Practical considerations relevant to treatment with the gene therapy beremagene geperpavec-svdt for dystrophic epidermolysis bullosa

Abstract

Background/purpose

Dystrophic epidermolysis bullosa (DEB), a rare genetic skin disease caused by loss-of-function mutations in COL7A1, the gene encoding type VII collagen (COL7), is characterized by skin blistering, scarring, and extracutaneous manifestations that markedly reduce patient quality-of-life. Beremagene geperpavec-svdt (‘B-VEC’) is a gene therapy employing a non-integrating, replication-defective herpes simplex virus type 1 (HSV-1)-based vector encoding two copies of full-length human COL7A1 to restore COL7 protein after topical administration to DEB wounds. B-VEC was approved in the United States in 2023 as the first topical gene therapy and the first approved treatment for DEB. However, few providers have experience with use of this gene therapy.

Methods

Data was obtained through literature review and the experience of providers who participated in the B-VEC clinical study or initiated treatment after B-VEC approval.

Results

This review discusses the burden of disease, describes the clinical trial outcomes of B-VEC, and provides physician and patient/caregiver recommendations as a practical guide for the real-world use of B-VEC, which can be administered in-office or at the patient’s home.

Conclusions

By continuing to optimize the practical aspects of B-VEC administration, the focus will continue to shift to patient-centric considerations and improved patient outcomes.

Keywords:

• Dystrophic epidermolysis bullosa
• DEB
• beremagene geperpavec
• B-VEC
• gene therapy
• topical therapy
• HSV-1
• practical guidelines

Introduction

The rare genetic disease dystrophic epidermolysis bullosa (DEB) is caused by loss-of-function mutations in COL7A1, the gene encoding type VII collagen (COL7). A deficit in COL7 leads to absent or nonfunctioning anchoring fibrils, which disrupt adhesion of the epidermis to the dermis (1, 2). DEB is inherited in an autosomal recessive (RDEB) or autosomal dominant (DDEB) manner, with RDEB distinguished by more severe symptoms; however, symptom severity varies across these subtypes with considerable overlap (3–6). Patients with DDEB have fewer functional anchoring fibrils, while many RDEB patients, in line with their increased symptom severity, demonstrate a complete absence of functional anchoring fibrils (2). The disease, which can present as early as birth, is characterized by skin fragility, separation of the epidermis from the dermis resulting from minor trauma (skin blistering), milia, and scarring (7). In addition to skin involvement, severe DEB can produce extracutaneous manifestations involving the eyes, oral mucosae, and gastrointestinal, cardiovascular, and genitourinary systems (8). Healing of skin erosions can result in debilitating scarring. With time, recurrent cycles of blistering, wound healing, and fibrosis can lead to limb deformities, life-threatening infections, and squamous cell carcinoma (SCC) (9–12). This rare disease has an estimated prevalence of 3 to 12 cases per million globally, with likely underreporting of milder cases from misdiagnosis or patients not aware they have a genetic disease (5, 13–15).

Burden of the disease

DEB places an enormous physical, emotional, and financial burden on patients, caregivers, and the healthcare system via both direct wound management and associated complications (16). Painful blistering and wounding, nail abnormalities, infections, dental problems, hand/foot contractures, constipation, ocular manifestations, anemia, malnutrition, esophageal and anal strictures, and mental health disorders are all common for DEB patients and often require hospitalization and specialized care teams to address each need (12, 17,18). A critical aspect of DEB care is the burden that wounds place on patients and their caregivers, including the cost, frequency, and duration of wound dressing changes, as well as the pain, itch, and risk for developing an infection. Dressings are changed at least every other day in 79% of wounds and up to twice daily with infection, leading to a high burden in dressing utilization (17). The time burden of dressing wounds is also high, with 21.4% of patients with DDEB and 63.2% with RDEB spending more than 2 h a day on wound dressing; 36.8% of patients with RDEB report more than 4 h daily (17). Other studies from South Korea, the United Kingdom, the United States (U.S.), and Ireland report similar financial and time burdens of DEB wound care (16, 19–22). Another concern is the development of SCC from chronic wounding and fibrosis, a leading cause of premature death for DEB patients (12). One study noted that RDEB patients develop SCC at a rate 3.5 times higher than the general population (16). These SCCs are most often on the arms/hands and legs/feet, particularly at bony prominences (9), and may necessitate limb amputation (12, 23).

Much of DEB management focuses on preventing blistering and wounding through protective bandages and careful monitoring for signs of infection and SCC (3, 24–26). A survey of epidermolysis bullosa (EB) patients regarding priorities for future treatment highlighted a desire to reduce the risk of skin cancer (77.8%), the number and severity of wounds (73.0%), and pain (73.0%), as well as accelerate wound healing and closure (71.4%) (17). The impact of routine bandage changes and wound care on patients and caregivers is significant, necessitating development of treatments that specifically address the wound burden of DEB.

B-VEC’s mechanism of action and therapeutic outcomes in clinical studies

Until recently, there were no approved corrective therapies for patients diagnosed with DEB, either in the U.S. or worldwide (27). Beremagene geperpavec-svdt (‘B-VEC’; commercially provided as VYJUVEK^®) was the first treatment for DEB approved by the U.S. Food and Drug Administration (FDA). It is a redosable topical gene therapy that employs a non-integrating, replication-defective herpes simplex virus type 1 (HSV-1)-based vector platform, engineered to deliver two copies of full-length human COL7A1 to restore COL7 protein expression in treated patients. Upon topical application to wounds, B-VEC can transduce both keratinocytes and fibroblasts (28). After entry of B-VEC into cells, the vector genome is deposited in the nucleus, leading to expression of the encoded human COL7A1. Because B-VEC is episomal, it does not intercalate into the DNA and thus repeated application of B-VEC is necessary to maintain optimal COL7A1 expression. The resulting transcripts allow for production and secretion of COL7 by the cell as soluble procollagen type VII (proCOL7) trimers, which diffuse to the dermal-epidermal junction where C-proteinases convert the proCOL7 molecules into their fibrillar state known as anchoring fibrils. Once assembled, anchoring fibrils extend from the basement membrane into the papillary dermis where they ensnare dermal collagen fibrils, thereby attaching the basement membrane to the superficial dermis. In this way, anchoring fibrils enhance dermal-epidermal cohesion to counteract disruptive external forces (29).

In an open-label, placebo-controlled, single-center Phase 1/2 clinical study (GEM-1; NCT03536143), repeated weekly application of B-VEC resulted in full-length COL7 protein expression and anchoring fibril formation at the dermal-epidermal basement membrane of treated RDEB patients (28). Initially, only subjects 18 years or older were eligible, but the enrollment age was reduced to subjects at least 6 years old in the later stages of the study. All subjects were diagnosed with generalized RDEB through clinical guidelines and molecular confirmation. B-VEC was found to be well-tolerated. The proportion of B-VEC-treated wounds that closed was significantly higher than placebo. B-VEC-treated wounds closed faster than those treated with placebo and the duration a wound remained closed was significantly longer when treated with B-VEC than with placebo. The mechanistic and clinical data from this 12-week open-label study provided preliminary efficacy supporting advancement to a confirmatory study of B-VEC in DEB (28).

A Phase 3, multicenter, double-blind, placebo-controlled, intra-patient randomized study (GEM-3; NCT04491604) evaluated the efficacy and safety of B-VEC in patients 6 months or older with DEB (1). Wound healing was assessed in 31 patients, who were eligible if they were 6 months of age or older and presented with a clinical diagnosis of DEB, characterized by blistering, wounds, and scarring and confirmed by genetic testing. One patient had DDEB, while the rest had RDEB. The median age of patients was 16 years (range, 1 to 44). The study met its primary endpoint of complete wound healing at 6 months and its key secondary endpoint of complete wound healing at 3 months, defined as 100% wound closure from the exact wound area selected at baseline, specified as skin re-epithelialization without drainage, as evaluated by the investigator (1). Only wounds that were healed for at least 2 consecutive weeks were counted as positive responses. After study completion, wounds that were completely healed at 3 months were reevaluated at 6 months to measure persistence of complete healing. Of B-VEC-treated wounds healed at 3 months, 67% were also healed at 6 months (1). B-VEC was well tolerated and no study participants stopped treatment due to side effects. No clinically significant immunologic reactions related to B-VEC were reported. After completion of the Phase 3 study, patients were eligible to enroll into an open-label extension (OLE) study, in which they continued to receive weekly treatment with B-VEC to assess long-term safety (NCT04917874). At the time of this publication, data from the OLE is not yet available.

