Gene Therapy with FBX-101 for Krabbe Disease

(RESKUE Trial)

Recruiting at 2 trial locations

Overseen By Maria Escolar, MD

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Forge Biologics, Inc

Disqualifiers: Congenital anomaly, Neurocognitive deficit, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

6 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a gene therapy given through an IV after a stem cell transplant in patients with Krabbe disease. The therapy uses a virus to deliver healthy genes to help fix the genetic problem. Gene therapy using viral vectors has shown some success in extending survival in mouse models of Krabbe disease.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the treatment FBX-101 for Krabbe Disease?

Research in mice with Krabbe Disease shows that using a treatment similar to FBX-101, called AAVrh10-GALC, can significantly extend lifespan and improve nerve function. This suggests that FBX-101 might also be effective in treating Krabbe Disease in humans. ^{1 2 3 4 5}

Is FBX-101 gene therapy generally safe for humans?

Research on animals, like mice and dogs, using AAVrh10 (a type of gene therapy) for Krabbe Disease shows promising safety results, with improved lifespan and normal behavior observed. However, these studies are in animals, and human trials are needed to confirm safety. ^{1 2 3 4 6}

How is the treatment FBX-101 different from other treatments for Krabbe Disease?

FBX-101 is a gene therapy that uses a high dose of a viral vector to deliver a healthy version of the GALC gene, potentially eliminating the need for bone marrow transplantation, which is the current standard treatment. This approach aims to reduce the side effects associated with stem cell transplantation and improve the quality of life for patients. ^{1 2 3 4 5}

Research Team

Jessie Barnum, MD

Principal Investigator

Div. of Blood & Marrow Transplantation & Cellular Therapies, UPMC Children's Hospital of Pittsburgh

Randy Windreich

Principal Investigator

Clinical Director, Division of Blood and Marrow Transplantation and Cellular Therapies, UPMC Children's Hospital of Pittsburgh

Eligibility Criteria

This trial is for infants up to 12 months old diagnosed with infantile Krabbe disease, who are eligible for a stem cell transplant. They must have specific enzyme activity levels and organ function. Infants cannot participate if they have untreated infections, HIV, prior gene therapy, major congenital anomalies affecting brain development, or are in another clinical study.

Inclusion Criteria

I am a baby aged between 1 day and 12 months.

My kidneys, liver, heart, lungs, and blood clotting functions are all within normal ranges.

My child has Krabbe disease with specific test results.

Exclusion Criteria

I have been treated with gene therapy before.

You are currently experiencing food or liquid going into your lungs.

You have HIV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Hematopoietic Stem Cell Transplantation (HSCT)

Participants receive standard of care hematopoietic cell transplantation for Krabbe disease

4-6 weeks

Gene Therapy Infusion

Participants receive a single infusion of an adeno-associated virus gene therapy product

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• FBX-101

Trial Overview The trial tests FBX-101 after a standard stem cell transplant in babies with Krabbe disease. It's an escalating dose study of intravenous AAVrh10 gene therapy following the transplant. The effects will be compared to those observed in extensive natural history control groups.

Participant Groups

Group I: Cohort 2 - High Dose FBX-101 (aka AAVrh.10-GALC) Experimental Treatment 1 Intervention

Participants will receive a single infusion at the higher dose (N=3 participants)

Group II: Cohort 1 - Low Dose FBX-101 (aka AAVrh.10-GALC) Experimental Treatment 1 Intervention

Participants will receive a single infusion at the lower dose (N=3 participants)

FBX-101 is already approved in European Union, United States for the following indications:

Approved in European Union as FBX-101 for:

• Krabbe disease

Approved in United States as FBX-101 for:

• Krabbe disease

Who Is Running the Clinical Trial?

Forge Biologics, Inc

Lead Sponsor

Trials

3

Recruited

40+

Findings from Research

In a murine model of Krabbe disease, combining hematopoietic stem cell transplantation (HSCT) with AAVrh10-mGALC gene therapy significantly extended survival from 40 days to about 400 days, indicating a promising treatment strategy.

The study identified optimal dosing and timing for the gene therapy, showing that both the timing of the viral vector injection and the dose are critical for improving survival and myelination, which is essential for planning future human trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease. Rafi, MA., Luzi, P., Wenger, DA.[2020]

In a study using Twitcher mice with Krabbe disease, high doses of gene therapy significantly increased lifespan and improved health outcomes without the need for hematopoietic stem cell transplantation (HSCT).

The treated mice exhibited normal fertility, weight, appearance, and strength, with no signs of neuro-inflammation, suggesting that high-dose gene therapy could be a safer alternative to HSCT for treating Krabbe disease in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can early treatment of twitcher mice with high dose AAVrh10-GALC eliminate the need for BMT? Rafi, MA., Luzi, P., Wenger, DA.[2021]

A single intravenous injection of AAVrh10-GALC given one day after bone marrow transplantation in neonatal twi mice significantly improved lifespan and behavior, indicating a potential enhancement in treatment outcomes for Krabbe disease.

This approach resulted in normal galactocerebrosidase (GALC) activity in the central nervous system and high activity in the peripheral nervous system, suggesting that combining gene therapy with standard hematopoietic stem cell transplantation could provide better results than current treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Improvements in Lifespan and Pathology in CNS and PNS After BMT Plus One Intravenous Injection of AAVrh10-GALC in Twitcher Mice. Rafi, MA., Rao, HZ., Luzi, P., et al.[2018]

AAV9 gene therapy, specifically engineered for Krabbe disease, significantly improved the health and lifespan of twitcher mice, extending their median lifespan from 41 days to 150 days with a single systemic injection.

The study demonstrates that optimizing the AAV9 vector for better delivery of galactosylceramidase across the blood-brain barrier can lead to substantial improvements in motor function and overall health in a model of Krabbe disease, suggesting promising potential for future human therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice. Pan, X., Sands, SA., Yue, Y., et al.[2023]

Researchers created neural stem cells from induced pluripotent stem cells (iPSCs) of a Krabbe disease patient, providing a new model to study this rare neurodegenerative disorder.

Using recombinant adeno-associated virus (rAAV) vectors, particularly rAAV2, successfully restored the activity of the deficient enzyme GALC in these neural stem cells, suggesting a promising gene therapy approach for treating Krabbe disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

rAAV2-Mediated Restoration of GALC in Neural Stem Cells from Krabbe Patient-Derived iPSCs. Tian, G., Cao, C., Li, S., et al.[2023]

In a canine model of globoid cell leukodystrophy (GLD), combining hematopoietic stem cell transplantation (HSCT) with intravenous adeno-associated virus rh10 vector (AAVrh10) gene therapy significantly improved survival and delayed disease progression compared to HSCT alone, with some dogs living beyond 1 year.

The highest dose of AAVrh10 (2E14 gc/kg) in combination with HSCT normalized neurological dysfunction and restored critical enzyme activity in the central nervous system, suggesting a promising approach for treating presymptomatic infantile GLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy. Bradbury, AM., Bagel, J., Swain, G., et al.[2023]

References

1. Iran pubmed.ncbi.nlm.nih.gov

Conditions for combining gene therapy with bone marrow transplantation in murine Krabbe disease. [2020]

2. Iran pubmed.ncbi.nlm.nih.gov

Can early treatment of twitcher mice with high dose AAVrh10-GALC eliminate the need for BMT? [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Long-term Improvements in Lifespan and Pathology in CNS and PNS After BMT Plus One Intravenous Injection of AAVrh10-GALC in Twitcher Mice. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

rAAV2-Mediated Restoration of GALC in Neural Stem Cells from Krabbe Patient-Derived iPSCs. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy. [2023]