 received rare pediatric disease and priority medicines (PRIME) designations from the FDA and European Medicines Agency, respectively.

At Orchard Therapeutics, our vision is to end the devastation caused by genetic and other severe diseases. We aim to do this by discovering, developing and commercializing new treatments that tap into the curative potential of hematopoietic stem cell (HSC) gene therapy. In this approach, a patient’s own blood stem cells are genetically modified outside of the body and then reinserted, with the goal of correcting the underlying cause of disease in a single treatment.

In 2018, the company acquired GSK’s rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Today, Orchard is advancing a pipeline spanning pre-clinical, clinical and commercial stage HSC gene therapies designed to address serious diseases where the burden is immense for patients, families and society and current treatment options are limited or do not exist. For more information, visit www.orchard-tx.com.