Topical Sirolimus for Plantar Keratoderma in Adults With Pachyonychia Congenita (PC)

Inclusion Criteria:

- Subjects must

1. Be capable of understanding the purpose and risks of the study and sign a
written Informed Consent Form (ICF)

2. Be male or female ≥ 16 years of age at the time of the screening visit

3. Have a confirmed diagnosis of PC by genotyping (e.g., familial) and clinically
correlated painful keratoderma.

4. Have roughly symmetrical calluses of similar severity on the plantar surface of
both feet

5. Weigh at least 40 kg (88.2 lbs.)

6. Have laboratory values within the range of normal

7. Women of childbearing potential must have a negative serum pregnancy test on Day
-14 and a negative urine pregnancy test within 48 hours prior to subject's
assignment to study treatment at the baseline visit (Visit 1, Week 1, Day 1).
All female subjects (including those with tubal ligations) will be considered to
be of childbearing potential unless one or more of the following criteria are
met:

- Over age 60

- Amenorrheic for at least 2 years if age 45-60 years

- Have had a hysterectomy and/or bilateral oophorectomy

8. Subjects with reproductive potential and who are sexually active must agree to
use double-barrier contraception methods BEFORE beginning the study and for the
duration of the study (37 weeks) or for 12 weeks after the last dose if study
drug is discontinued prematurely

Exclusion Criteria:

- A Subject with any of the following criteria is not eligible for inclusion in this
study:

1. Use of other investigational drugs within 30 days of the screening visit (for
dermatologic drugs see below) and/or has not recovered from any side effects of
prior investigational drugs or procedure in the affected area (e.g., a biopsy)

2. Significant condition in the dermatologic treatment area such as trauma, which
could impair evaluation for the treatment of PC or nonhealing chronic wound,

3. History of hypersensitivity to any of the study drugs or to drugs of similar
chemical classes or history of serious allergic reaction; known allergy to
sirolimus

4. Prior history of grafting surgeries or other surgeries in the dermatologic
treatment area

5. Prior history of liver disease

6. Poorly controlled hyperlipidemia

7. Pregnant or nursing (lactating) female, or a positive serum pregnancy test on
Day -14 and/or a positive urine pregnancy test within 48 hours of initiation of
treatment

8. Active infection (i.e. bacterial, viral, parasitic or fungal) either
systemically or local near the site of treatment requiring chronic or prolonged
use of antimicrobial agents

9. Known immunodeficiency including:

1. Hepatitis A

2. Hepatitis B

3. Hepatitis C

4. Human Immunodeficiency Virus (HIV)

10. Serious known concurrent medical illness or infection, or any medical condition
that could potentially present a safety risk and/or prevent compliance with the
requirements of the protocol

11. Any other severe, acute or chronic medical or psychiatric condition (including
current or history of substance abuse) or clinical laboratory abnormalities

12. Current malignancy or a history of malignancy (within the previous 5 years)

13. Myocardial infarction within 6 months prior to the baseline visit (Visit 1) or
history of cardiac dysrhythmia E2. Prior and Current Treatment

14. Unable to be discontinued from drugs known to either be inducers or inhibitors
(moderate or strong) of cytochrome P450 isoenzymes

15. Unable to be discontinued from drugs known to be strong or moderate
P-glycoprotein (P-gp) inhibitors within 7 days prior to the Screening Visit

16. Use of topical therapies on the dermatologic treatment area within 6 weeks prior
to Screening visit (Day -14): pulsed dye laser, carbon dioxide laser, surgeries
within the treatment area, topical sirolimus, topical retinoids, topical
steroids or other topical prescription or over the counter medications

17. Use of systemic drug therapies within 7 days prior to Screening Visit at Day
-14: e.g., cytotoxic drugs, immunomodulators or immunosuppressants, or
diltiazem, erythromycin, all azole antifungals, rifampin, nicardipine, verapamil