Gene Therapy with FBX-101 for Krabbe Disease

(RESKUE Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy, FBX-101, for treating Krabbe disease, a rare and serious condition affecting infants. The goal is to determine if this treatment, administered after a standard stem cell transplant, can better manage the disease. Two groups participate: one receives a low dose, and the other a high dose of the therapy. Infants diagnosed with Krabbe disease and approved for a stem cell transplant might be eligible. The trial compares treated participants to those with the natural history of the disease to assess the therapy's effectiveness. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that FBX-101, a gene therapy for Krabbe disease, was well-tolerated by patients in earlier studies. These studies indicate that the treatment is safe, with no major safety issues found in five patients. This suggests that the treatment is generally safe for humans at this stage of testing. However, since this trial remains in the early stages, monitoring patients for any possible side effects is crucial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Krabbe Disease, which often involve supportive care or hematopoietic stem cell transplantation, FBX-101 is a gene therapy that targets the root cause of the condition. FBX-101 uses an adeno-associated virus (AAVrh.10-GALC) to deliver a healthy copy of the GALC gene directly into patients' cells, potentially addressing the genetic deficiency responsible for the disease. This approach not only aims to slow disease progression but also holds promise for improving quality of life by addressing the underlying genetic issue, rather than just managing symptoms. Researchers are particularly excited about the potential of this therapy to bring significant improvements in a condition that currently has very limited treatment options.

What evidence suggests that FBX-101 might be an effective treatment for Krabbe disease?

Research has shown that FBX-101 may help treat Krabbe disease. Studies have found that FBX-101 can protect nerve cells and enhance movement abilities. This trial will test FBX-101 in two doses: low and high. This gene therapy has stabilized brain disease and repaired nerve damage outside the brain and spinal cord. In tests with mice and dogs, FBX-101 increased survival rates and improved nerve function. Early human trials showed that FBX-101 is well tolerated, meaning it doesn't cause serious side effects. Overall, these findings suggest that FBX-101 could effectively treat Krabbe disease. ^{2 6 7 8 9}

Who Is on the 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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

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However, while the brain disease stabilizes, the progression of peripheral neuropathy results in declining motor function limiting the survival to teen years.

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FBX-101 has been shown to functionally correct the central and peripheral neuropathy associated with Krabbe, improve myelination and gross motor function.

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Data from the RESKUE Phase 1/2 clinical trial continues to demonstrate safety and efficacy post-FBX-101 systemic administration in patients ...

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Forge Biologics' Novel AAV Gene Therapy FBX-101 for ...

Clinical data demonstrate that FBX 101 has been well tolerated and has an excellent safety profile after the treatment of five patients. Results ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT05739643

Study Details | NCT05739643 | Gene Transfer ...

The FBX-101-REKLAIM study has been modified on Q4 2023 to allow a broader patient recruitment of infantile and late infantile Krabbe patients. The updated ...