OTL-201 gene therapy leads to cognitive gains in Phase 1/2 trial

'These early results are very encouraging — but there’s still a long way to go'

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Four out of the five children with Sanfilippo syndrome type A in a Phase 1/2 clinical trial have continued to gain cognitive skills — which in three were similar to healthy children — after being given OTL-201, an experimental gene therapy being developed by Orchard Therapeutics.

The children were 6-24 months when they were treated and have been followed up for a median of two years, ranging from nine to 30 months. Researchers are cautious about the findings, however, as most children aren’t yet 4-5 years old, which is when the disease usually begins to worsen more rapidly. Follow-up will continue for up to 36 months (three years), with more data becoming available in future reports.

“We have been hopeful this therapy will be transformative for patients — and these early results are very encouraging — but there’s still a long way to go,” Brian Bigger, PhD, chair in cell and gene therapy at the University of Manchester, who carried out the preclinical work and is principal investigator on the trial, said in a university press release.

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Stem Cell Gene Therapy Improves Signs of Sanfilippo A: Trial Data

OTL-201 uses modified lentivirus to insert working SGSH copy into stem cells

People with Sanfilippo type A, also known as mucopolysaccharidosis type IIIA (MPSIIIA), carry mutations in the SGSH gene. SGSH codes for an enzyme called sulfamidase that helps break down a large sugar molecule called heparan sulfate.

Without the enzyme, heparan sulfate cannot be broken down and will build up in the body, leading to a range of symptoms. The symptoms typically appear in early childhood and worsen over time.

The build-up of heparan sulfate mainly causes damage to cells in the brain and spinal cord. As a result, symptoms often include delays in development, challenges in behavior, and impaired cognition.

OTL-201 works by harvesting a patient’s own blood stem cells and using a modified virus called a lentivirus to insert a working version of SGSH into the cells. The engineered stem cells are returned back to the patient where they can start producing the missing enzyme.

Blood stem cells can develop into many different blood cells. Once the cells reach and engraft into the bone marrow, they begin to grow and produce blood cells of all types. Some of these cells, called monocytes, are able to travel to the brain where they are expected to have a therapeutic effect.

The trial (NCT04201405), funded by Orchard and sponsored by the University of Manchester, is ongoing at the Manchester University NHS Foundation Trust in the U.K.

Its primary goal is to evaluate how safe and well-tolerated OTL-201 is and how well it works to increase the amount of sulfamidase being produced by blood cells.

While these early results are encouraging, longer follow up is needed, as the majority of the patients in this trial have not reached the age where the most severe stages of disease progression typically manifest.

Initial data from the first child dosed in the trial revealed an increase in sulfamidase and a decrease in heparan sulfate three months after treatment.

“These are encouraging results for children living with MPS-IIIA and their families, who currently have no effective treatment options,” said Robert Wynn, MD, principal investigator on the trial at The Royal Manchester Children’s Hospital, part of the Manchester University NHS Foundation Trust.

Secondary goals include changes on neurocognitive test scores. One of the children who received OTL-201 did better on the neurocognitive tests than would if the disease had been allowed to develop on its own without any therapy. This improvement was seen at the 18-month mark following therapy.

Three more children who received OTL-201 have shown normal cognitive development at the 9- and 18-month mark following treatment. This means that they are developing as expected for their age. Data from the longer follow-up are awaited.

“The early neurocognitive findings show most patients are gaining skills in line with the development of healthy children,” Wynn said. “In one patient, we also have seen a marked improvement from disease natural history, and we hope to see similar results in the other patients with longer follow-up.”

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No serious side effects related to the therapy were reported

After a median of two years, OTL-201 was generally tolerated well, and no serious side effects occurred related to the gene therapy.

The stem cells remained in the bone marrow for an extended period and resulted in an increase in sulfamidase to levels higher than those normally found in the blood and cerebrospinal fluid (the fluid that cushions the brain and spinal cord) of healthy children.

“While these early results are encouraging, longer follow up is needed, as the majority of the patients in this trial have not reached the age where the most severe stages of disease progression typically manifest,” said Leslie Meltzer, PhD, Orchard’s chief medical officer.

“We are working with our collaborators at The University of Manchester and Royal Manchester Children’s Hospital to continue following patients in this ongoing study and more fully characterize the clinical and safety profile of OTL-201,” Meltzer added.