First In-Human Trial to Assess Krabbe Disease Gene Therapy


Passage Bio presented data on both the Krabbe and GM1 gangliosidosis programs at WORLDSymposium.

A first in-human, phase 1/2 study (NCT04771416) is evaluating intracisternal magna (ICM) administration of PBKR03 (Passage Bio), an investigational gene therapy in children with early infantile Krabbe disease (globoid cell leukodystrophy).1

The trial design was presented at the 18th Annual WORLDSymposium, February 7-11, 2022, in San Diego, California, by Eric J. Mallack, MD, assistant professor of pediatrics and neurology, and director, leukodystrophy center, Weill Cornell Medical College.

“PBKR03 is an investigational gene therapy developed by Dr. Wilson at the University of Pennsylvania. It carries a functional GALC gene... It is designed to transduce both CNS and PNS to generate functional GALC to break down and restore normal myelin metabolism and to cross correct neighboring cells,” Mallack, who is also an assistant attending at New York-Presbyterian Hospital and assistant attending neurologist at Memorial Sloan Kettering Cancer Center, said during his presentation.1

The trial is now recruiting up to 24 participants with early infantile Krabbe disease who are between 1 to 9 months of age. Dose-escalation cohorts will be separated by age. Two dose levels—1.5 x 1011 GC/g and 5.0 x 1011 GC/g—will be evaluated over the study duration of 2 years with 3 years of follow-up. Trial sites are now open in the US and Canada and will soon open in Brazil, Israel, the Netherlands, and the UK. 

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Investigators will assess efficacy of PBKR03 based on longitudinal neurodevelopmental evaluations including the Bayley Scale of Infant and Toddler Developmnent, the Vineland Adaptive Behavior Scale-II, and a quality-of-life assessment including ventilator-free survival and feeding tube placement. Secondary outcomes will assess neurophysiological and neuroimaging assessments, investigational biomarker analysis, such as GALC activity in blood and cerebrospinal fluid and markers of disease progression, and quality-of-life assessments. Major analyses will be completed at 2- and 5-years post-treatment.

“Krabbe disease is even more devastating then GM1, these children oftentimes don't even make it to a few months of age before they deteriorate. So, the trial has sites throughout the world... to try to make sure that we can recruit children and treat them as soon as possible and make it as easy as possible for the family. The trial is now active in the United States and in Canada. We plan on showing results from that trial, we hope, in future meetings,” David Weinstein, MD, senior vice president, clinical development, Passage Bio, told GeneTherapyLive in an interview.

Weinstein presented data on Passage Bio’s GM1 gangliosidosis program at WORLDSympoiusm. The data, from the phase 1/2 IMAGINE-1 trial (NCT04713475), demonstrated that ICM administration of PBGM01 had efficacy in achieving and regaining developmental milestones in the first 2 children with GM1 gangliosidosis.2

1. Mallack EJ, Jones SA, Aran A, et al. A phase 1/2 open-label, multicenter, dose ranging and confirmatory study to assess the safety, tolerability and efficacy of PBKR03 administered to pediatric subjects with early infantile Krabbe disease (globoid cell leukodystrophy; GALax-C). Presented at: 18th Annual WORLDSymposium, February 7-11, 2022; San Diego, CA. Poster #189
2. Weinstein DA, Day-Salvatore DL, Ficicioglu C, et al. Safety, biomarker and preliminary efficacy results following ICM administration of PBGM01 in children with late onset infantile GM1-gangliosidosis. Presented at: 18th Annual WORLDSymposium, February 7-11, 2022; San Diego, CA. Poster #LB-71
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