Clinical trial NCT05435638: Study Designed to Evaluate Safety and Efficacy of 1% Topical Formulation of KM-001 on Type 1 Punctate Palmoplantar Keratoderma or Pachyonychia Congenita Diseases
Official title: Phase I, Open Label Study Designed to Evaluate the Safety and Efficacy of a 1% Topical Formulation of KM-001 in the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenital Diseases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Punctate Palmoplantar Keratoderma Type 1
Pachyonychia Congenita
Lead sponsor: Kamari Pharma Ltd
Sponsor class: NETWORK
First posted: 2022-06-28
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Patients with type I punctate palmoplantar keratoderma or pachyonychia congenita will be recruited to be treated, with 1% topical KM-001.

Arm 1: up to 10 eligible patients will be treated twice daily for 12 weeks. Treatment safety and efficacy will be assessed in the clinic visits up to day 84. In between, safety will also be assessed by phone. PK blood samples will be collected. 1 week after the end of treatment visit, patients will return to the clinic for final safety, efficacy and PK evaluations.

Arm 2: up to 8 eligible patients, will be treated twice daily, for 16 weeks, with 1% topical KM-001. Treatment safety and efficacy will be assessed in the clinic visits up to day 112. PK blood samples will be collected. In between visits, safety will also be assessed by phone. 2 weeks after the end of treatment visit, patients will return to the clinic for final safety, efficacy, and PK evaluations.
Primary purpose: TREATMENT

Brief summary: In this phase 1 open label study for patients with type I punctate palmoplantar keratoderma or pachyonychia congenital, 2 arms will be recruited to be treated twice daily, with 1% topical KM-001.

Arm 1: up to 10 eligible patients will be treated for 12 weeks. Arm 2: up to 8 eligible patients will be treated for 16 weeks.

Treatment safety and efficacy will be assessed in the clinic visits (for arm 1 up to day 91, for arm 2 up to day 126). In between safety will also be assessed by phone visits.

At the in-clinic visits, treatment efficacy (lesion clearance - IGA, CGI-S, PGI-C, PGI-S and VAS pain) will also be assessed.

PK blood samples will be collected for arm 1: on Days 0, 7, 84 (EoT visit). One week after the end of treatment (EoT) visit, patients will return to the clinic for final safety, efficacy and PK evaluations. For arm 2, PK blood samples will be collected on days 0, 7, 84, 112 (EoT visit). Two weeks after the end of treatment (EoT) visit, patients will return to the clinic for final safety, efficacy and PK evaluations.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Read, understood and signed an informed consent form (ICF) before any investigational procedure(s) are performed.
2. Male or female and aged 18 - 75 years at the time of screening
3. Clinical diagnosis of:

   punctate keratoderma type I disease with confirmed heterozygous mutation in AAGAB gene OR pachyonychia congenita with confirmed heterozygous mutation in either KRT16, KRT17, KRT6A, KRT6B or KRT6C mutations.
4. The target treatment region is 0.5%-4% body surface area (BSA) including target lesions
5. CGI-S score of ≥2 (as assessed by the PI at screening).
6. Female patients of childbearing potential must agree to use a highly effective and approved method of contraception throughout the study and for 4 weeks after the last study drug administration. Male patients: female partners of male patients must use a reliable method of contraception during this study, and for 12 weeks after the last dose of study medications.
7. Female patients must refrain from donating eggs throughout the study and for 4 weeks after the last study drug administration. Male patients must refrain from sperm donation throughout the study and for 12 weeks after the last study drug administration.
8. Female patients of non-childbearing potential must meet one of the following criteria:

   * Absence of menstrual bleeding for 1 year prior to screening without any other medical reason.
   * Documented hysterectomy or bilateral oophorectomy at least 3 months before the study.
9. Patient is willing and able to comply with all time commitments and procedural requirements of the clinical study protocol.

Exclusion Criteria:

1. Known hypersensitivity or any suspected cross-allergy to the active pharmaceutical ingredient and/or excipients.
2. Regular alcohol consumption for males \>21 units per week and for females \>14 units per week (1 unit = 8gr of alcohol; e.g., 200 mL of 5% beer, 25 mL of 40% spirits or 125 mL of 8% wine).
3. Any medical or active psychological condition or any clinically relevant laboratory abnormalities, such as, but not limited, to elevated ALT or AST (\>3 × upper limit of normal \[ULN\]) in combination with elevated bilirubin (\>2 × ULN), at screening/ baseline that may put the patient at significant risk according to the investigator's judgment, if he/she participates in the clinical study, or may interfere with study assessments (e.g., poor venous access or needle-phobia).
4. Planned or expected major surgical procedure during the clinical study.
5. Patient is unwilling to refrain from using prohibited medications during the clinical study.
6. Currently participating or participated in any other clinical study of a drug or device, within the past 4 months before screening, or is in an exclusion period (if verifiable) from a previous study.

   Note: patients who have participated in Cohort 1 of this study may be enrolled to Cohort 2 after a minimum of 4 weeks from last KM-001 dose.
7. Cutaneous infection or another active underlying skin condition, regardless of location.
8. Cutaneous infection of the area to be applied with KM-001, requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals, or any topical treatments during and/or up-to 2 weeks before screening.
9. Pregnant or breastfeeding.
10. Failure to convince the investigator of fitness to participate in the study for any other reason.
11. Having received any of the prohibited treatments in Table 4 (Section 5.8) within the specified timeframe before baseline.

Primary outcomes:
measure: Safety endpoint will be assessed through collection and analysis of adverse events
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Safety endpoint-will be assessed through collection and analysis of blood laboratory tests.
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Safety endpoint-will be assessed through collection and analysis of urine laboratory tes
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Safety endpoint-Vital signs- Heart rate
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Safety endpoint-Vital signs- Blood Pressure
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Safety endpoint-ECG
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Safety endpoint- Lesion Assessment
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
Secondary outcomes:
measure: Pharmacokinetic profile of the study drug- maximal concentartion- Cmax
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Pharmacokinetic profile of the study drug- Time to reach Cmax - Tmax
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Pharmacokinetic profile of the study drug- AUC
timeFrame: up to 91 days for arm 1 and 126 days for arm 2
measure: Efficacy endpoint- Investigator's Global Impression (IGA) score.
timeFrame: up to 84 days for arm 1 and 112 days for arm 2
measure: Efficacy endpoint- Patient Global Impression of Change scoring
timeFrame: up to 84 days for arm 1 and 112 days for arm 2
measure: Efficacy endpoint- Patient Global Impression of Severity scoring
timeFrame: up to 84 days for arm 1 and 112 days for arm 2
measure: Efficacy endpoint- Visual Analogue Scale
timeFrame: up to 84 days for arm 1 and 112 days for arm 2
Other outcomes:
Locations:
city: Beer-Sheva
country: Israel
facility: Soroka Medical Center
city: Petah Tikva
country: Israel
facility: Rabin Medical Center (Beilinson, Hasharon)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center - Ichilov Hospital
Study officials:
References: