Developments in Rare Genetic Skin Disease Therapies

For many people, this time of year is best known for Valentine’s Day, Saint Patrick’s Day, and even Groundhog Day. For those in the medical profession, February was also Rare Disease Month, spotlighting the estimated 300 million people worldwide living with rare genetic diseases. For dermatology, 2025 and 2026 mark a shift from supportive care toward therapies that target the molecular root cause, from gene delivery approaches in epidermolysis bullosa (EB) to pathway-directed small molecules in porphyria and mast cell disease. With Rare Disease Day just behind us on February 28, here is what dermatology providers should watch for in 2026 and how it may change evaluation and management in the clinic.

Last year, when writing about rare genetic skin diseases, I focused on ichthyosis and pachyonychia congenita,¹ highlighting the Foundation for Ichthyosis & Related Skin Types and the Pachyonychia Congenita Project. Both organizations continue to advocate for their patients and strive for new, effective therapies.

This year, I’ll focus on other therapies that reflect the trend toward disease-modifying strategies and the precision targeting of the molecular basis of genetic skin diseases. The goal of these cutting-edge therapies is to move past symptomatic management, bandages, and biopsies to an era of base pairs, proteins, and clinical breakthroughs.

Gene Therapy and the EB Revolution

Profound innovations are occurring in EB, a group of rare, inherited genetic disorders exemplified by very fragile skin, blistering, skin tearing with minor friction or trauma, skin pain, poor wound healing, and/or scarring. There are 4 major types of EB: (1) EB simplex, (2) junctional EB, (3) dystrophic EB, and (4) Kindler syndrome, with the differences between them based on where in the epidermis, dermis, or basement membrane the genetic and molecular defect(s) occur.²

The first 2 therapies approved by the FDA for EB were birch triterpenes (Filsuvez; Chiesi Global Rare Diseases) for junctional and dystrophic EB and beremagene geperpavec-svdt (Vyjuvek; Krystal Biotech, Inc) for dystrophic EB, both for pediatric and adult populations.^3,4

Birch triterpenes contains active compounds (eg, betulin, lupeol, and erythrodiol) that provide topical anti-inflammatory benefit and stimulate keratinocyte migration and differentiation to promote wound healing.³ Beremagene geperpavec differs in that it is a herpes simplex virus type 1 gene therapy that topically delivers COL7A1 genes into keratinocytes and fibroblasts in wounds to restore type VII collagen production and formation of functional anchoring fibrils.⁴

Pediatric and adult patients with COL7A1 gene mutations are ideal candidates for beremagene geperpavec gene therapy, which illustrates the molecularly targeted, disease-modifying approach of modern EB therapy. The topical gel formulation of beremagene geperpavec makes it easy for patients and caregivers to apply at home during dressing changes, and the FDA in September 2025 expanded its use to include infants from birth.⁴

In 2025, the FDA approved the autologous cell sheet–based gene therapy prademagene zamikeracel (Zevaskyn; Abeona Therapeutics Inc) for recessive dystrophic EB (RDEB) in pediatric and adult patients.⁵ Prademagene zamikeracel utilizes cells directly from the patient with RDEB to generate gene-corrected skin sheets; autologous cells are harvested from skin punch biopsies from the patient, functional full-length COL7A1 gene is transduced ex vivo into the cells using a replication-incompetent retroviral vector, and cell sheets expressing functional collagen VII are surgically grafted onto the patient’s wounds.⁵

In the phase 3 VIITAL clinical trial (NCT04227106), the total proportion of patients with RDEB achieving 50% or more healing of random wound pairs at month 6 using prademagene zamikeracel was 81%, 65 points higher than the standard-of-care control treatment.⁶

Porphyria and Mast Cell Breakthroughs

Erythropoietic protoporphyria (EPP) and indolent systemic mastocytosis (ISM) are 2 rare diseases with new molecularly targeted therapies. A small molecule glycine transporter inhibitor, bitopertin, is poised to make the most common form of childhood porphyria much easier to treat from the dermatology office.

