VYJUVEK

1 INDICATIONS AND USAGE VYJUVEK is indicated for the treatment of wounds in adult and pediatric patients with dystrophic epidermolysis bullosa (DEB) with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene. VYJUVEK is a herpes-simplex virus type 1 (HSV-1) vector-based gene therapy indicated for the treatment of wounds in adult and pediatric patients with dystrophic epidermolysis bullosa (DEB) with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene. (1)

2 DOSAGE AND ADMINISTRATION For topical application only. Age Range Maximum Weekly Dose (PFU) Maximum Weekly Volume (mL)* <3 years old 2×10 9 1 ≥3 years old 4×10 9 2 PFU=plaque forming units; mL=milliliter *Maximum weekly volume after mixing VYJUVEK biological suspension with excipient gel Apply VYJUVEK gel to the selected wound(s) in droplets spaced evenly within the wound, approximately 1cm-by-1cm apart. (2.3) Apply VYJUVEK gel on wounds once a week. (2.1) See full prescribing information for instructions on preparation and handling, (2.2) and administration (2.3) . 2.1 Dose For topical application on wounds only. The recommended dose of VYJUVEK gel is based on age (Table 1). VYJUVEK gel is applied topically to wound(s) once a week. Table 1 Maximum Weekly Dose of VYJUVEK by Age Age Range Maximum Weekly Dose (PFU) Maximum Weekly Volume (mL)* <3 years old 2×10 9 1 ≥3 years old 4×10 9 2 PFU=plaque forming unit; mL=milliliter *Maximum weekly volume is the volume after mixing VYJUVEK biological suspension with excipient gel. It may not be possible to apply VYJUVEK gel to all the wounds at each treatment visit. Apply VYJUVEK gel to wounds until they are closed before selecting new wound(s) to treat. Prioritize weekly treatment to previously treated wounds if they re-open. [ see Administration (2.3) ] If a dose is missed, apply VYJUVEK gel as soon as possible and resume weekly dosing thereafter. 2.2 Preparation Important Preparation Instructions Prepare VYJUVEK gel at the pharmacy by mixing the VYJUVEK biological suspension into the excipient gel for immediate use. [see Storage and Handling ( 16.2 )] The VYJUVEK gel prepared at the pharmacy, should be applied by a healthcare professional (HCP), patient, or caregiver either at a healthcare professional setting (e.g., clinic) or at a home setting. Individuals who are pregnant should not prepare or apply VYJUVEK gel and should avoid direct contact with the treated wounds or dressings from treated wounds [see Accidental Exposure to VYJUVEK ( 5.1 )]. Below is the list of supplies needed for VYJUVEK gel preparation: One (1) carton containing one (1) VYJUVEK biological suspension vial and one (1) excipient gel vial (Figure 1) Two (2) 18-gauge needles Two (2) to four (4) 1 mL administration syringes One (1) 3 mL preparation syringe Two (2) to four (4) syringe caps Protective gloves 70% isopropyl alcohol pads Biohazard container Labels for administration syringes Virucidal agent for clean-up Follow the steps below for VYJUVEK gel preparation. PREPARE THE PREPARATION SYRINGE 1. Wash hands and put on protective gloves. 2. Remove both vials from the carton and thaw the VYJUVEK biological suspension vial and the excipient gel vial at room temperature for AT LEAST 20 minutes (Figure 1). Figure 1 Carton containing the VYJUVEK biological suspension vial and excipient gel vial Note: Visually inspect the vials to ensure both are in liquid form and completely thawed. Excipient gel is more viscous and will take longer to thaw (Figure 2). Figure 2 Timelapse of excipient gel thaw from 0 minutes to 20 minutes Note: Once either the VYJUVEK biological suspension or the excipient gel is thawed, do not refreeze. 3. Invert the VYJUVEK biological suspension vial 4-5 times. Do not invert the excipient gel vial. 4. Remove the caps from the vials and clean each vial stopper with a 70% isopropyl alcohol pad. Allow them to dry. 5. Aseptically connect an 18-gauge needle to the 3 mL preparation syringe. 6. Remove the needle cap and puncture the VYJUVEK biological suspension vial stopper. 7. Hold the vial at 45 to 90 degrees and withdraw 1 mL of VYJUVEK biological suspension into the preparation syringe (Figure 3). 8. Remove the preparation syringe (still connected to the needle) containing 1 mL of VYJUVEK biological suspension from the vial. Do NOT engage the safety lock. Figure 3 The removal of 1 mL of biological suspension using the preparation syringe 9. Discard the VYJUVEK biological suspension vial in the biohaz…

5 WARNINGS AND PRECAUTIONS Accidental Exposure to VYJUVEK: Avoid direct contact with treated wounds and dressings of treated wounds until the next dressing change, following application. Clean the affected area if accidental exposure occurs. (5.1) 5.1 Accidental Exposure to VYJUVEK Accidental exposure to VYJUVEK may occur to close contacts and caregivers. VYJUVEK is a genetically modified, herpes-simplex virus type 1 vector-based, replication-deficient, non-integrating gene therapy. VYJUVEK will not replicate in the patient’s cells and does not integrate into the patient cells’ native genetic material. For precautions, Avoid direct contact with treated wounds (e.g., touching or scratching) and dressings of treated wounds until the next dressing change. Wear protective gloves when assisting patients with changing wound dressings and handling the disposal. In the event of an accidental exposure through a splash to the eyes or mucous membranes, flush with clean water for at least 15 minutes. 5.1 Accidental Exposure to VYJUVEK Accidental exposure to VYJUVEK may occur to close contacts and caregivers. VYJUVEK is a genetically modified, herpes-simplex virus type 1 vector-based, replication-deficient, non-integrating gene therapy. VYJUVEK will not replicate in the patient’s cells and does not integrate into the patient cells’ native genetic material. For precautions, Avoid direct contact with treated wounds (e.g., touching or scratching) and dressings of treated wounds until the next dressing change. Wear protective gloves when assisting patients with changing wound dressings and handling the disposal. In the event of an accidental exposure through a splash to the eyes or mucous membranes, flush with clean water for at least 15 minutes.