B-VEC is approved to treat DEB patients 6 months and older, with the maximum weekly volume dependent on age. Patients 6 months to <3 years old receive 0.8 ml (1.6 × 10⁹ PFU) weekly, while patients 3 years or older receive 1.6 ml (3.2 × 10⁹ PFU) weekly (30). The volume per wound is based on the approximate size of the wound area when B-VEC is applied dropwise in a 1 cm-by-1 cm grid, so that multiple wounds can be treated with the weekly volume of B-VEC. Contracted pharmacies are provided B-VEC and the mixed product is delivered to the site of care, after which health care professionals (HCPs) topically administer it to patients.

Physician insights for holistic DEB wound management

Effective wound management in DEB patients encompasses several factors outside of directly treating wounds. Some considerations for holistically managing wounds in DEB patients, especially the pediatric population, include monitoring nutrition, anemia, infections, and pruritus. Nourishment is important to heal wounds and to enjoy the best possible quality of life in children and adults with DEB, but is compromised by mucosal blistering and scarring, limited ability to open the mouth from progressive intraoral scarring, chronic disease, and increased nutritional need linked to generalized inflammation and nutrient loss through blisters. Promoting optimal nutrition, growth, and immunity will improve the chance of healing (31). Dental care may require treatment modifications to avoid tissue damage and sloughing of skin inside the mouth; to prevent dental caries, which RDEB patients are more likely to develop, a toothbrush with a small head and soft, short bristles may improve oral hygiene while minimizing damage to the mucosa (32, 33). If oral intake cannot meet the increased caloric needs of DEB patients, enteral tube feeding (most often gastrointestinal (G-) tube) should be considered.

Anemia is a common complication in DEB patients and can contribute to chronic fatigue, reduced energy levels, dyspnea, and impaired wound healing (34). HCPs should monitor for anemia every 6–12 months and consider iron infusions or even blood transfusions if warranted based on evaluation. Infection is also common for DEB patients; skin fragility and numerous, long-standing wounds are often associated with bacterial colonization or infection, especially from Staphylococcus aureus and/or Pseudomonas aeruginosa (35). Evaluating the wound for purulence and inflammation, as well as discussing the history and symptoms (e.g., increased pain) associated with the wound, can help to identify a new infection requiring local or systemic antibacterial treatment. Increased redness, local pain, odor, and exudate can all be indicative of infection (35).

Itching may be a common symptom, especially as the wound areas start to heal and form hemorrhagic crusts. Over-the-counter antihistamines or prescription medications may be helpful to alleviate symptoms and prevent scratching but are often of limited value. Therapeutic options may be discussed with the HCP and a plan for symptom relief may be established. Oral gabapentin has successfully been used in children aged 6–12 years to treat itch associated with burn wound healing (36) and in newborns with EB for pain management (37, 38). Topical gabapentin has been shown to reduce the size of pruritic lesions in EB patients in a randomized controlled trial, although this was not associated with a reduction in pruritus frequency and duration (39), and thus further study on gabapentin use for itch relief in DEB patients, particularly children, is necessary. Dupilumab may be helpful in some patients, especially those with EB pruriginosa, a form of DEB (40). Although caution should be used when treating DEB patients with dupilumab, as conjunctivitis has been an adverse event in individuals treated specifically for atopic dermatitis, to date dupilumab in DEB patients has been well tolerated. It should be emphasized that gene therapy is not an alternative to supportive care, but rather B-VEC works best when wound care, skin infections, nutrition, anemia, and itch are all properly addressed.

