Safety, Tolerability, and Efficacy of Oral KM-023 in Adult Patients With Pachyonychia Congenita (pEDD-PC)

• To be eligible to participate in this trial, an individual must meet all the following criteria:

  1. Read, understood, and signed an informed consent form (ICF) before any investigational procedures are performed.
  2. Male or female, aged ≥ 18 years at the time of Screening.
  3. Clinical diagnosis of KRT6A-pEDD-PC, KRT6B-pEDD-PC, KRT6C-pEDD-PC, KRT16-pEDD-PC and KRT17-pEDD-PC, with confirmed heterozygous variant in either KRT6A, KRT6B, KRT6C, KRT16, or KRT17 genes.
  4. Apparent and visible calluses on the plantar area.

  5. The Screening TUG test duration with socks was longer than the aged-matched healthy normal range (Kear, Guck \& McGaha (2016) and Bohannon (2006)).

     Age range Normative duration for TUG completion (Sec) 18-29 8.57 30-49 8.86 50 years or older 9.90

  6. The patient has trimmed the plantar calluses no later than 4 weeks prior to D1.
  7. The patient must have adequate renal function, defined as eGFR ≥60 mL/min/1.73 m² calculated using the Chronic Kidney Disease Epidemiology Collaboration CKD-EPI (or equivalent standardized method as reported by the local laboratory), with no clinically significant renal disease, as judged by the investigator.

  8. Female participants of childbearing potential, and male participants capable of fathering a child, must meet the contraception requirements and agree to use one highly effective method and one physical barrier method of contraception consistently and correctly with their partners:

     1. Female participants of childbearing potential must use contraception, hormonal contraceptives starting at least 1 month prior to screening and all other contraceptive methods from 14 days prior to first study drug administration and continuing for a duration of 6 months after the last dose of KM-023.
     2. Male participants and their female partners of childbearing potential must use contraception from the first day of study drug administration and continuing for a duration of 90 days after the last dose of KM-023. The female partners, if using hormonal contraceptives, should also have begun hormonal contraceptives at least 1 month prior to screening of the male participant.
  9. Negative pregnancy test at the baseline visit, and negative urinary pregnancy test at every clinic visit.

  10. Female participants of non-childbearing potential must meet one of the following criteria:

      1. Absence of menstrual bleeding for 1 year prior to screening without any other medical reason.
      2. Documented hysterectomy or bilateral oophorectomy at least 3 months before the trial.
  11. Not using prescription medication 14 days prior to admission; and 7 days prior to admission for over the counter (OTC) medication/vitamins/supplements (with the exception of contraception, occasional paracetamol and standard dose of multivitamins). As an exception, acetaminophen/paracetamol may be used at doses of ≤ 1g/day.
  12. Willing and able to comply with the treatment and follow-up visits.
  13. Willing to refrain from current treatments, in compliance with the list of prohibited medications.
  14. Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research.

Exclusion Criteria:

• An individual who meets any of the following criteria will be excluded from participation in this trial:

  1. Participants who are staff members at the investigational site directly involved in conducting the study, their family members, site staff members under the supervision of the Investigator, or Sponsor employees directly involved in the study.
  2. The presence of other significant dermatological conditions that could interfere with the evaluation of the study treatment's safety and efficacy.
  3. Active or uncontrolled infections (e.g., sepsis, tuberculosis, hepatitis B or hepatitis C at the screening visit, human immunodeficiency virus [HIV]) that could complicate participation in the study.
  4. Any medical or active psychological condition or any clinically relevant laboratory abnormality, such as, but not limited, to elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (> 2 × upper normal limit [ULN]) in combination with elevated bilirubin (> 1.5 × ULN), at the baseline visit.
  5. History or presence of any condition that may interfere with the absorption of the IMP, including but not limited to inflammatory bowel disease, chronic or recurrent gastrointestinal disorders, history of gastric or intestinal surgery that may affect drug absorption.
  6. Inability to swallow oral medication or the presence of any condition that may impair the safe administration of oral treatments (e.g., dysphagia).
  7. Evidence or history of clinically relevant cardiovascular disease, or family history of long QT syndrome.
  8. Supine (after 5 min of rest) 12-lead ECG demonstrating QTc >450 msec for men and >470 msec for women, or a QRS interval >120 msec. If QTc or QRS exceed these limits, the ECG should be repeated once and the average of the two QTc or QRS values should be used to determine the participant's eligibility (The Fridericia formula (QTcF) will be calculated for the purpose of this study).
  9. Has a diabetic foot ulcer.
  10. Having received any of the prohibited treatments in Table 2 within the specified timeframe before inclusion.
  11. Currently participating or has participated in any other clinical trial with an IMP or device within the 4 months prior to the screening visit. Prior participation in trials with KM-023 is acceptable.
  12. Cutaneous infection or another underlying condition of the skin which may impact the assessments or trial participants.
  13. Cutaneous infection of the assessed areas (plantar) within 2 weeks before enrollment or any infection of treatment area requiring treatment with oral, parenteral antibiotics, antivirals, antiparasitic or antifungals or any topical within 2 weeks before enrollment.
  14. Pregnant or breastfeeding.
  15. Known relevant allergies to any drug or excipients in the formulation.
  16. Major surgery within the last 3 months, or minor surgery (requiring local anaesthetic) in the month prior to enrollment in the study, or any planned surgery during the trial.
  17. Unwilling or unable to comply with all scheduled visits, treatment plan, laboratory tests and other study procedures and the restrictions described in the protocol.
  18. Any other condition or previous therapy that, in the opinion of the Investigator or their designee, would render the participant unsuitable for this study, including an inability to fully comply with the study protocol requirements or a likelihood of noncompliance with study procedures.