MPS Type IIIA Gene Therapy Trial Fails Primary Endpoint


Statistically significant improvements in cognitive development were only seen in the cohort of patients younger than 30 months.

Data from the phase 2/3 AAVance clinical trial (NCT03612869) of Lysogene’s LYS-SAF302, an investigational gene therapy intended for the treatment of mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome type A), demonstrated promising efficacy for patients enrolled under the age of 30 months, but failed to meet its primary and key secondary efficacy end points for older patients.

LYS-SAF302 consists of a functional copy of SGSH, the disease-targeted gene, delivered via AAVrh.10, an adeno-associated virus carrier directed at central nervous system cells. It is intended as a 1-time treatment and is administered at 6 intracerebral sites. LYS-SAF302 was previously granted fast track, rare pediatric disease, and orphan drug designations by the FDA and orphan medicinal product designation by the European Medicines Agency. Lysogene had previously granted Sarepta development and commercialization rights for LYS-SAF302 in the United States and other non-European Union territories and responsibility for global commercial supply of the gene therapy product, but this agreement was terminated effective July 11, 2022.2

Among the 12 patients in the trial’s main cohort, who were enrolled at 30 months of age or older, no statistically significant improvement in cognitive developmental quotient (DQ) at 24 months after treatment compared to patients in a natural history (NH) cohort was observed. In addition, there was no improvement observed in the main cohort compared to patients in the NH cohort with regard to percent of patients with stabilized or improved cognitive developmental age (DA), language DA, and motor DA at 24 months relative to baseline, nor was change observed in VABS-II standard scores.

However, for the study’s ancillary cohort, which included 6 patients enrolled at younger than 30 months of age, the mean rate of decline in DQ over 24 months (-1.0 ± 0.5 percentage points/month, mean ± SD, range -1.4 to -0.3) was 27% lower than for age-matched patients in the NH cohort (-1.5 ± 0.3 percentage points/month, mean ± SD, n=6; range -1.8 to -1.0), (P = 0.037). Furthermore, among the 5 patients in the ancillary cohort who are now aged at least 40 ± 3 months, the average cognitive DA at this age (30.2 ± 8.4, mean ± SD, n=5; range 19 to 41) was 48% higher than in age-matched patients from the NH cohort (20.4 ± 6.7, mean ± SD, n=13; range 5 to 27) (P = 0.019). Patients in the ancillary cohort additionally demonstrated at least 80% stabilization or improvement in cognitive DA, language DA, and motor DA, which were key secondary end points for the trial, and from baseline to 24 months after treatment showed no statistically significant reduction in mean VABS-II standard scores for total adaptive behavior, communication, daily living skills, socialization, and motor skills. From baseline to 24 months after administration, there was also no statistically significant reduction observed in mean cortical gray matter volume, a factor associated with cognitive decline that is typically known to decrease in patients with MPS IIIA. Lysogene expects that data analysis for this cohort will be completed in the first half of next year when all 6 of the children have reached the age of at least 48 months.

“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,” Karen Aiach, founder, chairman, and chief executive officer, Lysogene, said in a statement.1 “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 MPS IIIA might have a real beneficial effect on these patients and transform their lives. The trial results clearly delineate the patient population that would benefit from treatment with LYS-SAF302. 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.”

In terms of safety, adverse events observed in the study were noted to be consistent with the natural history of MPS IIIA. However, for all participants treated in the study, MRI data also showed white matter abnormalities near injection sites. In most of the patients, these lesions have either stabilized or decreased in size. There were no clinically significant symptoms observed that were directly attributable to the abnormalities. 

The single-arm, multi-center, open-label AAVance trial enrolled 19 children 6 months and older with a documented MPS IIIA diagnosis, based on confirmed mutations in the SGSH gene, and a cognitive DQ score on the BSID-III of 50% or above. Patients who had participated in another gene therapy or cell therapy clinical trial; patients who had previously used SGSH enzyme replacement therapy for more than 3 months; patients with a history of bleeding disorders and patients with a risk of bleeding following surgery; patients with any condition that would contraindicate treatment with relevant immunosuppressants; and patients who are homozygous for the S298P mutation or non-classical severe form of MPS IIIA, based on investigator's judgement, were excluded from the study. Running alongside AAVance is the app-based PROVide study, which is collecting video of patients in their home environments to further provide information on the treatment’s effect on children’s development.3

“Even though AAVance did not meet its primary endpoint, the results in the subset of patients with MPS IIIA 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”, Chester B. Whitley, professor at the Department of Pediatrics and Experimental and Clinical Pharmacology, University of Minnesota, and principal investigator, Lysosomal Disease Network, Minneapolis, MN, USA, added to the statement.1 “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.”

1. Lysogene provides updates and topline results from phase 2/3 AAVance gene therapy clinical study. News release. Lysogene. November 18, 2022. 
2. Lysogene announces termination of license agreement with Sarepta for LYS-SAF302 program, regaining global commercial rights. News release. Lysogene. January 13, 2022.
3. LYS-SAF302 clinical trial. Website. Lysogene. July 7, 2022. 
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