EPP occurs due to loss of function variants in ferrochelatase (FECH), an enzyme that catalyzes the final step in the formation of heme: the addition of iron to protoporphyrin IX (PPIX).⁷

Patients with EPP have elevated levels of PPIX, leading clinically to (1) cutaneous phototoxic reactions that result in severe and painful burning sensations and sometimes edema (eg, from sunlight, surgical lighting, or LED lights), (2) hepatobiliary disease, including gallstones, liver dysfunction, or failure​, and (3) osteoporosis and propensity for fractures due to sun avoidance and high risk for vitamin D deficiency.⁸ Patients with X-linked protoporphyria have PPIX accumulation like patients with EPP, but the driver is a gain-of-function mutation in 5’-aminolevulinate synthase 2 (ALAS2), an early enzyme in the heme synthesis pathway.⁸

Whether PPIX accumulation occurs due to early (ALAS2 variants) or late (FECH variants) errors in the pathway, bitopertin demonstrated significant, dose-dependent reductions in PPIX levels at both the 20 mg (–21.6%) and 60 mg (–40.7%) doses compared with an 8% increase in PPIX levels in the placebo arm during the phase 2 AURORA trial (NCT06736990).⁹ Improved light tolerance and fewer phototoxic reactions were also observed in patients. Bitopertin is currently being investigated in the phase 3 APOLLO trial (NCT06910358), with data anticipated in quarter 4 of 2026.¹⁰

Avapritinib (Ayvakit; Blueprint Medicines Corporation) is an advanced small molecule tyrosine kinase inhibitor approved to target KIT D816V mutations,¹¹ and it is elevating the standard of care for patients with mast cell disorders. It is currently the only FDA-approved treatment for adults with ISM, a disease driven by KIT D816V mutations approximately 95% of the time.¹¹

This mutation constitutively activates the KIT receptor, generating hyperactive mast cells and leading patients with ISM to experience numerous symptoms involving the skin (itch, flushing, hives), gastrointestinal tract (nausea, vomiting, diarrhea, abdominal cramping, heartburn), cardiovascular system (dizziness, anaphylaxis), nervous system (headache, depression, brain fog), and musculoskeletal system (osteopenia, osteoporosis, back or bone pain).¹²

Avapritinib was investigated in ISM during the phase 2 PIONEER clinical trial (NCT03731260). At week 24, patients with ISM demonstrated significant improvement in symptoms, reduced tryptase levels, reduced KIT D816V allele fraction in peripheral blood, and reduced bone marrow mast cells.¹³

Avapritinib also has FDA approval for advanced systemic mastocytosis and gastrointestinal stromal tumor.¹¹ Innovation in the precision targeting of the KIT inhibitor is ongoing; for example, BLU-808 is a next-generation, oral, wild-type KIT inhibitor being investigated in mast cell disorders. Together, targeted small molecule therapies such as bitopertin and avapritinib empower dermatology providers to comfortably treat patients with rare skin diseases in the local office.

Topicals for Orphan Conditions

Besides gene therapies and oral small molecules, other topical precision medicines are being studied in rare genetic skin diseases. This momentum to continue to investigate new topical therapies in rare diseases is encouraging, especially given recent unfavorable outcomes in phase 3 trials for TMB-001 (topical isotretinoin ointment) in congenital ichthyosis and topical rapamycin (rapamycin anhydrous 3.9% gel [Qtorin; Palvella Therapeutics, Inc]) for plantar foot pain and calluses in patients with pachyonychia congenita.

Palvella’s rapamycin 3.9% gel is currently being studied for the treatment of patients with microcystic lymphatic malformations in the fully enrolled phase 3 SELVA trial (NCT06239480); trial results should be forthcoming in 2026.¹⁴

QRX003 (Quoin Pharmaceuticals Ltd) is a topical 4% lotion being developed for Netherton syndrome, a rare disease in which SPINK5 mutations reduce the presence of LEKTI, a natural regulator of skin shedding and an inhibitor of kallikrein protease hyperactivity in the epidermis. QRX003 functions as a broad-spectrum serine protease inhibitor, normalizing the kallikrein activity and the native epidermal barrier turnover process.¹⁵

Navigating the New Genomic Frontier

As therapeutic pipelines continue to expand for inflammatory skin diseases, they also expand for rare genetic skin disorders. It is especially important for innovators, investors, and practitioners to remember patients with rare skin diseases because of the immense physical, mental, and emotional burden these diseases have on patients’ quality of life.

From new topical therapies utilizing advanced delivery systems, to molecularly targeted oral small molecules, to gene therapies, multifaceted and creative approaches are being applied to tackle rare skin diseases.

From the diseases and therapies discussed here, I wish to leave you with the following clinical pearls:

Implement early genetic testing: EB is a prime example for personalized and precision genomic medicine. With the availability of beremagene geperpavec and prademagene zamikeracel, early genetic confirmation of EB is essential to facilitate life-altering care. Early genetic testing in the neonatal period may prevent chronic wounding and trauma, minimizing extensive and deforming scarring.

