Increased Motor Development Seen in First 2 Patients With Infantile Krabbe Treated With FBX-101

FBX-101 (Forge Biologics) gene therapy restored galactocerebrosidase (GALC) activity and supported normal white matter development in the first 2 patients with infantile Krabbe disease (IKD) dosed in the phase 1/2 RESKUE clinical trial (NCT04693598). Data from the RESKUE trial were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.

“Given the results of the preclinical studies, we developed a clinical trial to evaluate the effects of FBX-101 given after UCBT, a source of healthy donor GALC with the advantage of decreased antibodies against the transgene since it recognizes GALC as its own,” first author Maria Escolar, MD, chief medical officer, Forge Biologics, and colleagues wrote in their poster. “More importantly, UCBT is naïve to adeno-associated virus (AAV) and is administered during myeloablation, decreasing the overall likelihood of antibody responses and increased biodistribution.”

Data were reported from the first 2 of 3 patients within 12 months of age dosed with low-dose (3.0x10¹³ vg/kg) of FBX-101. These participants were diagnosed through newborn screening based on deficient GALC, genetic mutations predicted of IKD, and increased psychosine. Prior to treatment, both infants were found to have abnormal motor development and neurophysiologic findings and were phenotypically asymptomatic.

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The first participant received umbilical cord blood transplantation (UCBT) and then FBX-101 treatment 24 days later. They achieved absolute neutrophil count (ANC) engraftment 16 days later and full donor chimerism in peripheral blood. The second participant required a second UCBT after losing the initial graft after COVID-19 infection. They were treated with FBX101 29 days later and achieved ANC engraftment 13 days later with full donor chimerism in peripheral blood.

FBX-101 was well-tolerated in both participants, neither of which experienced infusion reactions or treatment-related serious adverse events through 6 (participant 2) and 12 months (participant 1) of follow up. Investigators also found that liver function tests, liver ultrasounds, and nerve conduction velocity tests remained normal through follow-up.

Efficacy signals included the absence of anti-AAVrh10 antibodies, GALC levels 174-fold above normal controls in plasma, and 3-to-10 fold above normal in cerebrospinal fluid (CSF). MRI-diffusion tensor imaging revealed mean fractional anistropy values in the higher range of asymptomatic patients after UCBT and both participants so far have gross motor development above patients historically only treated with UCBT or in line with the normal range of development.

“FBX-101 shows an excellent safety profile...[and] significantly increases GALC enzyme activity in plasma and CSF to levels above controls for the duration of the subjects’ follow-up,” Escolar and colleagues wrote. “FBX-101 supports normal white matter development as measured by brain MRI-DTI during a period of rapid myelination that resulted in improved gross motor function.”

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REFERENCE

Escolar ML, Vander Lugt M, Poe M, et al. First-in-human phase 1/2 trial of intravenous FBX-101 following hematopoietic stem cell transplantation increases GALC activity, supports brain development, and improves motor function in patients with infantile Krabbe disease: RESKUE clinical trial. Presented at: WORLDSymposium 2023, February 22-26; Orlando, Florida. Abstract #108.