Study Designed to Evaluate the Safety and Efficacy of 1% Topical Formulation of KM-001 on Type 1 Punctate Palmoplantar Keratoderma or Pachyonychia Congenita Diseases

Study Overview
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Brief Summary
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In this phase 1 open label study, up to 10 eligible patients with type I punctate palmoplantar keratoderma or pachyonychia congenital will be recruited to be treated twice daily, for 12 weeks, with 1% topical KM-001. Treatment safety and efficacy will be assessed in the clinic on Days 7, 28, 42, 63and 84 after initiation of treatment. In between visits, safety will also be assessed by phone on Days 14, 21, 35, 49, 56, 70 and 77 of treatment. At the in-clinic visits, treatment efficacy (lesion clearance - IGA) will also be assessed. PK blood samples will be collected on Days 0, 7, 84 and One week after the end of treatment (EoT) visit, patients will return to the clinic for final safety, efficacy and PK evaluations.

Detailed Description
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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.

Official Title
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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

Conditions
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KPPP1, Pachyonychia, Congenital

Intervention / Treatment
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* Diagnostic Test: Serum chemistry
* Diagnostic Test: Hematology
* Diagnostic Test: Urinalysis
* Diagnostic Test: Physical Examination
* Diagnostic Test: Vital Signs
* Diagnostic Test: ECG Test
* Diagnostic Test: PK
* Diagnostic Test: IGA scoring
* Drug: KM-001 1%
* Diagnostic Test: Clinician global impression of severity (CGI-S)
* Diagnostic Test: Visual Analogue Scale (VAS)
* Diagnostic Test: Patient global impression of change (PGI-C) scoring
* Diagnostic Test: Patient global impression of severity (PGI-S) scoring
* Diagnostic Test: Lesion photography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Read, understood and signed an informed consent form (ICF) before any investigational procedure(s) are performed. Male or female and aged 18 - 75 years at the time of screening 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. The target treatment region is 0.5%-4% body surface area (BSA) including target lesions CGI-S score of ≥2 (as assessed by the PI at screening). 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. 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. 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. Patient is willing and able to comply with all time commitments and procedural requirements of the clinical study protocol. Exclusion Criteria: Known hypersensitivity or any suspected cross-allergy to the active pharmaceutical ingredient and/or excipients. Regular alcohol consumption in males >21 units per week and for females >14 units per week (1 unit = 8 gr of alcohol; e.g., 200 mL of 5% beer, 25 mL of 40% spirit or a 125 mL glass of 8% wine). 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). Planned or expected major surgical procedure during the clinical study. Patient is unwilling to refrain from using prohibited medications during the clinical study. Currently participating or participated in any other clinical study of a drug or device, within the past 4 months before the screening, or is in an exclusion period (if verifiable) from a previous study. Cutaneous infection or another underlying skin condition, regardless of location. Cutaneous infection of the area to be treated with KM-001, requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals or any topical treatment during and/or up-to 2 weeks before screening. Pregnant or breastfeeding. Failure to convince the investigator of fitness to participate in the study for any other reason. Having received any of the prohibited treatments in Table 3 (Section 5.8) within the specified timeframe before baseline.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Up to 10 eligible patients with type I punctate palmoplantar keratoderma or pachyonychia congenital will be recruited to be treated twice daily, for 12 weeks, with 1% topical KM-001.Treatment safety and efficacy will be assessed in the clinic on Days 7, 28, 42, 63 and 84 after initiation of treatment. In between visits, safety will also be assessed by phone on Days 14, 21, 35, 49, 56, 70 and 77 of treatment. At the in-clinic visits, treatment efficacy (lesion clearance - IGA) will also be assessed. PK blood samples will be collected on Days 0, 7, 84 and One week after the end of treatment (EoT) visit, patients will return to the clinic for final safety, efficacy and PK evaluations.