4 CONTRAINDICATIONS None. None. (4)

7 DRUG INTERACTIONS No drug interaction studies have been performed.

8.1 Pregnancy Risk Summary There are no data with VYJUVEK gel use in pregnant women to inform a drug-associated risk. Animal developmental and reproductive toxicity studies have not been conducted with VYJUVEK. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations If the patient becomes pregnant while being administered VYJUVEK gel, the patient should be apprised of the potential hazards to the fetus and neonate. Women of childbearing potential should be advised to use an effective method of contraception to prevent pregnancy during treatment with VYJUVEK gel.

12.3 Pharmacokinetics In an initial clinical study, viral vector DNA was detected in skin swab samples in all nine treated patients, with maximum level ranging from 5.1×10 4 to 4.1×10 8 vector genomes. In 6 out of 9 patients (67%), negative shedding was confirmed with three measurements below limit of detection within 8 weeks of treatment with VYJUVEK. No viral vector DNA was detected in blood or urine. In the 31-patient randomized, double-blind, intra-patient placebo-controlled trial, systemic and potential environmental exposure assessments were conducted at weekly clinical site visits via quantification of VYJUVEK genomes in blood, urine, skin swabs, and bandage samples (vector shedding) using a validated qPCR assay, and detection of infectious viral particles in skin swabs (infectivity) using a validated plaque titer assay. All blood samples and all but one urine sample collected throughout the study were below the limit of detection. Skin swabs from 19 of the 31 patients (61%) were positive for viral vector following treatment with VYJUVEK. Negative shedding from skin swabs was achieved in 16 of the 19 patients (84%) within six weeks following treatment with VYJUVEK. Most wound dressings (94%, 29/31) contained a range of detectable vector genomes. However, no extracellular infectious particles were detected on the skin surface of any patient at any timepoint tested, after topical VYJUVEK application.

6 ADVERSE REACTIONS The most common adverse reactions (>5%) were itching, chills, redness, rash, cough, and runny nose. The most common adverse drug reactions (incidence >5%) were itching, chills, redness, rash, cough, and runny nose. (6) To report SUSPECTED ADVERSE REACTIONS, contact Krystal Biotech, Inc. at 1-844-557-9782 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflects exposure to VYJUVEK gel in a randomized, intra-patient placebo‑controlled study. A total of 31 patients with dystrophic epidermolysis bullosa (DEB), including 30 patients with autosomal recessive DEB and one patient with autosomal dominant DEB received topical administration of VYJUVEK gel to their wounds. The age of the patients ranged from 1 year to 44 years (mean age 17 years). Of the 31 patients, 19 (61%) were pediatric patients (less than 17 years of age), and 11 (36%) were females. Each patient received weekly topical application of VYJUVEK gel at one or more wound sites and placebo at a matching wound site as an intra-subject comparator. The median duration of exposure to VYJUVEK gel was 25 weeks. The most frequent adverse reactions (incidence >5%) observed in the study are summarized in Table 3. There were no discontinuations due to adverse reactions. Table 3 Adverse Reactions (incidence >5%) Following Treatment with VYJUVEK gel (n =31) Adverse Reactions Patients n (%) Itching 3 (10) Chills 3 (10) Redness 2 (6) Rash 2 (6) Cough 2 (6) Runny Nose 2 (6) In addition, the safety profile of VYJUVEK in two patients with autosomal recessive DEB (RDEB) of six and seven months of age, respectively, who received topical VYJUVEK gel weekly in an open-label study was similar to the safety profile of VYJUVEK observed in the randomized, intra-patient placebo‑controlled study described above. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflects exposure to VYJUVEK gel in a randomized, intra-patient placebo‑controlled study. A total of 31 patients with dystrophic epidermolysis bullosa (DEB), including 30 patients with autosomal recessive DEB and one patient with autosomal dominant DEB received topical administration of VYJUVEK gel to their wounds. The age of the patients ranged from 1 year to 44 years (mean age 17 years). Of the 31 patients, 19 (61%) were pediatric patients (less than 17 years of age), and 11 (36%) were females. Each patient received weekly topical application of VYJUVEK gel at one or more wound sites and placebo at a matching wound site as an intra-subject comparator. The median duration of exposure to VYJUVEK gel was 25 weeks. The most frequent adverse reactions (incidence >5%) observed in the study are summarized in Table 3. There were no discontinuations due to adverse reactions. Table 3 Adverse Reactions (incidence >5%) Following Treatment with VYJUVEK gel (n =31) Adverse Reactions Patients n (%) Itching 3 (10) Chills 3 (10) Redness 2 (6) Rash 2 (6) Cough 2 (6) Runny Nose 2 (6) In addition, the safety profile of VYJUVEK in two patients with autosomal recessive DEB (RDEB) of six and seven months of age, respectively, who received topical VYJUVEK gel weekly in an open-label study was similar to the safety profile of VYJUVEK observed in the randomized, intra-patient placebo‑controlled study described above.