Forge Biologics receives US FDA approval to initiate phase 1/2 trial of AAV gene therapy, FBX-101 to treat Krabbe disease

Forge Biologics Inc., a gene therapy manufacturing and development company, announced that the company has received FDA clearance of the Investigational New Drug (IND) to initiate a phase 1/2 clinical trial evaluating its novel, first-in-human AAV gene therapy, FBX-101, for patients with Krabbe disease. FBX-101 is the company’s first therapeutic program to receive an IND which also received Institutional Biosafety Committee (IBC) and Institutional Review Board (IRB) approvals required prior to any patient enrollment. This marks a major step forward in building out the company’s hybrid model as a gene therapy manufacturing and development engine.

Krabbe disease is a rare and fatal pediatric leukodystrophy affecting about 1-2.6 in 100,000 people in the United States. Patients are born with mutations in the galactosylceramidase (GALC) gene, which encodes an enzyme that helps break down lipid molecules inside cells. This results in the toxic buildup of psychosine, a lipid molecule that can’t be degraded in cells, particularly in cells in the brain and peripheral nerves, and leads to toxic levels that cause cell death and myelin loss. The disease initially presents as physical delays in development, muscle tightness and irritability, and rapidly advances to difficulty swallowing and breathing, loss of vision and hearing, and increasing cognitive degeneration. Early onset, or “Infantile”, Krabbe disease cases usually results in death by age 2-4 years, while later onset or “Late Infantile” cases have a more variable course of progressive decline. There is currently no approved treatment for either form of Krabbe disease.

FBX-101 is an adeno-associated viral (AAV) gene therapy administered after hematopoietic stem cell transplant (HSCT), that delivers a functioning copy of the GALC gene, the enzyme needed to prevent the buildup of psychosine in myelinated cells of both the central and peripheral nervous system. FBX-101 has been shown to correct the central and peripheral myelination deficits, significantly improve the behavioral impairments associated with Krabbe disease in animal models, and drastically improve the lifespan of treated animals. The use of transplant and intravenous AAV gene therapy infusion has the potential to overcome some of the immunological safety challenges of traditional AAV gene therapies.

“The ground-breaking treatment approach using HSCT and AAV gene therapy, initially developed by Dr. Escolar, has safely demonstrated superior benefits in preclinical animal studies of Krabbe disease than either treatment method alone,” said Timothy J. Miller, Ph.D., Forge’s CEO, president, and co-founder. “We are grateful for the FDA’s engaged review and allowance of the IND, and look forward to enrolling patients very soon.”

FBX-101 is the culmination of nearly 20 years of Krabbe disease research, led by Maria Escolar, M.D., M.S., chief medical officer at Forge Biologics and the pioneer for evaluating the natural history and new treatment approaches for patients with Krabbe disease. “This combination approach is extremely exciting because the preclinical data demonstrate significant correction of survival, behavior and neuromuscular function in animal models compared to either transplant or AAV treatment alone. This is a significant milestone for Krabbe disease families suffering from this deadly disease,” said Dr. Escolar.

The initiation of the RESKUE trial in Forge’s gene therapy pipeline continues Forge’s momentum within the biotechnology industry in Columbus, Ohio, bringing positive impact to both Ohio and the global rare disease community.

Krabbe disease is a rare, pediatric leukodystrophy affecting about 1-2.6 in 100,000 people in the U.S. and is inherited in an autosomal recessive manner. Krabbe disease is caused by loss-of-function mutations in the galactosylceramidase (GALC) gene, a lysosomal enzyme responsible for the breakdown of certain types of lipids such as psychosine. Without functional GALC, psychosine accumulates to toxic levels in cells. The psychosine toxicity is most severe in the myelin cells surrounding the nerves in the brain and in the peripheral nervous system, eventually leading to the death of these cells. The disease initially manifests as physical delays in development, muscle weakness and irritability and advances rapidly to difficulty swallowing, breathing problems, cognitive, vision and hearing loss. Early onset or “Infantile”, Krabbe disease cases usually results in death by age 2-4 years, while later onset or “Late Infantile” cases have a more variable course of progressive decline. There is currently no approved treatment for Krabbe disease.

Forge is developing FBX-101 to treat patients with infantile Krabbe disease. FBX-101 is an adeno-associated viral (AAV) gene therapy that is delivered after a hematopoietic stem cell transplant. FBX-101 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 and correct the behavioral impairments associated with Krabbe disease in animal models, and to drastically improve the lifespan of treated animals. This approach has the potential to overcome some of the immunological safety challenges observed in traditional AAV gene therapies.

Forge Biologics is a hybrid gene therapy contract manufacturing and therapeutic development company.