The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis

Inclusion Criteria:

1. Subject is male or female, 6 years of age and older at Visit 2 (Baseline).

2. Subject has provided written informed consent/assent. A subject under 18 years ofage must provide written informed assent and be accompanied by the parent or legalguardian at the time of consent/assent signing. The parent or legal guardian mustprovide informed consent for the subject. If a subject becomes 18 years of ageduring the study, the subject must provide written informed consent at that time tocontinue study participation.

3. Females must be postmenopausal (defined as amenorrhea greater than 12 consecutivemonths in women 50 years of age and older), surgically sterile (hysterectomy,bilateral salpingectomy, or bilateral oophorectomy), or use 2 acceptable forms ofbirth control. WOCBP must have a negative serum pregnancy test at screening andnegative urine pregnancy test (UPT) at Visit 2 (Baseline) (UPTs must have a minimumsensitivity to detect 25 mIU beta human chorionic gonadotropin [β hCG]/mL). Femalesubjects who become sexually active or begin to have relations with a partner duringthe study must agree to use 2 forms of birth control for 30 days prior to havingrelations and to continue such forms of birth control for the duration of the study.

4. Subject has clinical diagnosis of CI and has a genetic confirmation of either ARCI (including but not exclusively transglutaminase 1-deficient, ALOX-12B) or RXLI (e.g., deletion of steroid sulfatase gene) subtypes of CI. Other geneticallyconfirmed ARCI-LI mutations can potentially be enrolled as long as the phenotype isconsistent with ARCI and the other inclusion criteria are met, as determined by theInvestigator.

5. The amount of CI affected skin in the Treatment Area at Baseline will be between aminimum of 10% and maximum of 90% of the total BSA (1% BSA is approximately equal tothe surface area of the subject's palm and fingers, with the fingers extended yetgrouped together, creating a flat oval-like surface area).

• For the Optional Maximal Use arm: The amount of CI affected skin in the TreatmentArea at Baseline will be between a minimum of 75% and maximum of 90% of the totalBSA.

6. Documented history of moderate to severe disease at Screening. Subject's designatedVIIS Assessment Areas at Baseline (not applicable for Optional Maximal Use arm):

• Include any of the 4 VIIS Assessment Areas that have some CI disease involving: (a) the upper back from the posterior axillary fold to the other encompassingthe T1-T10, (b) the upper arm (excluding elbows), left or right, (c) theshin/lower leg (the portion below the proximal aspect of the kneecap), left orright, and (d) dorsal foot (left or right); AND

• At least 2 of the 4 VIIS Assessment Areas MUST have a scaling score of 3 ormore.

7. Subject's IGA score in the Treatment Area at Baseline must be 3 or more.

8. Subject and parent/guardian (if applicable) are willing and able to apply the studytreatment(s) as directed, comply with study instructions, and commit to allfollow-up visits for the duration of the study.

9. Subject, in the Investigator's opinion, is in good general health and free of anydisease state or physical condition that might impair evaluation of the TreatmentAreas or exposes the subject to an unacceptable risk by study participation.

Exclusion Criteria:

1. Subject is pregnant, lactating, or is planning to become pregnant during the study.

2. Subject has inflammatory skin diseases that confound the interpretation of results (e.g., atopic dermatitis) unrelated to ichthyosis.

3. Subject has genetic abnormality consistent with non-lamellar type or syndromicichthyoses (including but not exclusively KRT1, KRT10, KRT2, GJB3, GJB4, CDSN)

4. Subject, in the Treatment Areas, has used: (a) any topical prescription orover-the-counter (OTC) therapies (except emollients, keratolytics, and topicalsteroids - see below), that are intended for, or that in the opinion of theInvestigator, may improve CI within 2 weeks of Visit 2 (Baseline), or (b)keratolytics or topical corticosteroids within 5 days prior to Visit 2 (Baseline).

5. Subject, in the Treatment Areas, has used TMB-001 in the past or oral isotretinoinin the past 12 months (not applicable for Optional Maximal Use arm).

6. Subject has used any topical products in the Treatment Areas, including blandemollients, on Visit 2 (Baseline).

7. Subject has used ultraviolet (UV) treatment within 4 weeks prior to Visit 2 (Baseline).

8. Subject has undergone systemic therapies using vitamin A supplements or St. John'sWort within 4 weeks prior to Visit 2 (Baseline). Note: Use of a multivitaminincluding vitamin A is not exclusionary provided it is taken as directed on thepackaging.

9. Subject is immunosuppressed (e.g., human immunodeficiency virus, systemicmalignancy, graft host disease) or receives systemic immunotherapy.

10. Subject is currently taking concomitant immunosuppressive drugs, including systemiccorticosteroids, within 2 weeks of Visit 2 (Baseline).

11. Subject has untreated secondary infections; however, subject may become eligibleafter successful treatment of his/her infection(s) at the Investigator's discretion.

12. Subject is currently enrolled in an investigational drug or device study or has usedan investigational drug or investigational device treatment within 30 days or fivehalf-lives prior to Visit 2 (Baseline).

13. Subject has lesions suspicious for skin cancer (if skin cancer is not ruled out bybiopsy) or untreated skin cancers within the Treatment Areas.

14. Subject has a physical condition or other dermatologic disorder that, in theInvestigator's opinion, might impair evaluation of CI, or that exposes the subjectto unacceptable risk by study participation.

15. Subjects with ALT or AST >2 x Upper Limit of Normal (ULN) and/or creatinine >1.5 xULN.

16. Subject is unable to communicate or cooperate with the Investigator due to languageproblems, impaired cerebral function, or physical limitations.

17. Subject has a history of drug or alcohol abuse within the past 6 months, or ifsuspected to be noncompliant or is unlikely to comply with the requirements of thestudy protocol (e.g., due to alcoholism, drug dependency, mental incapacity) in theopinion of the Investigator.

18. Subject has a history of sensitivity to any of the ingredients in the studytreatments.