Straight Dope on Medicine: Butterfly Children

Author

Scott Ganser
May 30, 2023

Butterfly children are fragile, like the wings of a butterfly. Their skin rips and tears too easily. These children sport bruises all the time. The condition is called recessive dystrophic epidermolysis bullosa.

“Dystrophic Epidermolysis Bullosa is referred to as ‘the worst disease you’ve never heard of’”

 said Suma Krishnan, Founder and Chief Operating Officer of Krystal.

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Why are they like this?

People with EB have mutations that disable genes for proteins that anchor together the layers of skin and the linings of some internal organs. Their skin tears easily, and blisters form in friction-prone areas such as the elbows, knees, and esophagus. Such tearing can result in painful open wounds, persistent infections, scars, skin cancer, and death by early adulthood.[i]

Scientifically speaking, this is caused by mutations in the COL7A1 gene (typically a hemizygous 40 kb deletion), resulting in the lack of functional type VII collagen, which disrupts the formation of anchoring fibrils in the skin and prevents the adhesion of the epidermis to the dermis.[ii]

Historical Treatment

Management of patients with RDEB is presently limited to wound care and attempts to minimize trauma. Avoidance of adhesives and compressive dressings is important as these can induce blister formation.

Care from a dermatologist, pediatrician, gastroenterologist, nutritional therapist, dentist, and psychologist, among other specialists, is essential. Constant, specialized treatment such as this regularly tallies $200,000 to $400, 000 per year. In addition, given the high incidence of developing aggressive SCCs as early as the second decade, regular skin cancer screenings are necessary. Patients should also be forwarded to support groups, such as the dystrophic epidermolyis bullosa research association (DebRA of America: www.debra.org).

New Treatment

Newly minted VYJUVEK™ has worked wonders.[iii] The FDA recently approved it for (DEB) in children and adults six months of age or older. VYJUVEK™ is a topical gel laden with viruses which are constructed to deliver gene therapy to the patients.

Krystal Biotech’s Vyjuvek (beremagene geperpavec-svdt) is a non-invasive, topical, re-dosable gene therapy that delivers functional human COL7A1 gene copies to offer wound healing.[iv]

Redosing is critical because skin cells rapidly turn over. We lose about 600 skin cells per second and up to 9 pounds of skin per year.

They use a modified HSV-1 virus that has been engineered to render the virus harmless to the patient.

The main measure of the study was complete wound healing at 6 months. 65% of wounds treated with VYJUVEK healed completely at 6 months compared to 26% of wounds treated with placebo.[v]

71% of wounds treated with VYJUVEKTM achieved the secondary endpoint of investigator assessed complete wound healing at the three-month timepoints as compared to 20% of wounds treated with placebo (absolute difference (95% CI): 51.0% (29.3%-72.6%); p<0.005).[vi]

VYJUVEKTM was well tolerated. No drug-related serious adverse events or discontinuations due to treatment were reported. One mild drug-related adverse event was reported during the trial.

In the GEM-1/2 trial, repeat topical applications of Vyjuvek resulted in full-length cutaneous COL7 expression, durable wound closure, and anchoring fibril assembly with minimal adverse events.

The company intends to commercialize Vyjuvek in the US in the third quarter of 2023.

An amazing transformation.

Population

Usually, epidermolysis bullosa blisters are noticed during infancy. But it's not uncommon for them to appear when a toddler first begins to walk or when an older child begins new activities that cause more friction on the soles of the feet.[vii]

Fewer than one in 20,000 children are affected.

Roughly speaking, there are 3000 patients in the US, 3000 patients in Europe and 3000 patients in South Africa. It is estimated that there are about 10000 patients worldwide.

In severe cases, patients become covered in painful sores that are difficult to heal on their own and can lead to vision loss, disfigurement, and other serious and sometimes fatal medical complications.

Progressive scarring leads to fusion of fingers and toes (pseudosyndactyly), loss of nail plates, joint contractures, and eye inflammation with visual impairment. Many patients survive only to their fourth decade as a result of aggressive squamous cell carcinomas (SCC) that arise within areas of repeated scarring.[viii]

The main types of epidermolysis bullosa are:

· Epidermolysis bullosa simplex. This is the most common type. It's brought on by heat and friction and develops in the outer layer of skin. It mainly affects the palms and feet. The blisters heal without scarring.

· Junctional epidermolysis bullosa. This type may be severe, with blisters beginning in infancy. A baby with this condition may develop a hoarse-sounding cry from continual blistering and scarring of the vocal cords.

· Dystrophic epidermolysis bullosa. This type is related to a flaw in the gene that helps produce a protein that glues the skin layers together. If this protein is missing or doesn't function, the layers of the skin won't join properly. It can cause skin that looks thin. Diseased mucous membranes can cause constipation and make it hard to eat.

· Kindler syndrome. This type tends to cause blisters in multiple layers and so can look very different from person to person. The blisters tend to show up in infancy or early childhood. It increases sun sensitivity and causes skin to look thin, mottled, and wrinkly.

Conclusion

With the increased prevalence of gene therapy, it may lead to the opening to the cell therapy floodgates. To date, the FDA has erected unfair, onerous, and ridiculous rules and regulations for cell therapy.

Here, we have a significant advance in gene therapy which could be extended to other health issues. Krystal is even thinking of anti-aging indications. They are considering Elastin and Col III, not just Col 7.

[i] https://www.science.org/content/article/dna-spiked-gel-heals-skin-wounds-butterfly-children

[ii] Klausegger A, Jeschko N, Grammer M, Cemper-Kiesslich J, Neuhuber F, Diem A, Breitenbach-Koller H, Sander G, Kotzot D, Bauer JW, Laimer M. Recessive Dystrophic Epidermolysis bullosa due to Hemizygous 40 kb Deletion of COL7A1 and the Proximate PFKFB4 Gene Focusing on the Mutation c.425A>G Mimicking Homozygous Status. Diagnostics (Basel). 2022 Oct 11;12(10):2460. doi: 10.3390/diagnostics12102460. PMID: 36292148; PMCID: PMC9600310.

[iii] https://www.biospace.com/article/releases/fda-approves-groundbreaking-new-product-utilizing-berkshire-sterile-excipient-gel-to-treat-butterfly-children-/?keywords=butterfly

[iv] https://www.pharmaceutical-technology.com/news/fda-krystal-biotech-vyjuvek/

[v] https://www.vyjuvek.com/

[vi] https://ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-announces-positive-topline-results-gem-3-pivotal

[viii] Soro L, Bartus C, Purcell S. Recessive dystrophic epidermolysis bullosa: a review of disease pathogenesis and update on future therapies. J Clin Aesthet Dermatol. 2015 May;8(5):41-6. PMID: 26029334; PMCID: PMC4445895.Blisters in the mouth can make eating difficult and lead to malnutrition and anemia, such as low iron levels in the blood. Problems with nutrition can also cause delayed wound healing and slowed growth in children.