Practical considerations for B-VEC application

Before deciding on a wound care management strategy, an inventory should be taken of the affected body surface area, types of skin involvement (e.g., intact blisters, erosions, chronic or recurrent wounds, infected areas), the patient’s wound dressing routine, and age. Once assessed, a treating HCP and the patient and/or caregiver can engage in shared decision-making about which wound areas (e.g., multiple wounds on the upper back) to prioritize for initial treatment. The weekly dose volume of B-VEC may not cover all open wounds at initial treatment, so it is important to decide which wound areas will receive treatment first. Often, the initial areas selected are wounds that most impact the patient’s daily activities, regardless of size. Before initiating treatment, the HCP should set reasonable expectations about time to wound closure, especially given its anticipated variability, and explain that areas of higher friction/impact and larger wounds may require prolonged treatment compared to smaller wounds and/or wounds in low-trauma areas.

A patient’s age is an important consideration when deciding which wounds or wound areas to initially treat. Infants typically require a more controlled environment to prevent trauma (41). For example, the diaper area is difficult to manage, as it is prone to more physical and chemical trauma; this may be an area to prioritize for treatment in young patients to prevent long-term wounding and scarring from repeated friction- and chemical-induced blistering. Congenital absence of skin in DEB patients (Bart syndrome) should be high priority for treatment in early infancy to prevent long-term fibrotic and wounding complications (42). An HCP, with the patient and/or the patient’s caregiver, may decide to prioritize treatment of the hands or feet to reduce the risk of deformity and functional loss from fusion of the digits and contractures after repetitive trauma or friction (11).

Immediately before the application of B-VEC, it is important to properly cleanse the skin. During the Phase 3 study, sites were instructed to use saline wipes or rinses for cleaning target wounds prior to the administration of B-VEC. A variety of gentle cleaners or saline-based solutions may be used for bathing, and some patients may choose to use additives like bleach, vinegar (acetic acid solutions), or salt (43, 44). Diluted bleach in bathwater can be beneficial in improving the skin barrier and reducing itching (45, 46) and small amounts of bleach (at a relative dilution of 0.005% or 1/2 cup in a 40-gallon bathtub of water/1 teaspoon in 1 gallon of water for localized soaks or compresses) do not affect B-VEC efficacy if the patient has rinsed after bathing. However, direct contact with a concentration of 0.05% bleach will render B-VEC inactive, as bleach has been shown to inactivate HSV-1 in previous studies (47, 48). Acetic acid solutions (at a relative dilution of 0.25% or 2 gallons of 5% acetic acid white vinegar in 38 gallons of bathwater for a 40-gallon bathtub) can help to reduce Pseudomonas, a frequent colonizer of DEB wounds (49), but it is still unclear if it can interfere with the efficacy of B-VEC. Patients should thoroughly rinse if soaking first with bleach or acetic acid to ensure B-VEC does not come into direct contact with these additives. Saltwater baths, which have been shown to reduce pain, skin odor, and wound discharge in EB patients (50), are not expected to impact B-VEC efficacy and can be safely taken prior to B-VEC application without the need for thorough rinsing.

The bathtub or shower should be cleaned and disinfected with bleach or other antiseptic before and after bathing. A patient or caregiver’s hands should also be cleaned prior to the bathing process (43, 44). Before entering or during the bath or shower, bandages and layers of padding can be removed; some patients may choose to enter with bandages still on to more easily remove them with water before continuing their bath or shower (44). Generous application of ointment such as petroleum jelly can also loosen bandages stuck to the skin to facilitate their removal and reduce associated pain (43). Gently washing the skin helps remove dry, dead skin and crusted areas of skin breakdown to prevent buildup of wound debris that can interfere with the penetration of B-VEC to skin cells in the wound bed, while reducing the number of bacteria on the skin, which may help to prevent infection (44). When cleaning wounds, avoid shearing the tissue by gently patting to clean and dry the area.

