Repurposing Dupilumab for Management of Pruritic Genetic Inflammatory Skin Disorders

Inclusion Criteria:

1. Male or female > 6 months of age at screening visit

2. Clinical diagnosis of a genetic skin disorder at the screening visit, ideally withgenetic or histological confirmation.

3. Must have had the gene with one or more variants identified by genotyping. If thegenotype has not been performed or has not been performed at a CLIA-approvedlaboratory, be willing to provide a sample (saliva, buccal swab, blood) for genetictesting before starting the dupilumab.

4. Average Itch Numerical Rating Scale (NRS) ≥ 4 and Worst Itch NRS of at least 5during the previous 7 days (self-reported if >8 years old; proxy reported if under 8years)

5. Must be willing to provide information weekly about Average and Worst Itch/self- orproxy-assessed severity and wear the sensor device to track itch and sleep weeklythroughout the first 24 weeks of the trial (Parts A and B).

6. Must be willing and able to adhere to the prohibitions and restrictions specified inthis protocol.

7. Subject, parent/caregiver or legal guardians, as appropriate, are able to understandand complete the study requirements and study-related questionnaires

Exclusion Criteria:

1. Subjects < 6 months of age at screening visit.

2. Unable to provide informed consent or assent (or who do not have consent from aLegally Authorized Representative if < 18 years).

3. Diagnosis of ichthyosis vulgaris as the sole inherited disorder

4. Used of dupilumab within 5 drug half-lives (105 days) of baseline visit

5. Subjects who have used any of the following treatments within 4 weeks, or within aperiod equal to 5 times the half-life of the drug, before the baseline visit,whichever is longer:

6. Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids,cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors,azathioprine, methotrexate, etc.), systemic anti-inflammatory medication, orphototherapy

7. Other biologics: within 5 half-lives (if known) or 16 weeks, whichever islonger

8. Initiation of topical or systemic retinoids, topical keratolytics, or topicalanti-inflammatory agents within 4 weeks before study start/Part A (systemicretinoids and topical medications/emollients can be used during the trial if startedat least 4 wks before the observation period and continued throughout Parts A andB). Note: Rescue therapy for disease flares or local infection will be allowed perinvestigator discretion but must be for no more than a total of 1 week during any 4-week period and, if topical, involve application to less than 10% BSA.

9. Subjects with active infections or recent history of serious infections,malignancies or history of malignancies, or any severe, progressive, or uncontrolledrenal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic orpsychiatric cerebral disease, or signs or symptoms thereof. It is recognized thatpatients with ichthyosis may have arthritis, while patients with junctional ordystrophic EB may have a variety of associated issues (eg nutritional, anemia, etc).The decision to include will be based on investigator's discretion but must reflectthe likelihood for stable disease and lack of anticipated interference withassessment of itch.

10. Treatment with a live (attenuated) vaccine within 4 weeks before the Week 0 visitwhen dupilumab is initiated; use of vaccination during the study requiresconsultation with the study investigator and primary care provider.

11. Active acute or chronic infection requiring treatment with systemic antibiotics/anti-virals/ anti-fungals within 2 weeks before the initiation of dupilumab (startof dupilumab can be delayed). Delay in initiation because of treatment with atopical antimicrobial to a localized superficial site will be determined by theinvestigator.