Leaflet VYJUVEK 5x10^9 UFP / ml suspension and gel for gel

Vyjuvek 5×109 plaque forming units/mL suspension and gel for gel

2.1 General description

Beremagene geperpavec is a replication-defective Herpes Simplex Type-1 HSV-1-based gene therapyvector that has been genetically modified to express the human type VII collagen (COL7) proteinunder the control of the human cytomegalovirus (hCMV) promoter.

Beremagene geperpavec is produced in Vero cells by recombinant DNA technology.

2.2 Qualitative and quantitative composition

Each vial contains 1 mL extractable volume of suspension containing 5×109 plaque forming units(PFU) of beremagene geperpavec.

After mixing 1 mL of the suspension with the gel, Vyjuvek contains 5×109 PFU in 2.5 mL. Extractablevolume is 2.0 mL (4×109 PFU).

For the full list of excipients, see section 6.1.

Suspension and gel for gel.

The suspension is opalescent yellow to colourless following thaw from its frozen state.

The gel is a clear viscous gel following thaw from its frozen state.

Vyjuvek is indicated for the treatment of wounds in patients with dystrophic epidermolysis bullosa(DEB) with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene, from birth.

Vyjuvek should be initiated by healthcare professionals experienced in the management of patientswith dystrophic epidermolysis bullosa.

Vyjuvek is applied cutaneously to wound(s) once a week in small droplets in a grid-like pattern,approximately 1-cm by 1-cm apart. All wounds may not be possible to be treated at each treatmentvisit.

The recommended total maximum weekly dosing for children from birth up to 3 years old is 1 mL(2×109 PFU). The recommended total maximum weekly dosing for children above 3 years of age,adolescents, and adults is 2 mL (4×109 PFU).

Vyjuvek should be applied to wounds until they are closed before selecting new wound(s) to treat.

Weekly treatment of previously treated wounds should be prioritised if they re-open. If no wounds arepresent, Vyjuvek should not be administered.

The table below provides a reference on dose per approximate size of the wound in children,adolescents, and adults.

Table 1. Dose by wound area

Wound area (cm2)* Dose (PFU)a Volume (mL)< 20 < 4×108 < 0.220 to < 40 4×108 to < 8×108 0.2 to < 0.440 to 60 8×108 to < 1.2×109 0.4 to < 0.660 to < 200 1.2×109 to < 4×109 0.6 to < 2

PFU= plaque forming units.a: The maximum dose in children below 3 years of age is 1 mL (2×109 PFU)

If a dose is missed, Vyjuvek should be administered as soon as possible, and weekly dosing should beresumed thereafter.

No dose adjustment is required in patients ≥ 65 years old.

This medicine contains genetically modified organisms (see section 4.4). During preparation,administration, and disposal, appropriate precautions must be taken. Personal protective equipment(e.g., gloves, mask, and eye protection) should be worn when handling Vyjuvek.

Pregnant women should not prepare or administer Vyjuvek and should avoid direct contact with thetreated wounds, or dressings from the treated wounds (see section 6.6).

For cutaneous use on wounds only.

Prior to cutaneous use the suspension and gel must be thawed, and the suspension must be mixed intothe gel in a pharmacy setting. For detailed instructions on preparation, shelf life after mixing,administration, measures to take in case of accidental exposure, logistics, and disposal of Vyjuvek, seesections 6.3 and 6.6.

A health care professional (HCP) should apply Vyjuvek, either at a healthcare professional setting(e.g., clinic) or the home setting. If deemed appropriate by the healthcare professional, trained patientsor caregivers may also apply Vyjuvek.

Wounds should be gently cleaned prior to cutaneous administration using a product that does notcontain a virucidal agent. Medicinal products and ointments at the wound area should be removed andthe wound should be cleansed prior to Vyjuvek administration to ensure no reduction in its activity(see section 4.5).

Table 2. Steps for administration

Step 1. The Vyjuvek syringe should be primed prior to the initial application by pulling the plungerdown and pushing it upwards, so that a small droplet of Vyjuvek forms at the tip of the syringe.

Step 2. Vyjuvek should be applied to theselected wound, in small dropletsapproximately 1-cm by 1-cm apart (width ofa fingertip) with only the droplet touchingthe wound.

Only the gel should contact the skin. The tipof the syringe should not touch the skin toprevent the contamination of the gel in thesyringe.

