Assessment of KM-001 - Safety, Tolerability, and Efficacy in Patients With PPPK1 or PC

Phase 1b, Open Label Study to Evaluate the Safety, Tolerability, and Efficacy of a 1% Topical Formulation of KM-001 for the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenita

This Phase 1b, open-label, single-center, prospective trial will be assessing the safety, tolerability, and efficacy of topical KM-001 1% in patients with PPPK1 or PC diseases. In this study 2 cohorts will be recruited:

1. Cohort 1: up to 11 eligible patients, will be enrolled to be treated twice daily, for 12 weeks, with 1% topical KM-001, on the plantar surfaces (2 feet).
2. Cohort 2: up to 8 eligible patients, will be enrolled to be treated twice daily, for 16 weeks, with 1% topical KM-001, on the plantar surfaces (2 feet).

Safety (AEs, blood work [at specific visits], vital signs), tolerability, and efficacy parameters (overall lesion improvement) will be assessed during in-clinic visits (Cohort 1: during Screening, Enrolment, and on Days 7, 28, 42, 63, 84 [end of treatment, EoT], 112 [End of Study, EoS] post first investigational medicinal product (IMP) administration; Cohort 2: during Screening, Enrolment, and on Days 7, 28, 42, 63, 84, 112 [EoT], 140 [EoS] post first investigational medicinal product (IMP) administration).

PK samples will be collected to assess plasma levels of KM-001 on

• Screening (Day -14 to -0): any time during the visit. (or on Day 1 up to 30 minutes pre-dose if missed during Screening)
• Day 7 and at EoT (Cohort 1: Day 84; Cohort 2: Day 112) up to 30 minutes pre-dose, and at 1 h, 2 h, 3 h, 6 h (+15 min) post-dose
• Days 28, 42 for both Cohorts, and Day 84 for Cohort 2: 1 sample after the first dose, before the second dose, as late as possible in the visit.
• End of Study (EoS, Day 112 (Cohort 1) or Day 140 (cohort 2)), or at Early Termination (ET): at any time during the visit.

The patient will complete a patient-reported diary, consisting of treatment compliance and self-assessments for efficacy.

Follow up- 2 weeks after EoT by phone call, and 4 weeks after EoT in clinic visit.

The palmoplantar keratoderma (PPK) group of skin disorders results from various mutations in several epidermal genes and is characterized by thickening of the skin on the palms and soles.

Punctate palmoplantar keratoderma (PPKP1) is a rare autosomal, dominant, inherited skin disease characterized by bilateral asymptomatic, tiny, hyperkeratotic punctate papules and plaques on the palmoplantar surface.

Pachyonychia congenita (PC) is a rare group of autosomal dominant skin disorders that are caused by a mutation in one of five different keratin genes. PC is often associated with thickened toenails, plantar keratoderma, and plantar pain. Its manifestations include bilateral PPK on palms and soles pattern with sharp margins and a yellow tone.

A common characteristic of these skin diseases is the impaired differentiation of keratinocytes, often caused by defective calcium homeostasis. Normal calcium homeostasis is regulated by calcium ion channels, including the transient receptor potential cation channel subfamily V, member 3 (TRPV3), which has been implicated in regulation of keratinocyte proliferation, differentiation, and apoptosis. As a result, it has been suggested as a drug target for a variety of dermatological conditions and itch. It has therefore been suggested that inhibition of TRPV3 by specific antagonists can address the above-mentioned conditions.KM-001, developed by Kamari Pharma, is a potent and selective TRPV3 antagonist. Kamari has demonstrated that KM-001 reduces Ca+2flux in keratinocytes and decreases cell proliferation accompanied by normalization of keratinocyte differentiation markers. Efficacy was demonstrated in in vivo studies, using the DS-Nh mice model, where it was able to normalize epidermal hyperkeratosis. In addition, the compound significantly reduced pruritus which is characteristic of this model and of many types of PPK.

