AAVance Gene Therapy Trial Data Highlight Importance of Early Dosing

Benefits seen in Sanfilippo type A children given LYS-SAF302 before age 2.5 years

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Children with Sanfilippo syndrome type A who were treated with the investigational gene therapy LYS-SAF302 before 2.5 years of age showed improvements in cognitive development compared to what is expected without treatment, according to top-line data from the Phase 2/3 AAVance clinical trial.

However, the trial did not meet its main goal of demonstrating an effect on older children, according to the therapy’s developer, Lysogene.

“The trial results clearly delineate the patient population that would benefit from treatment with LYS-SAF302,” Karen Pignet-Aiach, founder, chair, and CEO of Lysogene, said in a company press release. “We are very much encouraged by these results and are eager to continue our discussions with the regulatory agencies to take LYS-SAF302 to the next level in younger patients.”

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“Even though AAVance did not meet its primary endpoint, the results in the subset of patients with MPS IIIA [Sanfilippo type A] enrolled before the age of 30 months are extremely encouraging, as they show beneficial effects of treatment on cognitive development and key secondary outcome measures in this devastating childhood disease with no approved disease-modifying therapies,” said Chester Whitley, PhD, MD, a professor at the University of Minnesota and principal investigator of the trial.

“I look forward to continuing to work with Lysogene to analyze the Phase 2/3 data and determine the most appropriate path to bringing gene therapy with LYS-SAF302 to those patients who have the highest potential to benefit from it,” Whitley said.

Sanfilippo type A is caused by mutations in the SGSH gene. LYS-SAF302 uses a viral vector to deliver a healthy version of this gene to the body’s cells, particularly cells in the central nervous system that are most affected by Sanfilippo. The gene therapy is administered via infusions into the brain in a one-time procedure.

The main goal of the AAVance trial (NCT03612869) clinical trial was to assess whether treatment with LYS-SAF302 could slow the decline in developmental quotient (DQ), an age-adjusted measure of overall development. Since this study did not have a placebo group, data from the patients were compared against prior natural history data on the typical progression of untreated Sanfilippo type A.

The positive signs of efficacy observed in very young children enrolled before the age of 30 months indicate that early dosing of LYS-SAF302 gene therapy in children with [Sanfilippo A] might have a real beneficial effect

Results from the main cohort, which included 12 patients dosed with the gene therapy at the age of  30 months (2.5 years) or older, failed to meet the main goal — the decline in DQ was not significantly different from what’s seen in the natural history data. Secondary measures of cognition, language, and motor function also failed to show a benefit from treatment in this group.

“While we are disappointed with the results in the main cohort of the patients enrolled at 30 months or older, these can likely be explained by the rapid progression of the disease and the recent learning from other clinical studies that gene therapy treatment of neurodegenerative diseases should be initiated at the earliest possible age in order to provide a therapeutic benefit before the onset of irreversible neuronal damage,” Pignet-Aiach said.

In the trial’s ancillary cohort, which included six patients treated with LYS-SAF302 before age 30 months, the decline in DQ over two years was significantly slower compared to natural history data. The average rate of decline in natural history was 1.5 percentage points/month, as compared to 1 percentage point/month for patients given the gene therapy — meaning the rate of DQ worsening was slowed by about 27%.

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The younger group of patients also experienced significant improvements in rates of decline for measures of cognition, language, and motor function compared what’s seen in the natural history data.

“The positive signs of efficacy observed in very young children enrolled before the age of 30 months indicate that early dosing of LYS-SAF302 gene therapy in children with [Sanfilippo A] might have a real beneficial effect on these patients and transform their lives,” Pignet-Aiach said.

Among five of the patients who have reached 40 months of age (3 years 4 months), a measure of cognition called cognitive developmental age was 48% higher for patients treated with LYS-SAF302, compared to natural history data from patients of the same age.

“These exciting results, which bolster our confidence in the potential for LYS-SAF302 to become a therapeutic option for children with [Sanfilippo A] younger than 30 months of age, represent a major advance for a disease with such a high unmet medical need,” said Raymond Wang, MD, director of the Foundation of Caring Multidisciplinary Lysosomal Disorder Program at CHOC Children’s Specialists in California.