NEW YORK – Krystal Biotech aims to further develop in 2024 a reformulated version of its topical gel gene therapy, approved last year for dystrophic epidermolysis bullosa (DEB), to also treat disease-related vision issues. The company believes this will add millions to the existing billion-dollar market opportunity it sees for treating the rare genetic skin condition.
"We are committed to treating DEB comprehensively," said Suma Krishnan, president of R&D at Krystal, during a call to discuss 2023 financial results with investment analysts last week.
The US Food and Drug Administration in May approved Krystal's Vyjuvek (beremagene geperpavec-svdt) as a topical gene therapy to treat wounds in patients with DEB, a serious skin condition caused by mutations in the collagen type VII alpha 1 chain (COL7A1) gene, which encodes a protein necessary for binding layers of the skin. Without that type VII collagen protein, patients have fragile skin that easily blisters and tears.
Now, Pittsburgh-based Krystal said it is planning in the second half of the year a single-arm, open-label study of about 10 patients to assess an eyedrop formulation of the gene therapy that's already been used once on a compassionate-use basis.
Krystal last week said it has received pre-investigational new drug (IND) feedback from the FDA on its proposed clinical trial, and that the regulator has agreed that such a study could support an approval of this eyedrop formulation to treat ocular complications of DEB. Krystal has referred to this formational as ophthalmic B-VEC, short for beremagene geperpavec.
Krystal did not respond to a request for comment on its development and commercialization plans for the eyedrop version of the gene therapy.
But on the call last week, Krystal Chairman and CEO Krish Krishnan said, "we're confident in the total global market opportunity for Vyjuvek to get over $1 billion," with an early estimate of potentially an additional $250 million to $300 million when considering the eyedrop formulation. That contrasts with a previous global market opportunity estimate of $750 million that the company shared last year.
Krishnan said the new estimate incorporates trends from the initial six months since the US product launch, as well as expectations for regulatory approval in Europe in late 2024 and Japan in 2025.
Krystal posted $50.7 million in net product revenue for 2023 based on sales from Vyjuvek, which after approval that year became the company's first commercialized product. The firm reported $10.9 million in net income last year, up from a $140 million net loss in 2022, and $.40 in net income per common share for 2023, compared to a $5.49 net loss per common share in the previous year.
The skin blistering caused by DEB can result in severe wounds that lead to other complications, such as infections, scarring, and even vision issues.
That was the case for 13-year-old Antonio Vento, a patient at University of Miami Health System's Bascom Palmer Eye Institute who suffered severe vision loss caused by DEB and who so far is the first and only patient to receive the ophthalmic gene therapy. Prior to gene therapy treatment, Antonio was deemed legally blind, according to a case study published in the New England Journal of Medicine last month.
"The same thing that we see in the skin, we also see in the eye," said Alfonso Sabater, associate professor of clinical ophthalmology and the director of the Corneal Innovation Laboratory at Bascom Palmer. In severe cases of DEB, patients might develop sensitive blisters that break, creating scar tissue on the eye and potentially causing blindness.
Antonio had undergone two surgeries to clear that scar tissue; however, since blisters and scars continued to form, they opted not to operate again while the care team explored other options.
"He really needed an alternative treatment," Sabater said. "We didn't have anything that was working."
Sabater said, in 2020, he heard from Antonio's mother that he had experienced positive outcomes through a clinical trial of a gene therapy, now known as Vyjuvek, to treat his skin condition.
Vyjuvek is a topical gel that's applied to wounds weekly by a healthcare professional, and which uses a genetically modified herpes-simplex virus type 1 vector to deliver two functional copies of COL7A1 to patients. It's designed not only to heal wounds that are present but also to prevent skin from re-blistering with sustained protein expression from redosing.
That sparked an idea for Sabater to see if the same gene therapy could treat Antonio's eye problems. He reached out to the dermatologist treating Antonio, who put him in contact with Krystal's leadership to discuss developing an alternative form of the gene therapy for the eye. Sabater said the company was enthusiastic about the idea, and he provided advice as Krystal developed and conducted preclinical research on an eyedrop formulation in the eyes of healthy mice.
It was nearly two years from when Sabater had this idea to when the experimental gene therapy candidate was ready for use, but in August 2022, Sabater administered the eyedrop on the basis of the FDA granting expanded access, also known as "compassionate use," for Antonio. Sabater initially administered the experimental treatment to Antonio's right eye, and after seeing promising early results, in March 2023 he administered it to the patient's left eye.
So far, investigators say that scar tissue hasn't come back and that the patient experienced full corneal healing after three months of treatment, according to results from the right eye reported in NEJM. In addition, the patient's vision in the right eye had improved to 20/25, meaning that he is able to see at 20 feet what someone with "normal" vision would be able to see at 25 feet, after eight months.
"Our data support further investigation of B-VEC in the care of patients with dystrophic epidermolysis bullosa with ocular surface involvement," the study authors wrote in the paper, although they acknowledged the limitations of the singular case study, such as not having an untreated control eye or natural history for comparison and the contributions of other adjuvant treatments. "Nonetheless, the degree of improvement that we observed was remarkable, given the lack of change in the contralateral eye."
To apply the gene therapy, Sabater surgically removed scar tissue in the eye and then administered the eyedrop, which was given to the patient three times weekly for the first two weeks, then to once a week, and then to once a month after the corneal epithelium healed. Surgery wouldn't be needed for a patient that didn't have scar tissue on the eye, Sabater noted.
"We're very excited with the results," he said. Sabater added that he's optimistic about the treatment's potential to help other patients, but he cautioned that results are "very preliminary." So far, "it's only one patient that we've treated."