Gene Therapies for Sanfilippo Type A, B Show Promise in Early Trials

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A single dose of Abeona Therapeutics’ investigational gene therapy ABO-102 safely preserved normal cognitive development for up to three years in young children with Sanfilippo syndrome type A, according to updated data from the Phase 1/2 Transpher A trial.

In addition, treatment resulted in sustained and significant reductions in disease biomarkers up to two years after treatment. Similar drops were also seen in Sanfilippo type B patients receiving ABO-101, the company’s experimental gene therapy for type B disease, in the Phase 1/2 Transpher B trial.

These findings, supporting the potential benefits of both gene therapies, were shared in two oral presentations at the WORLDSymposium 2021, held virtually Feb. 8–12.

“We are excited to share updated positive efficacy and safety results that continue to suggest ABO-102 has the potential to be a life-altering treatment option for children with MPS IIIA [Sanfilippo type A], a rare, debilitating condition with no approved treatment,” Michael Amoroso, Abeona’s president and CEO, said in a press release.

The company has requested a meeting with the U.S. Food and Drug Administration to “discuss the ABO-102 data and the potential path towards a Biologics License Application filing for ABO-102,” Amoroso added.

“In addition, the new results from the Transpher B study continue to support ABO-101’s biologic activity in patients with MPS IIIB [Sanfilippo type B],” he said.

Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is caused by the absence or reduced activity of one of four enzymes involved in the breakdown of a complex sugar molecule called heparan sulfate, leading to its toxic accumulation inside cells.

Given that nerve cells are particularly sensitive to heparan sulfate buildup, Sanfilippo is characterized by progressive and severe neurodegeneration.

Type A, the most common and severe form, is caused by a deficiency in the heparan N-sulfatase enzyme, due to mutations in the SGSH gene. Type B is caused by low or no activity of the alpha-N-acetylglucosaminidase enzyme due to mutations in the NAGLU gene.

By delivering a healthy copy of the mutated gene to cells, gene therapy has the potential to halt or reduce neurodegeneration in this patient population.

ABO-102 was designed to provide a working copy of the SGSH gene to cells, and ABO-101 of the NAGLU gene. Both therapies use a modified and harmless version of the adeno-associated virus 9 (AAV9) that can reach the central nervous system (CNS, comprising the brain and spinal cord) and peripheral organs.

The therapies are given through a single infusion directly into the bloodstream.

In an oral presentation, “Updated results of Transpher A, a multicenter, single-dose, phase 1/2 clinical trial of ABO-102 gene therapy for Sanfilippo syndrome type A (MPS IIIA),” Kevin Flanigan, MD, the trial’s principal investigator, shared up to 4.5 years of data from the Transpher A trial (NCT02716246).

The international study is evaluating the safety and effectiveness of three doses of ABO-102 — 5×1012, 1×1013, and 3×1013 vector genomes (vg)/kg — in up to 22 infants and children with Sanfilippo type A.

Results from the first 19 treated patients (three in the low- and medium-dose group each, and 13 in the high-dose group) showed that the highest dose resulted in the preservation of normal cognitive development for up to three years in three young patients.

These children received a single dose of ABO-102 at 12, 19, and 27 months of age, and are now between 3.5 and more than 5 years old — a time at which Sanfilippo type A patients start to show cognitive decline, according to natural history data of disease progression.

Patients also showed dose-dependent and statistically significant reductions in several disease biomarkers, such as heparan sulfate and liver volume, for up to two years after treatment.

Transpher A’s results show that a single dose of ABO-102 “can help preserve neurocognitive development for up to 3 years following treatment in young MPS IIIA patients during early stages of their disease,” said Flanigan, who is director of the Center for Gene Therapy at the Nationwide Children’s Hospital, in Ohio.

“The data shows ABO-102’s ability to deliver a functional copy of the disease-causing SGSH gene to cells of the CNS and peripheral organs, as evidenced by the clinical benefits in neurocognition and biophysical measures and improvements in disease-specific biomarkers,” Flanigan added.

A second presentation, titled “Updated Results of Transpher B, a Multicenter, Single-Dose, Phase 1/2 Clinical Trial of ABO-101 Gene Therapy for Sanfilippo Syndrome Type B (Mucopolysaccharidosis IIIB),” was presented by Maria Jose de Castro, MD, study investigator at the Hospital Clínico Universitario Santiago de Compostela, in Spain.

The two-year, international Transpher B study (NCT03315182) is assessing the safety and effectiveness of three doses of ABO-101 — 2×1013, 5×1013, and 1×1014 vg/kg — in up to 15 Sanfilippo type B infants and children. The trial is still recruiting participants.

By this past January, 11 patients had received the therapy (two given the low dose, five the medium dose, and four the high dose) and had been followed for at least seven months (the high-dose group) and up to 2.5 years.

Results showed that ABO-101 was associated with dose-dependent and sustained drops in several disease biomarkers in the CNS and peripheral tissues, highlighting its biological effects.

“The results from the Transpher B study provide evidence of ABO-101’s impact on disease biomarkers and potential to break down the accumulation of [complex sugar molecules] that underlie MPS IIIB,” de Castro said.

Cognitive evaluation will require a longer follow-up in children in the medium- and high-dose groups, de Castro noted in her presentation.

“We look forward to continued follow-up to assess ABO-101’s potential to preserve neurocognitive development in patients with MPS IIIB,” she added.

Both therapies were generally well-tolerated, with no deaths, infusion-related adverse events, or clinically significant adverse events. Most adverse events were mild to moderate and easily resolved.