KM-001 topical formulation demonstrates favorable safety profile in rodents and minipigs and significant efficacy in animal models.

Inclusion Criteria:

1. Read, understood, and signed an informed consent form (ICF) before any investigational procedure(s) are performed.

2. Male and female and aged 18 - 75 years (inclusive) at the time of screening.

3. Clinical diagnosis of:

   • Punctate palmoplantar keratoderma type I disease with confirmed heterozygous mutation in AAGAB gene.

   OR

   • PC with confirmed heterozygous mutation in either KRT16, KRT17, KRT6A, KRT6B or KRT6C mutations.

4. The target treatment region is 0.5% to 4% BSA including target lesion.

5. CGI-S score (as assessed by the CI at the screening visit) of ≥2.

6. Female patients of childbearing potential1 must use a highly effective birth control method2 (failure rate ˂1% per year when used consistently and correctly) (28) throughout the trial and for at least 4 weeks after last application of IMP.

In addition to the hormonal contraception, female patients must agree to use a supplemental barrier method during intercourse with a male partner (i.e., male condom) throughout the trial and for at least 4 weeks after last application of IMP.

Female patients must be having regular menstrual periods (interval of 21 to 35 days, duration of 2 to 7 days for several months) at the baseline visit (as reported by the patient); exception: patients using hormonal contraceptives that preclude regular menstrual periods, menopausal or hysterectomised patients.

A male patient with a pregnant or non-pregnant female partner of childbearing potential1 must use adequate contraceptive methods (adequate contraceptive measures as required by local regulation or practice; as a minimum, the male patient must agree to use condom during treatment and until the end of relevant systemic exposure in the male patient (7 days post-treatment).

1. A female patient is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for at least 12 months without an alternative medical cause prior to screening (28).
2. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) 28 days prior to screening, bilateral tubal occlusion, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomised/permanently sterile by bilateral orchidectomy partner (given that the partner is the sole sexual partner and has received medical assessment of the surgical success), or sexual abstinence (refraining from heterosexual intercourse during the entire trial/treatment period of risk associated with the IMPs) (28). This period of contraception should be extended for at least 4 weeks after last application of IMP.

7. Female patients must refrain from donating eggs throughout the trial and for 4 weeks after the last IMP administration.

Male patients must refrain from sperm donation throughout the trial and for 7 days after the last IMP administration.

8. Female patients of non-childbearing potential must meet 1 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.

   9. Patient is willing and able to comply with all the time commitments and procedural requirements of the protocol.

   Exclusion Criteria:

   1. History of drug or alcohol abuse in the past 2 years.

   2. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine).

   3. Positive hepatitis B surface antigen [HbsAg], hepatitis B core antibody [HbcAb], hepatitis C antibody, or human immunodeficiency virus (HIV) antibody serology results at the screening visit.

   4. Known hypersensitivity or any suspected cross-allergy to the API and/or excipients.

   5. Any medical or active psychological condition or any clinically relevant laboratory abnormalities, such as, but not limited, to elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 × upper limit of normal [ULN]) in combination with elevated bilirubin (>2 × ULN), at the screening/baseline visit.

   6. Planned or expected major surgical procedure during the clinical trial.

   7. Patient is unwilling to refrain from using prohibited medications during the clinical trial.

   8. Currently participating or participated in any other clinical trial of an IMP or device, within the past 4 months before the screening visit.

   9. Cutaneous infection or another underlying condition of the skin which may impact the assessments or trial participation.

   10. Cutaneous infection of the area to be treated with IMP within 2 weeks before the screening visit or any infection of treatment area requiring treatment with oral, parenteral antibiotics, antivirals, antiparasitics or antifungals or any topical within 2 weeks before the screening visit.

   11. Pregnant or breastfeeding patient.

   12. Failure to satisfy the investigator of fitness to participate for any other reason.

   13. Having received any of the prohibited treatments in Table 5 within the specified timeframe before the baseline visit.

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