Step 3. Once Vyjuvek has been administeredto the wound, a hydrophobic dressing shouldbe applied. The dressing should be cut to asize slightly larger than the wound but mayvary upon patient preference.

Once the Vyjuvek droplets are covered bythe hydrophobic dressing, a thin even layerof Vyjuvek will form within the wound.

Step 4. The standard dressing should be cutto a size larger than the hydrophobicdressing. The standard dressing will beplaced over the hydrophobic dressing toprevent dissemination of the gel to otherareas of the body or close contacts.

The dressing should be left in place for approximately 24 hours after Vyjuvek application. Once the

Vyjuvek dressings are removed, the patient may continue with their standard of care.

Vyjuvek should continue to be administered weekly until the wounds are closed. If previously treatedwounds re-open, Vyjuvek should be applied again. If no wounds are present, Vyjuvek should not beadministered.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of the biological medicinal product, the name and the batchnumber of the administered medicinal product should be clearly recorded.

Squamous cell carcinoma

Vyjuvek should not be applied to wounds with a confirmed or suspicious diagnosis of squamous cellcarcinoma (SCC). Vyjuvek may still be applied to other wounds in patients who develop SCC.

Transmission of an infectious agent

Beremagene geperpavec will not replicate in cells and does not integrate into or otherwise interactwith the native DNA.

Although beremagene geperpavec is tested for sterility, a risk of transmission of infectious agentsexists. Healthcare professionals administering Vyjuvek must, therefore, monitor patients for signs andsymptoms of infections after treatment and treat appropriately, if needed.

Individuals handling beremagene geperpavec or assisting with dressing changes should wearprotective equipment (see section 6.6).

Pregnant women should not handle dressing waste. Carers or HCPs applying the gel should complywith the requirement to cover wounds with dressings. Patients should also be advised to avoidtouching or scratching wound sites to avoid contamination of other areas of the body or close contacts.

Long-term follow-up

Patients are expected to enroll in a non-interventional multi-country study, to assess the long-termsafety of beremagene geperpavec in a real-life setting.

No interaction studies have been conducted with Vyjuvek. Interactions with topical medicinal productshave not been investigated in clinical trials. Other topical medicinal products should not beconcomitantly administered with Vyjuvek.

The safety of immunisation with live viral vaccines during or following Vyjuvek treatment has notbeen studied. There is no data to suggest that Vyjuvek may interfere with the body’s ability toappropriately respond to a live virus vaccines.

There are no data from the use of beremagene geperpavec in pregnant women. Animal studies areinsufficient with respect to reproductive toxicity (see section 5.3).

The use of Vyjuvek is not recommended during pregnancy.

It is unknown whether beremagene geperpavec is excreted in human milk.

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Vyjuvek therapy taking into account the benefit of breast feeding for the child and the benefit oftherapy for the woman.

No nonclinical or clinical studies have been performed to evaluate the effect of beremagenegeperpavec on fertility.

Vyjuvek has no or negligible influence on the ability to drive or use machines.

Eighteen patients (58%) in the clinical trial reported at least one adverse reaction. The most commonlyreported adverse reactions were chills (9.7%) and pruritus (9.7%)..

No adverse reactions led to discontinuation.

Unless otherwise stated, the frequencies of adverse reactions are based on all causal adverse eventfrequencies identified in 31 patients exposed to beremagene geperpavec during a median duration of25 weeks in the Phase 3 randomised, intra-subject placebo-controlled study. See section 5.1 forinformation on the main characteristics of patients in clinical trial.

In the following table, adverse reactions are listed by MedDRA system organ class (SOC), preferredterm, and by frequency. Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to< 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), notknown (cannot be estimated from the available data).

Table 3. Adverse reactions

All subjects

System organ class (N=31)

Preferred term

Cough Common

Rhinorrhea Common

Pruritus Common

Erythema Common

Rash Common

Chills Common

Of the 31 subjects in the Phase 3 study, 19 (61%) were paediatric subjects (17 years of age or less),including 3 (9.7%) aged 3 years or less. Of the 19 paediatric subjects, 8 were female (42%).

Given the identity of the product, and its route of administration and localized containment, frequency,type and severity of adverse reactions in children are expected to be the same as in adults.

There was minimal evidence of systemic vector exposure after cutaneous application of Vyjuvek.