Recognize the pain of EPP: If a patient, especially a child, presents complaining of intense skin pain after exposure to the sun or other light sources despite minimal skin findings, suspect and test for EPP. The primary diagnostic test is total erythrocyte PPIX with metal-free and zinc-bound erythrocyte protoporphyrin fractions, not plasma porphyrins.¹⁶

Screen for systemic mastocytosis: If you suspect a patient has a form of mastocytosis, check for indolent systemic involvement. One test to obtain is the serum tryptase level; if levels are greater than 20 ng/mL, further evaluation is warranted, and the patient may be a candidate for avapritinib.

References

1. Bunick CG. Supporting patients with rare genetic skin diseases and the foundations dedicated to them. Dermatology Times. May 6, 2025. Accessed February 16, 2026. https://www.dermatologytimes.com/view/supporting-patients-with-rare-genetic-skin-diseases-and-the-foundations-dedicated-to-them

2. Epidermolysis bullosa. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Updated September 2023. Accessed February 16, 2026. https://www.niams.nih.gov/health-topics/epidermolysis-bullosa

3. Filsuvez. Prescribing information. Chiesi Global Rare Diseases; 2024. Accessed February 16, 2026. https://resources.chiesiusa.com/Filsuvez/FILSUVEZ_PI.pdf

4. Vyjuvek. Prescribing information. Krystal Biotech Inc; 2025. Accessed February 16, 2026. https://www.krystallabel.com/pdf/vyjuvek-us-pi.pdf

5. Zevaskyn. Prescribing information. Abeona Therapeutics Inc; 2025. Accessed February 16, 2026. https://d1io3yog0oux5.cloudfront.net/_b5e1508de5143194ab6ee1c9b3a6cb66/abeonatherapeutics/files/LBL-000008_%28v3%29_ZEVASKYN_USPI.pdf

6. Tang JY, Marinkovich MP, Wiss K, et al. Prademagene zamikeracel for recessive dystrophic epidermolysis bullosa wounds (VIITAL): a two-centre, randomised, open-label, intrapatient-controlled phase 3 trial. Lancet. 2025;406(10499):163-173. doi:10.1016/S0140-6736(25)00778-0

7. Dickey AK, Leaf RK, Balwani M. Update on the porphyrias. Annu Rev Med. 2024;75:321-335. doi:10.1146/annurev-med-042921-123602

8. Toenne M, Schaefer T. Erythropoietic protoporphyria in childhood: clinical clues, missed diagnoses and emerging therapy. Eur J Pediatr. 2025;184(9):580. doi:10.1007/s00431-025-06418-9

9. Yeung AK, Bonkovsky HL, Balwani M, et al. Bitopertin shows efficacy in patients with erythropoietic protoporphyria: results from the randomized, double-blind, placebo-controlled AURORA trial. J Am Acad Dermatol. 2025:S0190-9622(25)03368-7. doi:10.1016/j.jaad.2025.12.024

10. Study of bitopertin in participants with EPP or XLP (APOLLO). Clinicaltrials.gov. Updated February 2, 2026. Accessed February 16, 2026. https://clinicaltrials.gov/study/NCT06910358

11. Ayvakit. Prescribing information. Blueprint Medicines Corporation; 2024. Accessed February 16, 2026. https://www.blueprintmedicines.com/wp-content/uploads/uspi/AYVAKIT.pdf

12. About ISM. Ayvakit. Accessed February 16, 2026. https://www.ayvakithcp.com/ism/impact-of-ism/about-ism/

13. Akin C, Elberink H, Gotlib J, et al. PIONEER: a randomized, double-blind, placebo-controlled, phase 2 study of avapritinib in patients with indolent or smoldering systemic mastocytosis (SM) with symptoms inadequately controlled by standard therapy. J Allerg Clin Immuno. 2020; 145. doi10.1016/j.jaci.2019.12.062

14. Programs & research. Pavella Therapeutics. Accessed February 16, 2026. https://palvellatx.com/pipeline/

15. Pipeline. Quoin Pharmaceuticals Ltd. Accessed February 16, 2026. https://quoinpharma.com/pipeline/#pipeline

16. Dickey AK, Naik H, Keel SB, et al; Porphyrias Consortium of the Rare Diseases Clinical Research Network. Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria. J Am Acad Dermatol. 2023;89(6):1227-1237. doi:10.1016/j.jaad.2022.08.036