A five-year-old girl with Mucopolysaccharidosis Type IIIA (MPS IIIA) has died in the Phase II/III AAVance clinical trial (NCT03612869), designed to evaluate the efficacy of Lysogene’s gene therapy candidate LYS-SAF302 in improving or stabilizing the neurodevelopmental state of MPS IIIA patients, the company has acknowledged.

In a statement, Lysogene said the immediate cause of death was unknown, that additional information was being collected, and that no evidence had surfaced linking the death to the administration of LYS-SAF302.

“Lysogene is profoundly saddened by the passing of this child and extends its deepest sympathies to the family. The company remains committed to the LYS-SAF302 development program and the Sanfilippo patient community,” the company said October 15 in a statement.

The company added that per study protocol, it was “diligently” following the 18 other patients who have been treated in the AAVance trial, conducted at eight clinical sites.

The girl died at home several months after receiving the therapy, which Lysogene told French news agency AFP consisted of a single injection administered at one of the four U.S. clinical sites.

Lysogene shares have tumbled 21% since news of the death became public, falling to €1.99 ($2.36) at the close of trading Friday, from €2.53 ($3.00) the day before the announcement.

Earlier clinical hold

The FDA on June 5 issued a clinical hold for the trial following observations in some patients of localized findings on MRI images at the intracerebral injection sites, suggesting a potential connection to delivery, Lysogene disclosed. But the company added that “no clinical symptoms have been observed that could be directly attributed to the observed MRI findings.”

LYS-SAF302 is an adeno-associated virus (AAV)-mediated gene therapy for MPS IIIA, also called Sanfilippo syndrome type A, that is designed to work by replacing the faulty SGSH (N-sulfoglucosamine sulfohydrolase) gene with a healthy copy of the gene. SGSH is involved in producing an enzyme necessary for the breakdown and disposal of long chain sugar molecules. MPS III is caused by mutations in the SGSH gene, which encodes Heparan-N-sulfamidase for heparan sulfate (HS) recycling in cells.

LAF-SAF302 is intended to deliver a functional copy of the SGSH gene and allow the brain to secrete the missing enzyme. LYS-SAF302 employs the AAVrh10 virus, chosen for its ability to target the CNS.

The trial is designed to show improved or stabilized neurodevelopmental status of MPS IIIA patients.

Trial to enroll up to 20 patients

LAF-SAF302 is intended to deliver a functional copy of the SGSH gene and allow the brain to secrete the missing enzyme. The goal of the trial is to show improved or stabilized neurodevelopmental status of MPS IIIA patients. The trial was designed to enroll up to 20 patients at eight sites in the United States and Europe.

Lysogene granted Sarepta Therapeutics exclusive commercial rights to LYS-SAF302 in the United States and other markets outside Europe in 2018. Sarepta agreed to pay Lysogene $15 million at the close of their licensing agreement, up to approximately $125 million in development, regulatory, and commercial milestone payments, plus sales-based royalties. Sarepta also made an equity investment in Lysogene of $2.5 million under the licensing agreement, which included Lysogene granting to Sarepta option rights to an additional CNS-targeted gene therapy candidate.

Lysogene’s patient death occurred months after the deaths of three patients in the Phase I/II ASPIRO trial (NCT03199469), in which Audentes Therapeutics, an Astellas company, was evaluating its gene therapy candidate AT132 in patients with X-linked Myotubular Myopathy (XLMTM). All three were treated with the trial’s high dose of 3×1014 GC/kg, and began to demonstrate signs of liver dysfunction within 3 to 4 weeks after dosing. The AT132 program remained on clinical hold as of October 16.

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