Forge Biologics | Our Focus on Krabbe Disease and Genetic Disorders

Pipeline & Science 

Forge is developing innovative gene therapies that aim to help patients suffering from devastating rare diseases.

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Science

Krabbe Disease & FBX-101Our foundation is hope

About Krabbe Disease

Krabbe disease is a rare neurodegenerative disease affecting about 1-2.5 in 100,000 people in the U.S. 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 tightness and weakness; symptoms rapidly advance to difficulty swallowing, breathing, regression of neurodevelopment followed by vision and hearing loss and seizures. Infantile Krabbe disease (0 –12 months of age at onset) usually leads to death in untreated patients by an average of 2 years of age; Late Infantile patients (12-36 months of age at onset) usually die by the age of six1. 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 onset2. However, HSCT does not correct the peripheral neuropathy that is progressive as the patient grows, leading to loss of gross motor skills and eventually death3. Early diagnosis is key for treating Krabbe patients before significant neurological damage has occurred. Currently, 11 states in the U.S. are conducting newborn screening for Krabbe disease. Infants who screen positive due to insufficient GALC activity get tested for psychosine levels and mutation analysis, they may need additional testing to confirm the diagnosis and determine which of these infants need immediate treatment because they are at high risk to start progressing.


About FBX-101

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 after HSCT infusion. 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 myelination and gross motor function, and significantly prolong lifespan in animal models. This is a novel approach that has the potential to overcome some of the immunological safety challenges observed in traditional AAV gene therapies (without transplantation). HSCT has normal GALC and brings an immune system that does not recognize GALC as an antigen. The FDA has granted FBX-101 Fast Track Designation, Orphan Drug Designation, Rare Pediatric Disease Designation, and the EMA has granted FBX-101 Orphan Drug Designation and Priority Medicines (PRIME) designation.


About the REKLAIM Trial

REKLAIM is a Phase 1b, nonblinded, non-randomized dose escalation clinical trial currently enrolling children with asymptomatic infantile and symptomatic late infantile Krabbe disease to investigate the safety and efficacy of a single intravenous infusion of FBX-101 administered more than 21 days after HSCT, the current standard of care, when the patient is at different stages of immune competence. Data from an extensive natural history study of untreated and transplanted subjects will be used to compare as the control group. The FBX-101-REKLAIM trial was modified in the fourth quarter of 2023 to allow a broader patient recruitment of infantile and late infantile Krabbe patients. The updated REKLAIM study merges the recruitment populations of the RESKUE (NCT04693598) and the REKLAIM clinical trial (NCT05739643). More information on the REKLAIM trial can be found online at https://clinicaltrials.gov/study/NCT05739643.


About the RESKUE Trial

The RESKUE clinical trial is currently not recruiting since both trials have been merged into the REKLAIM clinical trial. 


Expanded Access Policy

We recognize the value of the Expanded Access program and are dedicated to patient-focused drug development. At this time, we are unable to commit to expanded access of FBX-101 for the general Krabbe patient population while safety assessments are ongoing. All requests for Expanded Access will be referred to study investigators to determine a patient’s eligibility for a clinical study. In very exceptional circumstances, Expanded Access requests may be considered on a case-by-case basis. These will only be considered in lieu of a patient who does not qualify for an ongoing clinical study and based on the potential benefit/risk profile of the experimental medicine for that specific individual patient based on existing safety and efficacy data.

For more information about our clinical trials or Expanded Access, patients, pediatricians, caregivers, and foundations are encouraged to reach out to advocacy@forgebiologics.com. Physicians may also email to refer a patient to our clinical trials. A team member from Forge will respond within five business days.


A Note from the Forge Team

If someone you love was recently diagnosed with Krabbe disease, you are the reason we are aiming – our time, talents, and resources – towards safely, effectively, and expediently bringing health and a better quality of life to patients with Krabbe disease. We are more than just a company; we are a collection of people that care deeply about connecting with, listening to, and understanding the patients and families we serve. If you or someone close to you has been affected by Krabbe and you’d like to connect with us, simply reach out at. We’re here to listen, learn, and help however we can.

References

1. Bascou, N., A. DeRenzo, M. D. Poe, and M. L. Escolar. 2018. 'A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life', Orphanet J Rare Dis, 13: 126.

2. Escolar, M. L., M. D. Poe, J. M. Provenzale, K. C. Richards, J. Allison, S. Wood, D. A. Wenger, D. Pietryga, D. Wall, M. Champagne, R. Morse, W. Krivit, and J. Kurtzberg. 2005. 'Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease', N Engl J Med, 352: 2069-81.

3. Wright, M. D., M. D. Poe, A. DeRenzo, S. Haldal, and M. L. Escolar. 2017. 'Developmental outcomes of cord blood transplantation for Krabbe disease: A 15-year study', Neurology, 89: 1365-72.

4. Rafi MA, Rao HZ, Luzi P, et al. Long-term improvements in lifespan and pathology in CNS and PNS after BMT plus one intravenous injection of AAVrh10-GALC in twitcher mice. Mol Ther 2015; 23:1681–1690.

Science

About Gene Therapy

Our foundation is hope

Gene therapies are transformative medicines that hold promise for treating diverse, genetically-driven diseases. Genetic diseases are caused by alterations in genes that result in the defective function or complete absence of important proteins in cells. Gene therapies can help to correct these defects by replacing or modifying the mutated gene(s). The essential components of a gene therapy are:

Gene therapies commonly use viral vectors to transport functional versions of a gene (or gene modifiers) into cells. Viral vectors are engineered viruses that can infect cells and deliver the functional gene without causing diseases themselves. One type of virus used for this purpose are adeno-associated viruses (AAVs), which have been proven to be safe and efficient delivery vehicles for gene therapy. The specific choice of viral vector can influence where in the body the gene therapy has its therapeutic effect.

Genes (or gene modifiers) are the “payloads” of a gene therapy, helping to correct the underlying genetic defect at a molecular level. Genetic constructs are packaged into viral vectors during the manufacturing process and delivered, by those vectors, into the nucleus of cells. There, these genes are expressed into proteins that have the desired therapeutic effect: usually either replacing or repairing, a defective protein. The design of the genetic construct is a critical factor in determining when, where and how well a gene therapy will work.

The selection of the delivery method for a gene therapy is just as important as what viral vector or payload is used. This is because not all cells necessarily need to receive the therapy, and there may in fact be reasons to avoid whole-body exposure. The delivery method is usually tailored to the disease. For example, a musculoskeletal disease may require an intravenous injection to allow viral vectors to access all cells in the body, and central and peripheral nervous system disorder may need a systemic approach but other diseases just affecting an area of the brain might need a direct injection of vector into the brain area.
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