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

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 14 (actual)
• Sponsor: Kamari Pharma Ltd · Network
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Accepted

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.

Conditions

• Punctate Palmoplantar Keratoderma Type 1
• Pachyonychia Congenita

Interventions

Type	Name	Description
DIAGNOSTIC_TEST	Serum chemistry	Approximately 5 mL whole blood will be collected after an ≥8 h fast for complete blood count (CBC) during Screening, and on Days 7 and 84 of treatment, at early termination (ET), if required, and at the EoT (Arm 2: Day 112) and follow-up EoS visits (Cohort 1: Day 91; Cohort 2: Day 126). Serum chemistries will include assessment of total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase, glucose, sodium, potassium, blood urea nitrogen (BUN), and creatinine.
DIAGNOSTIC_TEST	Hematology	Approximately 5 mL whole blood will be collected after an ≥8 h fast for complete blood count (CBC) during Screening, and on Days 7 and 84 of treatment, at early termination (ET), if required, and at the EoT (Arm 2: Day 112) and follow-up EoS visits (Cohort 1: Day 91; Cohort 2: Day 126). The CBC assessment will include a red blood cells (RBC), hemoglobin, hematocrit, platelet count, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean platelet volume (MCV), white blood cells (WBC), neutrophils (% and abs.), lymphocytes (% and abs.), monocytes (% and abs.), eosinophils (% and abs.), basophils (% and abs.), large unstained cells (% and abs.).
DIAGNOSTIC_TEST	Urinalysis	General urinalysis will be performed, by dipstick, during Screening, on Days 7 and 84 of treatment, at early termination (ET), if required, and at the EoT (Cohort 2: Day 112) and follow-up EoS visits (arm 1: Day 91; Arm 2: Day 126). Approximately 7-10 mL urine will be collected. Urinalysis will include pH, specific gravity, blood, nitrites, glucose, ketones, protein, bilirubin urobilinogen and leukocytes. A microscopic examination of the urine will be performed only if clinically indicated.
DIAGNOSTIC_TEST	Physical Examination	A complete physical examination will be performed at Screening, at all in-clinic study visits, and at the End of Study visit. The physical examination will cover a careful assessment of all body systems, including the head, eyes, ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine systems. Particular attention will be placed on the areas affected by the disease. • Symptom-directed physical examinations will be performed at all other study visits.
DIAGNOSTIC_TEST	Vital Signs	Vital sign measurements (body temperature, pulse and resting systolic and diastolic blood pressure) will be measured at Screening, at all in-clinic study visits, and at the End of Study visit. Vital signs will be measured in supine position after at least five minutes of rest.
DIAGNOSTIC_TEST	ECG Test	A 12-lead, resting, digital ECG will be taken for each participant during Screening, on Days 42 and 84 (for both arms), and on day 112 (Arm 2 only), after the patient has been supine for at least 5 min. At minimum, the following ECG parameters will be recorded: heart rate (HR), PR, QT and QRS intervals and QTC. The report will be signed by the Investigator, who will record in the CRF whether it is normal, abnormal but not clinically significant, or abnormal AND clinically significant. In the latter case the eligibility of the participants will be reviewed.
DIAGNOSTIC_TEST	PK	Blood PK analyses will be performed on ≥5ml blood collected in 5-mL K-EDTA CRO coded pre-labeled tubes, refrigerated immediately after collection. Plasma will be separated by centrifugation within 2h, and then frozen at -20C. Blood samples will be collected pre-dose on Days 0, 7, and 84, as well as pre-dose at EoT (Arm 2: Day 112), and at any point during the in-clinic visit at EoS (Arm 1: Day 91; Arm 2: Day 126).
DIAGNOSTIC_TEST	IGA scoring	Lesions severity will be assessed using the Investigator's Global Assessment (IGA) scale,which is a 5-point scale (from 0 ="no disease" to 4="severe disease") based on Simpson et al. 2020, IGA for atopic dermatitis (see Table 4; Simpson et al. 2020). The IGA score is selected using the descriptors below that best describe the overall appearance of the lesions at a given timepoint. It is not necessary that all characteristics under morphological description are present. Excoriations should not be considered when assessing disease severity.
DRUG	KM-001 1% cream 12 weeks treatment	KM-001 1% cream will be applied to the treated area twice daily for 12 consecutive weeks, 2 gr per treatment, and overall, 4 gr of daily dose. KM-001 will be supplied in glass jars (30 g) and will be provided to patients with spatulas and polyethylene gloves.
DIAGNOSTIC_TEST	Clinician global impression of severity (CGI-S)	Lesions severity will be assessed using the CGI-S scale, which is a 5-point scale (from 0= "none" to 4= "very severe") modified from Busner et al. 2007 (30) by the investigator at screening and on Days 0, 7, 28, 42, 63, 84, 91, 112, and 126 (as applicable, per arm), and at ET visit, if applicable. The clinician scoring takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms (pain), behaviour, and the impact of the symptoms on the patient's ability to function (ability to walk). investigators will complete the CGI-S at various timepoints based on the question. "Please choose the response that best describes your assessment of the disease severity, based upon the totality of information available to you"
DIAGNOSTIC_TEST	Visual Analogue Scale (VAS)	The VAS score will be collected on every in-clinic visit during the treatment period (Days 0, 7, 28, 42, 63, 84, 91, 112, and 126 (as applicable, per arm), and at ET visit, if applicable.). The PGIs will be evaluated on Days 0, 7, 28, 42, 63, 84, 91, 112, and 126 (as applicable, per arm), and The following parameter will be evaluated on a VAS from 0 (no pain) to 100 (severe intolerable pain) based on the question: "How was your worst pain intensity in the past 24 hours?"
DIAGNOSTIC_TEST	Patient global impression of change (PGI-C) scoring	The PGI-C scale was developed to provide a brief, stand-alone assessment of the patient's view of his/her global functioning prior to and after initiating a trial medication. The PGIs will be evaluated on Days 7, 28, 42, 63, 84, 91, 112, and 126 (as applicable, per arm), and at ET visit, if applicable. The PGI-C will be evaluated using a 7-point scale from 1 (very much improved) to 7 (very much worse) answering the question Since the start of the trial, my overall status has.
DIAGNOSTIC_TEST	Patient global impression of severity (PGI-S) scoring	The PGI-S scale was developed to provide a brief, stand-alone assessment of the patient's view of his/her global functioning prior to and after initiating a trial medication. The PGIs will be evaluated on Days 0, 7, 28, 42, 63, 84, 91, 112, and 126 (as applicable, per arm), and at ET visit, if applicable. The PGI-S will be evaluated using a 5-point scale from 1 (none) to 5 (very severe) answering the question Please rate the severity of your disease right now.
DIAGNOSTIC_TEST	Lesion photography	High-quality photographic documentation of the treated lesions will be performed on screening, and on Days 0, 7, 28, 42, 63, 84, 91, 112, and 126 (as applicable, per arm), and at ET visit, pre-dose, if applicable.
DRUG	KM-001 1% cream 16 weeks treatment	KM-001 1% cream will be applied to the treated area twice daily for 12 consecutive weeks, 2 gr per treatment, and overall, 4 gr of daily dose. KM-001 will be supplied in glass jars (30 g) and will be provided to patients with spatulas and polyethylene gloves.

Timeline

• Start date: 2022-07-17
• Primary completion: 2024-09-05
• Completion: 2024-09-05
• First posted: 2022-06-28
• Last updated: 2025-01-07

Locations

3 sites across 1 country: Israel