Antibodies against the viral vector (HSV-1) and transgene protein (COL7) were evaluated in a subsetof subjects in the randomised, intra-subject placebo-controlled clinical study. A total of 64% ofevaluated subjects (14/22) were anti-HSV-1 antibody positive at baseline. Six of the 8 anti-HSV-1seronegative subjects seroconverted by week 26 following treatment with Vyjuvek. For subjects withavailable matched baseline and end-of-study serum samples, anti-drug antibodies (ADAs) to COL7were detected in 72% (13/18) of subjects treated with Vyjuvek for up to 26 weeks. Neutralizingimmunity was not observed at first or repeated Vyjuvek exposure. The impact of seroconversion onmaintenance of treatment effect is unknown as data are not available after 26 weeks.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose of Vyjuvek has been reported. Symptomatic and supportive treatment, as deemednecessary by the treating healthcare professional, is advised in case of overdose.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Preparations for the treatment of wounds and ulcers, cicatrizants, ATCcode: D03AX16

Beremagene geperpavec is a gene therapy based on an engineered, replication-defective herpessimplex virus 1 (HSV-1) encoded with COL7A1 gene, addressing the underlying genetic cause ofdystrophic epidermolysis bullosa. The HSV-1 vector belongs to the human herpes virus (HHV) familyof double-stranded DNA viruses. Upon cutaneous application to the wounds, beremagene geperpaveccan transduce both keratinocytes and fibroblasts. Following entry of beremagene geperpavec into thecells, the vector genome is deposited in the nucleus without integrating into, or otherwise disrupting,host cell DNA. Once in the nucleus, transcription of the encoded human COL7A1 is initiated. Theresulting transcripts allow for production and secretion of COL7 by the cell in its mature form. These

COL7 molecules arrange themselves into long, thin bundles that form anchoring fibrils. The anchoringfibrils hold the epidermis and dermis together and are essential for maintaining the integrity of theskin.

The efficacy of Vyjuvek in subjects one year of age and older with DEB with mutation(s) in the

COL7A1 gene was evaluated in a randomised controlled trial. All study subjects had DEB withgenetically confirmed mutation(s) in the COL7A1 gene. Two comparable wounds in each subject wereselected and randomised to receive either cutaneous application of beremagene geperpavec or placebo(gel only) weekly for 26 weeks. The total maximum weekly dose was defined based on age category:subjects ≥ 6 months to < 3 years received 1.6×109 PFU/week, subjects ≥ 3 years to < 6 years received2.4×109 PFU/week, and subjects ≥ 6 years received 3.2×109 PFU/week.

The study enrolled 31 subjects (20 males and 11 females), including 30 subjects with autosomalrecessive DEB and one subject with autosomal dominant DEB. The size of the beremagenegeperpavec-treated primary wounds ranged from 2 to 57 cm2, with 74% of wounds < 20 cm2 and 19%from 20 to < 40 cm2. The size of the placebo gel-treated wounds ranged from 2 to 52 cm2, with 71% ofwounds < 20 cm2 and 26% from 20 to < 40 cm2. The largest size secondary wound treated was≥ 130 cm2. The mean age of the subjects was 17 years (1 year to 44 years), including 61% paediatricsubjects (n=19, age 1 to < 17 years) and 9.7% subjects less than 3 years. Sixty-four percent of subjectswere White; 19% were Asian, and the remainder were American Indian or Alaska Native.

Efficacy was assessed on the basis of improved wound healing defined as the difference in theproportion of complete (100%) wound closure at 24 weeks confirmed at two consecutive study visits 2weeks apart, assessed at weeks 22 and 24 or at weeks 24 and 26, between the beremagene geperpavec

- treated and the placebo gel-treated wounds. Efficacy was also assessed by the difference in theproportion of complete wound closure assessed at weeks 8 and 10 or at both weeks 10 and 12 betweenthe beremagene geperpavec-treated and the placebo gel-treated wounds. Complete wound healing wasdefined as 100% wound closure from the exact wound area selected at baseline, specified as skin re-epithelialization without drainage, evaluated at two consecutive visits two weeks apart. The efficacyresults are summarised in Table 4.

Table 4. Primary end point and key secondary end point*

Wound closure assessment Primary Primary Absolute difference ptimepoints wounds wounds (95% CI) valueexposed to exposed toberemagene placebogeperpavec (N=31)(N=31)

Primary end point: complete 20.9 (67%) 6.7 (22%) 46 0.002wound healing at 6 (24-68%)months†‡

Key secondary end point: 21.9 (71%) 6.1 (20%) 51 <0.001complete wound healing at (29-73%)3months‡

*The primary and key secondary end points were analysed in the intention-to-treat population.