While B-VEC itself is odorless, used dressings may have an odor due to wound discharge, bacterial colonization on the patient’s skin/wounds, or prolonged use of the same dressing. Skin infections should be addressed by a medical professional and may require topical/oral antibiotics or a hospital admission for intravenous antibiotics. Oral antibiotics do not disrupt the B-VEC administration schedule; however, topical antibiotics should not be administered concomitantly in case they limit diffusion of B-VEC. Prophylactic topical antiseptic/antibiotic or oral antibiotic treatment in patients with draining or purulent wounds prior to treatment with B-VEC may help prevent wound discharge from interfering with B-VEC penetration. Because SCC is a common complication in DEB patients, the HCP should examine wound areas for possible SCCs prior to treatment and periodically while using therapy. SCC may present as a nonhealing or rapidly growing wound, a deep ulcer with a raised or rolled edge, an area of hyperkeratosis, especially if surrounded by raised skin, or a wound with altered sensation relative to normal DEB wounds, such as tingling or increased pain (51).

Consider the patient’s comfort when setting up to apply B-VEC. Forced air (e.g., air conditioning, heat, ceiling fans) may need to be turned off to alleviate pain caused by the chilled air on open wounds once the dressing has been removed, especially after wound cleansing. A pillow may be required to pad bony prominences if the patient is required to lean during application, especially for prolonged periods. If the plane of the wound to be treated makes treatment difficult (e.g., the vertical nature of the back), the patient can be positioned to facilitate administration (e.g., rotated forward during application). Placement of a nonabsorbent dressing beneath the wound area allows capture of any B-VEC droplets that do not stay at the wound area during application.

B-VEC is administered by an HCP to the selected wound or wound areas that are clean and patted dry. Syringes containing B-VEC should be refrigerated until application to maintain appropriate viscosity for best control during application. If the cold temperature of B-VEC is uncomfortable during application, the syringe can be left at room temperature for 3–5 min before beginning application. With prolonged warming, B-VEC may have a thinner consistency, making it more challenging to apply and thus leaving it at room temperature for longer periods is not recommended. Before application, the cap is removed, the syringe plunger pulled back slightly, and B-VEC is pushed to the syringe tip. Only the convex surface of the B-VEC droplet should touch the wound, with minimal pressure and avoiding contact of skin with the syringe tip itself. Small droplets are spaced evenly within the wound, approximately 1 cm-by-1 cm apart, to resemble a grid (30). Application should begin at the top of the wound and work downward in case of dripping. Dripping of B-VEC can be prevented by keeping the droplets small and well-spaced so that they do not coalesce. If B-VEC comes into contact with the patient or caregiver’s clothing, a bleach- or non-bleach-based liquid stain remover pen (such as Tide To Go^®) can be applied to the area to deactivate B-VEC; washing the article with detergent in warm water and drying on a warm cycle is also sufficient.

Before administration of B-VEC, the HCP, caregiver, or patient may need to drain blisters to prevent extension. After puncture of the blister and egress of wound fluid, the roof of the blister is left intact to protect the wound area. Blisters can be opened for drainage with a sterile needle, scalpel, or clean sharp scissors; gauze is held below the blister to absorb drainage. Pressing on or rubbing the blister as a means to increase emptying should be avoided, as these maneuvers may force fluid away from the opening and lead to blister expansion (44). Depending on the size of the incision, it may not be possible to space the droplets in a 1 cm-by-1 cm grid underneath the blister roof, especially for smaller blisters that are lanced with a needle. B-VEC can be applied into the blister opening at an approximate number of droplets to the size of the wound beneath the opening.

To assure positioning of B-VEC within the wound, decrease discomfort associated with uncovered wounds, and facilitate penetration and uptake of B-VEC, each treated wound should be covered with a hydrophobic layer before treatment of the next wound. Suggested hydrophobic first-layers are soft-plastic or silicone such as Glad^® or Saran^TM Wrap, Mepitel^® (with the side not in contact with the wound retaining the plastic covering), or silicone scar sheets. Alternatives may include, but are not limited to, Xeroform^® Petrolatum dressings with a Mepilex^® Lite absorbent dressing on top; Aquaphor^® Healing Ointment, Vaseline^®, or Vitamins A&D ointment with a hydrophobic wrap; or Curity^TM oil immersion non-adherent strips with a hydrophobic layer on top (such as Glad^® Wrap). Care should be taken not to place an absorbent dressing directly over droplets of B-VEC to avoid absorption into the dressing and away from the wound. The hydrophobic layer should be trimmed to fit the shape of the wound being treated in order to avoid placing excess material over the surrounding intact skin, which may lead to irritation; however, some patients prefer a larger-sized hydrophobic layer and the decision should be made by the patient and/or caregiver. Patients may opt for various hydrophobic layer types or duration of coverage after treatment at different wound areas (such as the scalp or high friction areas). If wound drainage cannot be avoided, creating a border with Vaseline^®, Aquaphor^® or another barrier cream around the wound may prevent loss of B-VEC and potential irritation of surrounding skin, as well as decrease movement of the hydrophobic layer once placed. Wounds that exhibit a lot of drainage will accumulate fluid under the occlusive layer, which can dilute B-VEC. Although some draining can be normal after B-VEC application due to wound healing, draining can often be attributed to inflammation or an active wound infection. The HCP should plan ahead and consider pre-treating these wounds with topical antibiotics to minimize infection and inflammation and reduce drainage; topical antiseptics may also be an option if there are concerns of resistance. For all wounds, the HCP should plan optimal wound management with each patient and caregiver(s).

After the hydrophobic layer, the patient’s standard dressing material (larger than the hydrophobic layer) is placed to absorb drainage and pad or protect delicate parts of the body. Dressings should not be so heavy that they cause overheating. Some patients use a layer of netting or Tubifast^® to hold the top dressings in place. These materials are breathable, stretchable, and conform to the shape of the patient’s body, but should not directly contact skin (44). When applying the netting or Tubifast^® on an extremity, it is best gathered into a circle, placed over the hand or foot, and then gently pulled to cover the extremity, avoiding contact that shears the skin.

The hydrophobic layer over B-VEC should remain in place for approximately 24 h after administration, but can vary based on patient/family discretion. If patients note irritation after treatment, ensure that the hydrophobic layer was flat against the wound and cut to the wound size to avoid bunching of excess material on intact skin surrounding the wound. If discomfort is still reported, the layer can be left on for a shorter period. Decreased duration of coverage may be necessary in hot, high humidity environments, especially if using an occlusive plastic wrap. Once the patient removes the hydrophobic layer after treatment, standard-of-care routines may be followed. It is best for wounds to remain covered with non-adherent dressings and ointment until fully healed in order to prevent crusting or scabbing, which can slow wound healing and impair B-VEC absorption. If crusting still occurs despite these measures, patients should be instructed to avoid scratching the crust off and instead to apply moisturizer after bathing to allow scabs to soften and detach.

It may be impossible to apply B-VEC to all wound areas at each treatment visit. Wounds selected by the patient and HCP should be treated until they are completely closed, and if additional B-VEC remains, new wound areas may be selected for application based on need (e.g., wound itch or pain, an upcoming surgery, a new injury, etc.). The HCP may be tempted to reduce the interval between wound treatments to once every two or three weeks compared to the standard once per week. However, B-VEC administration is optimized for once-a-week use. Longer intervals between B-VEC treatments may result in portions of healed wounds not receiving molecular correction. Thus, the HCP should attempt to follow weekly dosing when wounds are present. There is no benefit in applying B-VEC once wounds are closed; however, if a previously treated wound re-opens, it should be prioritized for treatment until it closes again. Additionally, the HCP or caregiver may still apply B-VEC to a closed wound if only a thin layer of new skin is present. Allowing a reprieve in treatment is acceptable and can be a joint decision among the patient, caregiver, and HCP. A summary of the key physician recommendations discussed in this section is presented in Table 1.

Table 1. Summary of the key considerations for each step of B-VEC application.

Steps to B-VEC application	Considerations for HCPs
1. Decide which wounds to treat	Prioritize wounds that most impact daily life, regardless of size. Set reasonable expectations about time to closure. In infants, consider prioritizing the diaper area and areas with congenital absence of skin (Bart syndrome) to prevent long-term wounding and scarring. Consider prioritizing hands/feet to reduce risk of deformity.
2. Cleanse the skin	Gentle cleansers or saline-based solutions can be used prior to application. If additives like bleach or acetic acid are used, rinse thoroughly before applying B-VEC to ensure efficacy. Bandages can be removed before or during a bath/shower. Ointments (e.g., petroleum jelly) can loosen bandages for easier removal. Pat gently to clean and dry skin without shearing the tissue.
3. Examine wounds for infection or SCC	Infection can present as increased redness, local pain, odor, and exudate. SCC can present as a nonhealing or rapidly growing wound, a deep ulcer with a raised edge, an area of hyperkeratosis (especially with surrounding raised skin), or a wound with altered sensation (e.g., tingling, increased pain).
4. Position the patient comfortably	Forced air (such as air conditioning, heat, ceiling fans) may need to be turned off. Use a pillow to pad bony prominences. Place a nonabsorbent dressing below the wound to capture B-VEC droplets that migrate from the wound area.
5. Drain blisters	Drain blisters with a sterile needle, scalpel, or clean sharp scissors, using gauze to absorb drainage. Use care when emptying blisters to avoid blister expansion. Leave the blister roof intact to protect the wound area.
6. Apply B-VEC to wounds	B-VEC syringes can be left at room temperature for 3–5 min before application if the temperature is uncomfortable; longer periods are not recommended. Avoid contact of skin with syringe tip itself. Place B-VEC droplets in a 1 cm-by-1cm grid, evenly spaced apart. Start at the top of the wound and work downward. Apply B-VEC into the blister opening at an approximate number of drops to the size of the wound beneath.
7. Cover with a hydrophobic layer	Suggested first-layers are soft-plastic or silicone (Glad^® or Saran^TM Wrap, Mepitel^®, silicone scar sheets), etc. Should be trimmed to fit the shape of the wound (unless patient prefers otherwise). Cover each wound with a hydrophobic layer before moving to the next wound. Should stay in place for ∼24 h after administration (but can vary based on patient preference). Ensure the layer is flat so bunching does not occur and irritate the surrounding skin.
8. Apply standard dressings	Standard dressing material to absorb drainage and pad/protect the body should be larger than the hydrophobic layer. Ensure dressings are not heavy enough to cause overheating. Netting or Tubifast^® are options to hold top dressings in place, but should not contact skin. Continue to cover wounds with non-adherent dressings and ointment until fully healed. If scabbing occurs, apply moisturizer after bathing to allow scabs to soften and detach.
9. Continue application weekly	Wounds should be treated until they are completely closed. Continue weekly administration even when wounds begin to heal. Prioritize wounds that re-open. Allowing a reprieve in treatment or moving to new wound areas while prior-treated wounds have not completely closed is acceptable, but weekly application until closure is recommended.

The versatility of B-VEC may provide new options for HCPs to consider when optimizing wound care after surgery. For example, pseudosyndactyly often requires multiple hand surgeries to separate the digits (52, 53). Skin reepithelization is achieved around 14 – 35 days post operation, while full skin healing may take up to three months (54). HCPs may consider using B-VEC to treat the open areas of skin post-surgery, especially between the digits. Current guidelines post-operation, after the initial change of dressing performed in the operating room with anesthetic, recommend using a non-adherent layer cut to the area of the surgically affected skin and changing dressings every one to three days (54); addition of B-VEC once weekly could be seamlessly introduced into this routine. Another possible application may be to surgical sites after removal of SCC lesions through Mohs micrographic surgery (MMS) or wide-local excision in DEB patients to aid in the healing process at these sites (9, 10, 55). A third potential application is around the ports of G-tubes following their insertion. G-tubes can be valuable in improving BMI and growth in DEB patients (56), but adverse effects like skin complications at the G-tube site and leakage may be present in as many as 70% of cases (57). B-VEC application around the G-tube insertion site may therefore aid in healing in this area and allow for proper nutritional support. Recently, ophthalmic application of B-VEC was associated with improved visual acuity in a DEB patient with cicatrizing conjunctivitis who underwent surgery (58). These different applications for B-VEC post-surgery may provide new options for HCPs when designing a care plan for each specific DEB patient.

Conclusion

The burden of wounds for the DEB community is immense. Painful blistering and open wounds interfere with the ability of DEB patients to perform daily activities, such as bathing, sleeping, and physical exercise. Patients and caregivers spend hours every day changing wound dressings, a process that is costly and uncomfortable. Concerns over life-threatening infections and development of highly aggressive SCCs are at the forefront of DEB management, with a focus on monitoring and prevention. B-VEC fundamentally addresses the defect underlying the wound burden of DEB patients by delivering full-length human COL7 protein to wounds and promoting their durable closure. This review has discussed the burden these wounds have on patients, their caregivers, and the healthcare system, reviewed the Phase 1/2 and 3 clinical trial outcomes for B-VEC, and provided real-world recommendations for DEB patient care and B-VEC application to providers who may take on DEB patients in the clinic. This novel treatment allows for in-office or home application, making it a practical option for DEB patients who are seeking a flexible treatment plan or are unable to visit an office.

B-VEC is engineered to address the wound burden of DEB patients, but this disease can have numerous extracutaneous manifestations and thus requires a multidisciplinary team for long-term care even once B-VEC has been introduced into a patient’s routine. It must be emphasized that even with B-VEC treatment, providers must recognize that there is still an important need for DEB patients to periodically seek specialized care such as SCC surveillance, nutritional and pain support, ophthalmological care, esophageal dilations, and hand surgeries. Following the approval of B-VEC by the FDA, the recommendations provided in this review reflect the suggestions of clinicians and providers who have experience applying B-VEC to DEB wounds. By continuing to optimize the practical administration of B-VEC in the greater context of wound management in DEB, patient outcomes will continue to improve as the healthcare focus shifts to patient-centric considerations.

Compliance with ethical guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Disclosure statement

AP has been an Investigator for AbbVie, Arcutis, Dermavant, Eli Lilly, Incyte, Janssen, Krystal Biotech, and UCB; a consultant for BioCryst, Boehringer-Ingelheim, Bristol Myers Squibb, Dermavant, Johnson & Johnson, Krystal Biotech, LEO Pharma, Mitsubishi Tanabe Pharma, Novartis, Primus Pharmaceuticals, Procter and Gamble, Regeneron, Sanofi/Genzyme, TWI Biotechnology, and UCB; and on the data safety monitoring board for AbbVie, Abeona, Catawba, and Galderma. SVG has been an Investigator for Arcutis, Boehringer-Ingelheim, Castle Biosciences, Dermavant, Incyte, Jeune, Krystal Biotech, Novartis, Pfizer, Sanofi, and consultant and speaker for Krystal Biotech. DA participated in the Phase 3 clinical trial of beremagene geperpavec sponsored by Krystal Biotech. MEG has been an Investigator for AbbVie, Arcutis, Amgen, Anterogen, Dermavant, Eli Lilly, Incyte, Krystal Biotech, Neilsen Biosciences, Novartis, Regeneron, Sanofi; a consultant with honorarium for Abeona, Apogee, Arcutis, Alphyn, Dermavant, Eli Lilly, Incyte, Krystal Biotech, Verrica Pharmaceuticals and on the Speaker’s bureau for Verrica Pharmaceuticals, Regeneron, Sanofi, Genzyme, Eli Lilly, Abbvie, Pfizer, and Krystal Biotech. AWL has been an Investigator for Krystal Biotech and Phoenicis. ISB has been an Investigator for Krystal Biotech and Castle Creek Biosciences. MPM has been an Investigator for Krystal Biotech. All trademarks are the property of their respective owners.

Additional information

Funding

Sponsorship, publication fees and the cost of open access for this article were sponsored by Krystal Biotech, Inc.