Gene Therapy After Umbilical Cord Blood Transplantation May Help Prevent Immune Response in Patients With Krabbe Disease


Maria Escolar, MD, the chief medical officer of Forge Biologics, discussed the atypical approach being used in the company’s trial for AAV gene therapy FBX-101.

Maria Escolar, MD, the chief medical officer of Forge Biologics

Maria Escolar, MD

FDA-approved adeno-associated virus (AAV) vector-based gene therapies have provided new options for patients in a number of inherited disease indications, and AAV vector-based approaches remain popular among gene therapies currently in preclinical and clinical development. Although, the potential for patients to have immune responses to AAV vectors can negatively affect the efficacy of these therapies. With that in mind, some investigators are exploring novel approaches to circumvent or mitigate this issue.

Maria Escolar, MD, the chief medical officer of Forge Biologics, recently presented data from the company’s phase 1/2 RESKUE clinical trial (NCT04693598) evaluating FBX-101, an investigational AAV vector-based gene therapy intended to treat Krabbe disease, at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16 to 20, in Los Angeles, California. The study is administering FBX-101 to patients following standard of care treatment with umbilical cord blood transplantation (UCBT).

CGTLive™ sat down with Escolar at the conference to discuss the unusual design of the trial and how it may help mitigate patients’ immune responses to FBX-101's AAV vector. Escolar spoke about the promising results observed in the 2 patients treated so far, noting that neither patient has experienced an increase from baseline in antibodies to the AAV vector.

CGTLive: What does the current state of care for Krabbe disease look like?

Maria Escolar, MD: Krabbe disease is a demyelinating rapidly progressive disease in which children get diagnosed unfortunately [usually only] after they have symptoms, and it is very difficult for treatments to reverse these problems. Currently, the standard of care is to transplant when they are asymptomatic—so if there is a sibling as an index case, then the next child is diagnosed and in the first 30 days of life they get treated with hematopoietic stem cell transplantation, usually UCBT. This has been the standard of care now for 17 years. Unfortunately, when you follow these children, by the time they get to their teenage years, and even before that, they can have peripheral nerve disease, which is also caused by demyelination. The reason why they demyelinate is because they are deficient in an enzyme called galactocerebrosidase (GALC) and they accumulate a by product called psychosine, which is very toxic to the cells that make myelin.

What advantages could FBX-101 offer in treating Krabbe?

FBX-101 was developed with the purpose of being administered after the transplant is given and it was designed in a way that we would avoid the antibody response [to the AAV vector]. This is done by taking advantage of the chemotherapeutic regimen that you need to give the transplant—when you are administering a transplant, you have to empty the bone marrow from the cells; you do this by using chemotherapy and conditioning—so you myeloablate the hematopoietic system so that when you administer the infusion of cord blood cells they go into the bone marrow, repopulate, and produce new stem cells. Taking advantage of the fact that the patient was myeloablated, we believed that if we then administered FBX-101 with an AAVrh.10-hGALC vector, that the antibody response would be avoided. Sure enough, that is what we're finding. Now, we have treated 2 patients and we have followed the patients for 9 to 12 months—and we have seen that the antibodies don't increase beyond their baseline. This is a very novel approach to providing intravenous administration of an AAV vector.

Can you go over some of the latest data from the trial?

Our hypothesis was correct that the myeloablation and immune suppression that is achieved with the conditioning regimen for transplant is able to prevent the typical antibody response that you would get in a gene therapy that is administered intravenously. Another key finding is the longer-term follow-up showing that the patients continue to have improved myelination and improved motor function to the point that they are now in the average range. Patients are walking independently, which less than 10% of patients that are only transplanted and don't receive gene therapy will be able to achieve—so we are seeing some functional gains. Biomarker data also show that the GALC enzyme is actually increased by more than 170-fold and that psychosine is normalized.

This seems to be a potentially very effective treatment for Krabbe disease and potentially [this type of approach] could even help other indications where transplant is the standard of care in order to augment the therapeutic effect. It is an exciting preliminary finding. We still have to follow up children for a longer time, but right now we have every indication to believe that the therapy is effective both at the biomarker level and functionally.

What research remains to be done with FBX-101?

Currently, the enzyme activity continues to go up, so we don't know what is going to happen long-term. We have to follow up and see if it plateaus or if it decreases with time. That's one of the things that we are very interested in following. In terms of the antibody response, we also want to see if this is maintained; have we actually tolerized the patient or not against AAV10? What type of immunologic implications could that potentially have? So, there are a few areas that we need to continue exploring and making sure that the safety and efficacy continues to be as good as it is right now.

Is there anything else that you would like to share with our audience?

I've been working on this disease for over 20 years, and it is extremely exciting to see patients that are walking at this age. It is an amazing experience to be able to go from all the preclinical work to now seeing the effects in patients. I'm very excited and hopefully results continue to be good in the future.

The other thing that I think is exciting is that a lot of the lysosomal storage diseases are now being screened at birth. While Krabbe disease has been proposed as 1 of the diseases to be screened at birth it has not yet been approved. Hopefully that will happen in the future so that we're able to pick out those babies that are still asymptomatic because the key aspect to have good outcomes is to prevent disease progression.

Transcript edited for clarity.

Click here for more coverage of ASGCT 2023.

1. Escolar ML, Vander Lugt M, Poe MD, et al. First in human RESKUE phase 1/2 clinical trial of intravenous FBX-101 (AAVrh10. hGALC) administered after immune and myeloablation for unrelated umbilical cord blood transplantation prevented immune responses, increased GALC activity, restored normal brain development, and normalized motor function in patients with infantile Krabbe disease. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Abstract #359
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