Multiple-imputation methods were used to account for missing data. Fractional counts are dueto the multiple-imputation procedure used for analysis. Hypothesis testing was performed withthe use of exact McNemar’s test.

†Primary wounds were assessed at weeks 22 and 24 or weeks 24 and 26.‡Primary wounds were assessed at weeks 8 and 10 or weeks 10 and 12.

In the confirmatory trial, systemic exposure assessments were conducted at weekly clinical site visitsvia quantification of beremagene geperpavec genomes in blood and urine samples (vector shedding)using a validated qPCR assay. All blood samples and all but one urine sample collected throughout thestudy were below the limit of detection/quantification for all subjects, indicating no significantsystemic exposure of the subjects to the vector.

Clinical pharmacokinetics and shedding

Biodistribution and vector shedding studies were supportive and indicated a lack of systemic exposureafter localised, cutaneous administration of beremagene geperpavec.

Non-clinical data revealed no special hazard for humans based on conventional studies of single andrepeated dose administration in toxicology studies.

Animal developmental and reproductive toxicity studies have not been conducted.

No studies have been conducted to evaluate the effects of beremagene geperpavec on carcinogenesis,mutagenesis, or impairment of fertility.

6 PHARMACEUTICAL PARTICULARS

Suspension

Glycerol (E422)

Sodium chloride

Disodium phosphate (E339)

Potassium chloride (E508)

Dipotassium phosphate (E340)

Hypromellose (E464)

Trometamol

Sodium chloride

Disodium phosphate (E339)

Dipotassium phosphate (E340)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened cartons2 years when stored in the freezer.

After thawing

If a freezer is not available, the carton(s) may be stored in a refrigerator (2°C to 8°C) for up to 1month.

Once stored in the refrigerator, the medicinal product should not be re-frozen.

After mixing

Chemical and physical in-use stability has been demonstrated for 168 hours (7 days) at 2-8°C.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8°C, unless mixing has taken place in controlledand validated aseptic conditions.

Syringes can be stored at room temperature for up to 8 hours.

Transport conditions for mixed product

Transport mixed product at 2-8°C to site of administration.

Unopened cartons

Store frozen at -15°C to -25°C. Transport frozen (< -20°C).

Keep the vials in the carton prior to thawing in order to protect from light.

After thawing and mixing

For storage conditions after thawing and after mixing of the medicinal product, see section 6.3.

Each carton of Vyjuvek contains one vial of suspension and one vial of gel.

Suspension1 mL extractable volume containing 5×109 PFU in a cyclo-olefin copolymer vial with a thermoplasticelastomer closure and green cap.

Gel1.5 mL fill volume in a separate Type-1 glass vial with a bromobutyl elastomer stopper and blue cap.

This medicine contains genetically modified organisms (see section 4.4). During preparation,administration, and disposal, appropriate precautions must be taken. Personal protective equipment(e.g., gloves, mask, and eye protection) should be worn when handling Vyjuvek.

HCPs or carers who are pregnant should not administer Vyjuvek and should not come into directcontact with treated wounds, or all material that has been in contact with treated wounds.

Preparation prior to administration

Follow the steps below for Vyjuvek preparation.

Each carton contains one vial of suspension (1 mL extractable volume containing 5×109 PFU) and onevial of excipient gel (1.5 mL).

Concentration of the medicinal product is 2×109 PFU/mL after mixing.

Table 5. Preparation steps prior to administration

Before use, frozen vials must be Step 1 Step 2removed from the carton and left atroom temperature. (Step 1).

Once the vials are thawed (forapproximately 30 minutes), theycannot be re-frozen. (Step 2)

Visually inspect the suspension vial.

The suspension may contain whiteto off-white particulates that areinherent to the product.

The suspension may vary in colourfrom opalescent yellow tocolourless. Do not use thismedication if you notice anydiscolouration.

Visually inspect the gel vial. The gelis a clear, colourless, viscous gel.

Do not use the gel if you notice anyparticulates or discolouration.

Gently invert the suspension vial 4-5times to mix the contents.

Remove the caps from the vials and Vyjuvekclean each vial stopper with an suspensionalcohol pad. Allow them to dry. Gel vial (left) vial (right)

Using an aseptic technique, Step 1 Step 2withdraw 1 mL of thawedsuspension (Step 1) using a 3 mLsyringe and needle (e.g., 16G or18G).

