The most expensive drug ever approved: A gene therapy that cures butterfly skin and could cost $20 million per patient

When Mía Millán was born at Linares Hospital in the early hours of August 11, 2017, one of the first things that caught her parents’ attention was a large, bright red spot on her right leg: “The doctors said it could be an angioma,” recalls Ana González. During that first night, however, it became clear that the cause wasn’t that benign blood vessel malformation. “The poor child spent the whole night crying desperately. She was born at three in the morning, and by 10 in the morning she hadn’t stopped screaming. They took her to Jaén Hospital and she was taken directly to the ICU,” recalls her mother.

Mía had dystrophic epidermolysis bullosa, better known as butterfly skin due to the extreme fragility of this tissue in people with this rare and serious genetic disease that prevents the body from synthesizing the protein collagen 7. Without it, the two outer layers of the skin—the epidermis and the dermis—cannot stay together, and the slightest touch or bump causes painful sores and wounds. They require daily treatment, and the lesions can remain open for years.

“These recessive dystrophic forms, which are the most severe, affect not only the skin but also the internal mucous membranes. These patients experience complications in all their organs and can develop squamous cell carcinoma, an aggressive type of cancer that shortens their life expectancy,” says Rocío Maseda, an associate physician in the Dermatology Department at La Paz Hospital (Madrid), a national reference center for this rare disease, along with Clínic and Sant Joan de Déu (Barcelona).

The European Medicines Agency’s (EMA) approval of a new gene therapy for this condition on February 28th has opened a world of hope for patients and families. “This is historic; we’ve been waiting for this for years,” exclaims Evanina Morcillo Makow, director of DEBRA Piel Mariposa. This association supports the nearly 500 patients in Spain living with the condition, approximately half of whom have the more complex recessive forms. The disease affects between one in every 17,000 and 50,000 live births.

The name of the therapy is Vyjuvek (beremagene geperpavec), and it is extraordinary for several reasons. The first is the outstanding results obtained in the clinical trials, which have allowed wounds that had been open for years to heal in less than three months. Until now, these patients had no choice but to live with “a minimum of three hours a day of treatment, bandages, and pain, in addition to a life highly conditioned by all the limitations imposed by the blisters themselves and the precautions to avoid opening new ones,” explains Mía’s mother.

Vyjuvek is also very striking for its ease of administration, as it is a gel that is applied drop by drop to the skin—one centimeter apart—without the need to manipulate the wounds. The drug contains a modified herpes simplex virus that carries two healthy copies of a gene called COL7A1. When it infects the cells of the dermis, the pathogen harmlessly transfers these copies to them, and the cells learn to produce the protein that corrects the disease. “The gel is administered once a week and improves healing in more than 70% of wounds after three months of treatment,” explains Maseda.

A study published in the scientific journal JAMA Dermatology highlights another characteristic of the new therapy that makes it unique. According to the study, Vyjuvek is the most expensive drug ever approved by the EMA and by the U.S. Food and Drug Administration, with a cost that could be in the range of $20 million over the lifetime of each patient. These amounts are explained because, unlike other gene therapies approved to date—with prices exceeding $3 million but administered in a single dose—Vyjuvek may have to be used chronically for life, with sometimes weekly doses in vials whose official wholesale price is $24,250 per vial

These figures have raised fears among patients, physicians, and experts that the therapy may not reach all those who need it. “There is, without a doubt, a potential problem with patient access to this therapy. Depending on the number of patients eligible to receive it in each country, the high price could pose affordability issues for payers and limit patient access,” Adam Raymakers, the study’s lead author and a researcher at Harvard Medical School specializing in health economics, told EL PAÍS in a written statement.

“Estimated lifetime total costs per patient were $15 million (range, $10 million-$20 million) per patient with autosomal recessive DEB and $17 million (range, $11 million-$22 million) for patients with autosomal dominant DEB,” the study states in its conclusions. The experts consulted acknowledge some limitations of the work. One is that the price used in the calculations is the official price, while in Europe, governments negotiate confidential discounts with pharmaceutical companies. Another is that, over the years, the price of the drug may drop as patents expire and drugs comparable to Vyjuvek come onto the market.

Miquel Serra, a researcher in Health Economics at the University of Zurich (Switzerland), nevertheless emphasizes the relevance of the work and the “enormous challenge” that the increasingly high prices of new drugs pose for healthcare systems. “Our research shows, for example, that the price drop caused by competition for biological medicines [with biosimilars] after patent expiration occurs later and is smaller than for chemically synthesized molecules [with generics]. In the case of gene therapies, there are no precedents for this, so we cannot be sure that this competition will actually occur,” argues this expert.

Raymakers and Serra focus on another important point in the approval process. Both the FDA and the EMA have approved Vyjuvek for use in both patients with the recessive (more severe) and dominant forms of the disease, “despite the fact that the clinical trial included almost exclusively patients from the former group.” This, in both their opinion, “increases uncertainty about the drug’s effectiveness”—it could be administered to a patient profile in which it has barely been tested—and may lead healthcare systems to adopt more restrictive access criteria to the therapy to prevent an escalation in costs.

DEBRA Piel Mariposa acknowledges these fears. “We are concerned that the therapy won’t reach families as quickly as we would like,” acknowledges Morcillo Makow, who nevertheless hopes that “the small number of people with the disease and the enormous impact it has on their lives will accelerate the funding process.”

Following the EMA’s approval, the European Commission must now formally authorize Vyjuvek for marketing, which typically takes about two months. At that point, the Pittsburgh, Ohio-based pharmaceutical company Krystal Biotech will begin seeking public funding for the therapy from European governments.

César Hernández, Director General of the Common Portfolio of Services and Pharmacy at Spain’s Ministry of Health, celebrates the “success” of developing therapies for rare diseases that lack alternative treatments. “The development of these drugs is practically a social commitment to which we all have to contribute,” he adds. Despite this, he does not hide the “challenge” of funding them due to reasons such as their high price and the uncertainty surrounding their safety and efficacy.

“Public systems must develop solutions, in some cases imaginative ones, that address these challenges while facilitating patient access to the therapies they need. The introduction of these medications must be based on a fair assessment of their benefits, and the final result must be compatible with the principles of affordability and sustainability,” he concludes.

Hernández explains that one of the reasons pharmaceutical companies cite for imposing these high prices is the difficulty of recovering the investment made in developing a drug intended for very few patients. Overall, however, there are more than 6,000 rare diseases affecting nearly 30 million people in Europe, so the challenge for healthcare systems is enormous, considering that the prices of new drugs for these patients tend to be “invariably high.”

A Krystal Biotech spokesperson expressed the company’s willingness to “engage in a constructive dialogue with European governments in accordance with local regulations on pricing and reimbursement” and pledged to “work with health authorities to ensure patients have access to treatment.” Regarding Raymakers' study, Krystal Biotech believes it “overestimates treatment costs because it assumes Vyjuvek is a lifelong treatment, which is not the case because it will only be administered if there are open wounds.”

Ana González has high hopes for the new therapy: “I know it’s not a cure, but Mia could see a huge improvement in her quality of life. She’s had large, open wounds that have been causing her a lot of pain for a long time. The daily treatment is so painful that she’s developed anticipatory anxiety. Now that she’s seven, she realizes many things, and seeing her frustration is heartbreaking. If the wounds heal, even if others emerge, new ones can be treated, and the healing process would be much easier, and she could have a life similar to any other child’s. I dream about that.”

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