Forge Biologics Announces Updated Positive Clinical Data in RESKUE, a Novel Phase 1/2 Gene Therapy Trial for Patients With Krabbe Disease

Forge Biologics recently announced Chief Medical Officer Maria Escolar, MD, MS, presented updated clinical data from the RESKUE Phase 1/2 clinical trial for FBX-101—the company’s novel gene therapy for the treatment of patients with Krabbe disease—during the 29th Congress of the European Society of Gene & Cell Therapy (ESGCT).

RESKUE is the first-in-human clinical trial where patients with Krabbe disease are administered FBX-101, a systemic adeno-associated virus (AAV) gene replacement strategy, during full myeloablation and hematopoietic stem cell transplantation (HSCT). Krabbe is a rare, genetic, neurodegenerative leukodystrophy affecting the central nervous system (CNS) and peripheral nervous system (PNS). Krabbe disease affects infants with an incidence rate of 1-2.5 in 100,000 and leads to premature death, often by 2 years of age. Clinical data support preclinical observations that this gene therapy approach during HSCT may lessen many of the immune challenges previously observed with systemic AAV gene delivery and may create a safer environment for gene replacement. Findings also support this novel approach for extending the delivery of gene replacement strategies to target metabolic diseases amenable to HSCT.

The data from treated subjects demonstrate that intravenous FBX-101 during HSCT has been safe and well tolerated. Notably, the data indicate an absence of humoral immune response against the systemically delivered AAV, and significantly increased galactocerebrosidase (GALC) enzyme activity is observed in plasma and cerebrospinal fluid (CSF). Krabbe disease is characterized by mutations in the GALC gene which lead to loss of motor function. All subjects treated to date have also exhibited improved motor activity and normal brain development, which would not be anticipated in the absence of systemic gene transfer of the GALC gene.

“We are excited to present the data from multiple patients in our RESKUE trial and encouraged by the safety and efficacy results observed in FBX-101 treated subjects,” said Dr. Escolar. “An update on our first cohort data demonstrates that intravenous FBX-101 during HSCT was safe and well tolerated, including increased GALC enzyme activity in plasma and CSF, normal myelination of white matter, and normalization of motor development. The results are exciting and give us hope for patients suffering from Krabbe disease who typically do not live past 2 years of age untreated.”

Dr. Escolar’s presentation, Intravenous FBX-101 (AAVrh10.hGALC) following Hematopoietic Stem Cell Transplantation increases GALC activity, supports brain development and improves motor function in patients with Infantile Krabbe Disease: RESKUE Phase ½ Clinical Trial, is available for all ESGCT attendees October 11, 2022, and through October 14. For more details on the conference, please visit: https://www.esgctcongress.com/

 Krabbe disease is a rare neurodegenerative disease affecting about 1-2.5 in 100,000 people in the US. Krabbe disease is caused by autosomal recessive mutations in the galactocerebrosidase (GALC) gene, an enzyme responsible for the breakdown of certain types of sphingolipids, such as psychosine, associated with myelination of the nervous system. Without functional GALC, psychosine accumulates to toxic levels in cells, specifically in cells insulating the nerves in the brain and peripheral nervous system, causing rapid demyelination. Krabbe disease initially manifests as irritability, developmental delay, and progressive muscle weakness; symptoms rapidly advance to difficulty swallowing, breathing, worsening developmental delay, and vision and hearing loss. Infantile Krabbe disease (0-12 months of age at onset) usually leads to death in untreated patients by 2 years of age. Late Infantile patients (12-36 months of age at onset) usually die by the age of six. The current standard of care, hematopoietic stem cell transplantation (HSCT), has been shown to stabilize cognitive decline and significantly improve long-term neurological outcomes when performed prior to symptom onset. However, HSCT does not correct the peripheral neuropathy that is progressive as the patient grows, leading to loss of gross motor skills and eventually death. Early diagnosis is key for treating Krabbe patients before significant neurological damage has occurred. Currently, 10 states in the US are conducting newborn screening for Krabbe disease. Infants who screen positive, meaning insufficient GALC activity is detected, undergo psychosine and mutation analysis to confirm the diagnosis and predict disease onset.

FBX-101 was developed to treat children with Krabbe disease. FBX-101 is an adeno-associated viral serotype rh10 (AAVrh10) gene therapy that is delivered intravenously during HSCT. The vector delivers a functional copy of the GALC gene to cells in both the central and peripheral nervous system. FBX-101 has been shown to functionally correct the central and peripheral neuropathy associated with Krabbe, improve gross motor outcomes, and significantly prolong lifespan in animal models. This approach has the potential to overcome some of the immunological safety challenges observed in traditional AAV gene therapies and extend the duration of gene transfer.

RESKUE a Phase ½ clinical trial to investigate the safety and efficacy of FBX-101 in patients with Infantile Krabbe disease. It is a nonblinded, non-randomized dose escalation study of intravenous AAVrh10 during HSCT, in which subjects receive standard of care hematopoietic cell transplantation for Krabbe Disease, followed by a single infusion of an adeno-associated virus gene therapy product. Extensive natural history subjects will be used to compare as control group. More information on the RESKUE trial can be found online at https://www.clinicaltrials.gov/ct2/show/NCT04693598.

Forge Biologics is a hybrid gene therapy contract manufacturing and clinical-stage therapeutics development company. Forge’s mission is to enable access to life changing gene therapies and help bring them from idea to reality. Forge’s 200,000-sq-ft facility utilizes 20 cGMP suites in Columbus, OH, the Hearth, to serve as its headquarters. The Hearth is a custom-designed cGMP facility focused on AAV manufacturing and can host end-to-end manufacturing services to accelerate gene therapy programs from preclinical through clinical and commercial stage manufacturing. By taking a patients-first approach, Forge aims to accelerate the timelines of these transformative medicines for those who need them the most. For more information, visit www.forgebiologics.com.