Transfer 1 mL of thawed suspensioninto the thawed gel vial.(Step 2).

Vyjuvek suspension vial Gel vial

Without removing the needle fromthe gel vial, pull the needle so it isabove the liquid, remove 1 mL of air(air pocket) to vent the gel vialfollowing the addition of the 1 mLof Vyjuvek suspension, and onlythen remove the syringe and needleand discard them.

The vial with the combinedsuspension and gel will be referredto as the Vyjuvek vial for theremainder of these instructions. Air pocket

Vyjuvek vial

Place an alcohol pad on the gel vialstopper and shake the vialvigorously by hand for at least 10seconds. The excipient gel shouldincorporate the suspension to form ahomogeneous gel.

Visually inspect the Vyjuvek vial.

The gel containing the activesubstance may contain white to off-white particulates that are inherentto the product.

The mixed product, like thesuspension, may vary in colour fromopalescent yellow to colourless. Donot use this medication if you noticeany discolouration. Vyjuvek vial

Connect a new needle (e.g., 16G or Step 1 Step 218G) to a 1 mL syringe and slowlywithdraw 0.5 mL of Vyjuvek(Step 1). Do not invert the vial towithdraw the Vyjuvek syringe.

Without removing the needle fromthe vial, lift the tip of the needle Airpocketabove the Vyjuvek and disconnect Airthe syringe, leaving the needle pocketwithin the vial stopper (Step 2).

An air pocket may form, this isnormal.

Vyjuvek vial

Gently manipulate the plunger upand down to remove the air pocket.

DO NOT flick the syringe toremove the air pocket. Airpocket

Small bubbles may remain, this isnormal.

Cap the syringe and set aside.

Obtain the next 1 mL syringe and connectit to the needle in the gel vial stopper andwithdraw 0.5 mL of Vyjuvek, remove theair pocket and cap the syringe.

Extractable volume is 2.0 mL(4×109 PFU).

Repeat as applicable based on therecommended posology.

Label the syringe with patient’s ID, nameof the product, lot number, EXP date, andstorage conditions. Avoid covering thesyringe marks needed for administration.

Place the capped Vyjuvek syringes into asealable plastic bag .

Label the plastic bag with patient’s ID,name of the product, lot number, EXPdate, and storage conditions.

No more than 2 mL (four 0.5 mLsyringes) can be used in the same week asthis is the maximum weekly dose.

Place a sealable plastic bag with Vyjuvek syringes into an appropriate insulated tertiary container(“outer container”) to maintain a transport temperature of 2°C to 8°C suitable for transport and inorder to protect from light.

The outer container needs to be fully closed for transportation.

Open the outer container designed for transportation of prepared Vyjuvek syringes only at the site ofadministration.).

Reception and storage at administration site

After receipt of the outer container, store the outer container in a secure, room-temperature locationthat is clean, out of reach of children, and free from potential contamination.

Only the person responsible for the administration should open the outer container.

The person responsible for the administration should check that the outer container is intact and thereare no signs of leakage before use (see section 4.2).

Measures to take in case of accidental exposure

In case of accidental exposure local guidance for pharmaceutical waste must be followed.

All surfaces that may have come in contact with beremagene geperpavec must be cleaned and all spillsmust be disinfected with a virucidal agent such as 70% isopropyl alcohol, 6% hydrogen peroxide or< 0.4% ammonium chloride.

In the event of an accidental exposure through a splash to the eyes or mucous membranes, flush withclean water for at least 5 minutes.

In the event of exposure to intact skin or needlestick injury, clean the affected area thoroughly withsoap and water and/or a disinfectant.

Precautions to be taken for the disposal of the medicinal product

Any unused medicinal product or waste material (e.g., vial, syringe, needle, cleaning materials) thatthat may have come in contact with Vyjuvek should be disposed of in compliance with local guidancefor pharmaceutical waste.

Disinfect dressings with a virucidal agent, such as 70% isopropyl alcohol, 6% hydrogen peroxide or< 0.4% ammonium chloride, and dispose of the disinfected dressings in a separate sealed plastic bag inhousehold waste or according to local requirements.

Krystal Biotech Netherlands, B.V.

Atrium Gebouw

Strawinskylaan 3051

Amsterdam 1077 ZX

Netherlands

EU/1/25/1918/001

Date of first authorisation: 23 April 2025

Month YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu