Gene Therapy for Krabbe Disease

(REKLAIM Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy called FBX-101 for treating Krabbe disease, a rare and serious condition affecting the nervous system. Researchers aim to assess the safety of this treatment and its potential benefits for those with infantile and late infantile forms of the disease. The trial includes two groups: one receiving a low dose and the other a high dose of the therapy. It is designed for individuals who have undergone or are about to undergo a stem cell transplant for Krabbe disease and meet other specific health criteria. As a Phase 1/Phase 2 trial, this research focuses on understanding the treatment's function in people and measuring its effectiveness in an initial, smaller group.

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.

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, has promising safety results. In earlier studies, researchers assessed the safety of this treatment by examining the number and seriousness of unexpected medical issues after treatment, known as adverse events. These studies found that FBX-101 improved nerve function, suggesting the therapy works without causing serious harm.

So far, reports of serious side effects directly linked to FBX-101 have been few. This indicates that patients might tolerate the treatment well. It is important to note that the current trial is in its early stages (Phase 1/2), focusing mainly on safety and understanding how patients respond to the treatment. While early results are encouraging, further research is needed to confirm these findings. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about FBX-101 because it offers a novel approach to treating Krabbe disease, which traditionally relies on bone marrow transplants and supportive care. Unlike these standard treatments, FBX-101 uses a gene therapy approach, employing the AAVrh.10-GALC vector to deliver a functional copy of the GALC gene directly to patients’ cells. This method could potentially address the root cause of the disease by restoring the deficient enzyme, rather than just managing symptoms. Additionally, FBX-101 is administered as a single infusion, offering a simpler and potentially more effective treatment option compared to the ongoing regimen required with current therapies.

What evidence suggests that this trial's treatments could be effective for Krabbe disease?

Research shows that FBX-101, an experimental gene therapy for Krabbe Disease, looks promising in treating this condition. Earlier studies found that FBX-101 helps form protective coverings around nerve fibers and improves movement abilities. It also appears to fix nerve issues related to Krabbe Disease. These findings suggest that FBX-101 might help with the nerve damage caused by the disease. While these results are encouraging, they come from early studies, and more research is needed to confirm the treatment's effectiveness. Participants in this trial will receive either a low dose or a high dose of FBX-101 to further evaluate its effectiveness. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04693598

Gene Transfer Clinical Trial for Krabbe Disease ... FBX-101 infusion. ... AAVrh10 Gene Therapy Ameliorates Central and Peripheral Nervous System Disease in Canine Globoid Cell Leukodystrophy (Krabbe Disease).

2. forgebiologics.com forgebiologics.com/forge-biologics-announces-positive-fbx-101-clinical-trial-update-in-patients-with-krabbe-disease-identified-by-newborn-screening-ahead-of-rusp-vote/

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

3. 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 ...

4. alextlc.org alextlc.org/research/forge-biologics-positive-clinical-trial-update-krabbe-disease/

Forge Biologics Announces Positive FBX-101 Clinical Trial ... Five patients with Krabbe Disease who were identified by newborn screening (NBS) in the US have been treated with hematopoietic stem cell transplantation (HSCT) ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8633897/

Krabbe Disease: Prospects of Finding a Cure Using AAV ... This review highlights recent findings in the pathogenesis of Krabbe disease, and evaluates AAV-based gene therapy as a promising strategy for treating this ...

6. synapse.patsnap.com synapse.patsnap.com/drug/20b05396eb6b402fbb8470239e2efb54

FBX-101 - Drug Targets, Indications, Patents A Long-term Follow-up Study to Evaluate Safety and Efficacy of Krabbe Patients From Gene Therapy Clinical Trials Involving the Administration of FBX-101 ...

7. clinicaltrials.eu clinicaltrials.eu/inn/adeno-associated-virus-serotype-rh10-containing-the-human-galc-gene/

A Gene Therapy for Infantile Krabbe Disease Evaluate the safety of FBX-101 when given to infants with Krabbe disease after stem cell transplantation; Collect evidence of potential therapeutic benefits ...