Gene Therapy for Krabbe Disease

(REKLAIM Trial)

Recruiting at 2 trial locations

Overseen By Maria Escolar

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Forge Biologics, Inc

Must not be taking: Immunosuppressive drugs

Disqualifiers: HIV, GvHD, Infections, 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

Duration: 1 day

9 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a single dose of a virus carrying a healthy gene in patients with severe forms of Krabbe disease. The virus helps by delivering the healthy gene to the patient's cells. Gene therapy has shown promise in extending survival in previous studies.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive drugs due to anti-AAV10 antibody titers, you may need to continue them as part of the study's immune response management.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are taking investigational products or are enrolled in another study with clinical interventions, you may not be eligible to participate.

What data supports the idea that Gene Therapy for Krabbe Disease is an effective treatment?

The available research shows that Gene Therapy for Krabbe Disease, specifically using AAVrh10-GALC, can significantly improve outcomes in animal models. In studies with twitcher mice, which are used to model Krabbe Disease, increasing the dose of the gene therapy without bone marrow transplantation led to longer lifespans and normal physical characteristics. Another study showed that a single injection of the therapy after bone marrow transplantation greatly extended the mice's lifespan and improved their behavior. Additionally, an engineered version of the therapy using AAV9 significantly improved motor function and extended the median lifespan of treated mice compared to untreated ones. These results suggest that Gene Therapy could be a more effective treatment option than the current standard, which is hematopoietic stem cell transplantation, as it may avoid some of the associated side effects and improve overall outcomes. ^{1 2 3 4 5}

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

Research on mice with Krabbe Disease shows that using a high dose of the AAVrh10-GALC gene therapy can significantly extend their lifespan and improve their health without needing a bone marrow transplant. This suggests that the treatment could be effective for humans with Krabbe Disease, potentially avoiding the side effects of current treatments. ^{1 2 3 4 5}

What safety data exists for gene therapy treatment for Krabbe Disease?

The safety data for gene therapy treatment for Krabbe Disease, specifically using AAVrh10-GALC, has been primarily evaluated in animal models such as twitcher mice and a canine model. Studies have shown that high doses of AAVrh10-GALC can significantly extend lifespan and improve neurological function in these models without the need for bone marrow transplantation (BMT). In twitcher mice, high doses of the viral vector resulted in normal weight, appearance, and behavior, with no signs of neuro-inflammation. In the canine model, intravenous AAVrh10 alone improved nerve conduction and normalized enzyme activity in the peripheral nervous system, although the best results were seen when combined with HSCT. No significant adverse effects, such as liver pathology or hepatic neoplasia, were reported in these studies, suggesting a favorable safety profile for the gene therapy. ^{1 2 3 4 6}

Is the gene therapy treatment AAVrh10-GALC safe for humans?

Research in animal models like mice and dogs shows that AAVrh10-GALC gene therapy, alone or combined with other treatments, can improve lifespan and health without significant safety concerns. These studies are guiding human trials, suggesting the treatment is generally safe. ^{1 2 3 4 6}

Is the treatment FBX-101 a promising treatment for Krabbe Disease?

Yes, FBX-101 is a promising treatment for Krabbe Disease. Studies in mice show that it can significantly extend lifespan and improve behavior when combined with bone marrow transplantation. It may also work well on its own at higher doses, potentially eliminating the need for other treatments. This suggests it could greatly improve outcomes for patients with Krabbe Disease. ^{1 2 3 4 5}

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

FBX-101 is unique because it combines gene therapy with a single intravenous injection of a viral vector to deliver the GALC enzyme, potentially improving outcomes when added to the standard hematopoietic stem cell transplantation (HSCT). This approach may enhance enzyme activity in both the central and peripheral nervous systems, offering a more effective treatment option compared to HSCT alone. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for children with Krabbe Disease who've had a stem cell transplant at least 90 days before. They must have certain diagnostic criteria met, including specific test results or mutations, and sufficient engraftment of donor cells. Children can't join if they have recent infections, MRI or lumbar puncture contraindications, used investigational products recently, live virus immunizations within the last month, severe organ function issues, neurocognitive deficits not due to Krabbe disease, heart problems without pulmonary hypertension evidence or previous gene therapy treatments.

Inclusion Criteria

I am getting or have had a transplant for Krabbe disease diagnosed in infancy.

I had a transplant over 3 months ago and meet the chimerism requirements.

I am eligible for a stem cell transplant or had one at least 21 days ago.

Exclusion Criteria

Any other medical condition, serious intercurrent illness, other genetic condition or extenuating circumstance that, in the opinion of the PI, would preclude participation in the study

I have not received any live virus vaccines in the last 30 days.

Immunoassay with total anti-AAVrh10 antibody titers of >1:100

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of the gene therapy product FBX-101 after more than 21 days post-HSCT

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• FBX-101

Trial Overview The study tests FBX-101 in kids who previously received a stem cell transplant for Krabbe Disease. It's an escalating dose trial where participants get one infusion of this gene therapy product. The effects will be compared to data from untreated and transplanted patients with infantile and late infantile forms of the disease.

Participant Groups

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

N=3-6 patients with Infantile or Late Infantile Krabbe disease will receive a single infusion at the high dose

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

N=3 patients with Infantile or Late Infantile Krabbe disease will receive a single infusion at the low dose

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 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]

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]

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

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

2. 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]

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

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

4. Iran pubmed.ncbi.nlm.nih.gov

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

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]