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Topical Gene Therapy Shows Promise for DEB

Peter Marinkovich

A novel topical gene therapy, developed by Krystal Biotech, shows promise for treating wounds of patients with dystrophic epidermolysis bullosa (DEB).1 The therapy KB103 targets the type VII collagen gene (COL7A1), missing in patients with DEB, to improve wound closure and skin cohesion.                                            

Final analysis from a phase 2 study, which included 6 wounds on 3 participants, showed 5 wounds treated with KB103 achieved 100% closure.1 The wound that did not achieve 100% closure was reported as a chronic, deep wound that had been open for over 4 years and was 35% and 42% closed after 30 days and 90 days, respectively. For the 5 wounds with 100% wound closure, the average time to achieve 100% closure was 23.4 days. All wounds, aside from the 1 chronic wound, remained 100% closed after 90 days.1

In an interview with The Dermatologist, Principle Investigator Peter Marinkovich, MD, associate professor of dermatology at Stanford University, discusses the implications of these results and the potential of gene therapy for patients with DEB, as well as what is expected in the phase 3 clinical trial.

The Dermatologist: What lead to the development of this therapy?

Dr. Marinkovich: DEB is one of the more severe subtypes of epidermolysis bullosa and causes a lot of pain and disability. These patients have blisters all over their bodies and also in their mucosa, for example, in their oropharynx and esophagus, which starts at birth and continues through their life.

Currently, the only therapies that are available are supportive. It is very frustrating for patients, families, and even physicians. We haven’t had any specific therapies for this disease. All we can do at the moment is provide wound care, help with nutrition, and fight infections while we watch patient get blisters.

For a number of years at Stanford, we have been working on trying to develop different types of genetic- or cell-based therapies for this disease.

In our first attempt we took the gene that was absent in this disease, which is type VII collagen (COL7A1) and put it into a viral vector called retrovirus, which can only be used in ex vivo because it has cancer causing properties. The modified retrovirus was put into patients’ keratinocytes that we grew from a skin biopsy. We grew the keratinocytes that had been correc­­­­­ted and then we replaced these keratinocytes as part of a skin graft on the patient. We followed the grafts over time and found that those grafted with corrected keratinocytes did a great job of producing collagen VII and helped heal the wound. We followed the grafts for 2 years and saw some long-term improvement, which gradually dropped off over the course of time, but still showed very good long-term improvement.

This was our first generation of gene therapy, but the problem was that it was very expensive. The cells have to be grown in a good manufacturing practice (GMP) facility and they take time to grow. They also require several large biopsies from patients in order to produce these cells, and everything is tied to the individual patient.

Also, there is a cancer risk from these retroviruses as they potentially can insert randomly into a patient's DNA. Theoretically, they can insert into an oncogene, for example, and actually cause cancer. This was documented in another gene therapy study done back in the 1990s with patients with severe combined immunodeficiency on some blood cells. It turns out that a few of those patients developed leukemia. So, it is a very real risk. Using it on the skin, we do not have as much of an issue because we can at least see the cancers when they form and surgically excise them if needed.

With the expense, time, and all the effort to achieve ex vivo gene therapy, it made us think about better, easier ways, maybe less expensive ways, that could be more accessible for patients all over the world.

The Dermatologist: How is KB103 different from ex vivo therapies and what are the mechanisms of action?

Dr. Marinkovich: This product is virally based and carries the COL7A1 gene but uses a different kind of vector that can be used in vivo. The idea with this vector, the herpes simplex virus (HSV) 1 vector, is that it can be injected or applied using a cream or gel directly to the skin, right on top of the wound. We tested this preclinically and it worked really well in our animal models in vivo. We went straight into phase 1 and phase 2 clinical trials.

So far, in two total clinical studies we have treated eight patients and a number of wounds. What we found is that we have been able to show good wound healing as well as freedom from blistering after the wound has healed. This is an important point because DEB is not necessarily a sore or wound healing disorder per se—it is a disorder of skin cohesion. We definitely want to help make sure patients stay healed, so we have been monitoring them for several months after treatment and have been able to show wound healing.

At the same time, we are able to show expression of both the COL7A1 gene and collagen VII protein in the actual basement membrane, where it is supposed to be located during this time as well. We have molecular correction correlated with wound healing in these patients. Basically, what this therapy does is provide a molecular glue to hold the skin together and makes the skin tougher and more resistant to the blistering.

When I first learned about this therapy and the mechanism of how it worked, I was really intrigued, and I thought it had great potential. My main concern was that there could be an immune reaction upon repeated application of this product due to the virus. Fortunately, we have not found immune inflammation, even with repeated use of this product over several months. We think it is probably because of the properties that come from virus itself.

The HSV1 virus, which typically produces cold sores, has some beneficial properties in that it is very good at infecting skin cells and can lay dormant in the skin for long periods of time undetected by the immune system. It does have the ability to evade the immune system, which in gene therapy is a good thing. In KB103, the vector has been made replication incompetent, which is important because replication is part of the basis the herpes disease. Without replication, KB103 has all the good properties of HSV, such as infection, minimal activation of the immune system, etc., without properties that cause the associated disease.

We just recently completed the phase 2 trial this past summer and we are hoping to be able to start phase 3 trial in the last quarter of this year.

The Dermatologist: What are the implications of these findings for the treatment of DEB?

Dr. Marinkovich: I think this has great potential. It is very easy to reapply, and it seems to have a nice durability, where after the wound heals, they stay healed for several months, maybe up to 6 months. If the wounds open up again, it is easy to reapply this therapy topically. Also, the nice part about this too is that it can potentially reach more patients than the cell-based therapies.

Cell-based therapies are created patient by patient, cells are grown in a GMP facility, and placed back onto the patient at a very specialized medical facility as well. Whereas, this product is basically off the shelf.

KB103 is good for any patient and shipped to places, such as China, India, and Africa, to many more patients with DEB compared with cell-based therapies. Ultimately, I think that it could be used in home and not necessarily in an office or special facility. That is one of the major reasons I am excited about this therapy because I think it can reach and help a lot of patients.

The Dermatologist: What are the expectations for the phase 3 trial?

Dr. Marinkovich: In the phase 3 trial, we want to involve a sufficient number of patients, about 15, and quantitively show the ability of KB103 to heal wounds and to keep them healed for a number of months. We will look at rate of wound healing and durability, as well as molecular correction, COL7A1 expression, and the expression of the collagen VII protein into the basement membrane, which turns into anchoring particles that have a glue-like structure that molds the skin together. In addition, we want to be able to see if it has a similar safety profile to what was reported in the phase 1 and 2 trials.

The Dermatologist: Are there other areas for this therapy that you plan to study?

Dr. Marinkovich: Another aspect that we are going to be pursuing in the future, as an extension active, phase 2 trial, is using KB103 in non-cutaneous areas. For example, we are very interested in looking at this product in the eye because these patients have a lot of blistering in the conjunctiva, as well as the cornea. Also, we are interested in introducing it in the oropharynx as a possible topical preparation, and even a topical preparation for the esophagus or the rectum, where these patients also have problem with blisters.

Reference

1. Krystal Biotech announces positive results from phase 2 clinical trial (“GEM-2 study”) of KB103 and receives Regenerative Medicine Advanced Therapy (“RMAT”) Designation from FDA for KB103 [press release]. Pittsburg, PA: Krystal Biotech; June 24, 2019. http://ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-announces-positive-results-phase-2-clinical. Accessed August 8, 2019.

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