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KM-001 1% cream<br>KM-001 1% cream will be applied to the affected area twice daily for 12 consecutive weeks. KM-001 will be supplied in glass jars (30 g) and will be provided to patients with spatulas and polyethylene gloves | Diagnostic Test: Serum chemistry<br>* Approximately 5 mL whole blood will be collected after an ≥8 h fast for serum biochemistry assessments at the Screening visit, and on and on Days 7 and 84 of treatment and at the follow-up visit on Day 91. 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.<br>Diagnostic Test: Hematology<br>* Approximately 5 mL whole blood will be collected after an ≥8 h fast for complete blood count (CBC) at the Screening visit, and on Days 7 and 84 of treatment and at the follow-up visit on Day 91. 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.).<br>Diagnostic Test: Urinalysis<br>* General urinalysis will be performed, by dipstick, at the Screening visit, and on and on Days 7 and 84 of treatment and at the follow-up visit on Day 91. 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.<br>Diagnostic Test: Physical Examination<br>* 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.<br>Diagnostic Test: Vital Signs<br>* 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.<br>Diagnostic Test: ECG Test<br>* A 12-lead, resting, digital ECG will be taken for each participant at Screening and on Days 42 and 84, 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.<br>Diagnostic Test: PK<br>* 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 on Days 1, 7 and Day 84 predose, and on Day 91, at any point during the study visit.<br>Diagnostic Test: IGA scoring<br>* 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.<br>Drug: KM-001 1%<br>* 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.<br>Diagnostic Test: Clinician global impression of severity (CGI-S)<br>* 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 (baseline, prior to first dosing), 7, 28, 42, 63, 84 and at ET visit). 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<br>Diagnostic Test: Visual Analogue Scale (VAS)<br>* The VAS score will be collected on every in-clinic visit during the treatment period (Days 0, 7, 28, 42, 63, 84 and ET visit). 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?<br>Diagnostic Test: Patient global impression of change (PGI-C) scoring<br>* 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 PGI-C will be evaluated on Days 7, 28, 42, 63, 84 and at ET visit (Day 91). 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.<br>Diagnostic Test: Patient global impression of severity (PGI-S) scoring<br>* 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 PGI-S will be evaluated on Days 0, 7, 28, 42, 63, 84 and at ET visit (Day 91). 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.<br>Diagnostic Test: Lesion photography<br>* High-quality photographic documentation of the treated lesions will be performed on screening and on Days 0, 7, 28, 42, 63, 84 and at ET visit (Day 91) before treatment if applicable.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoin will be assessed through collection and analysis of adverse events | Incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) grouped by body system will assessed. | up to 91 days | 
| Safety endpoin-will be assessed through collection and analysis of blood laboratory tests | Data management team will assess and review the lab test results (blood), assessment will be compared to the normal range. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition | up to 91 days | 
| Safety endpoint-will be assessed through collection and analysis of urine laboratory tes | Data management team will assess and review the lab test results (urine), assessment will be compared to the normal range. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition | up to 91 days | 
| Safety endpoin-Vital signs | Vital signs (resting heart rate, systolic and diastolic blood pressure) will be assesed and the changes from the baseline. units: BPM (beats per minute) Data management team will assess and review the vital signs. The category of the assessments will be compared to the normal ranges. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition | up to 91 days | 
| Safety endpoin-Vital signs | Vital signs (resting heart rate, systolic and diastolic blood pressure) will be assesed and the changes from the baseline. units:blood pressure [mm Hg]. Data management team will assess and review the vital signs. The category of the assessments will be compared to the normal ranges. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition | up to 91 days | 
| Safety endpoin-ECG | A 12-lead, resting, digital ECG will be taken for each participant at Screening and on Days 42 and 84, 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. Resting ECG parameter and changes from baseline will be assesed | up to 91 days | 
| Safety endpoin- Lesion Assessment | 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). | up to 91 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile of the study drug- maximal concentartion- Cmax | CMAX measurement (mg/ml) | up to 91 days | 
| Pharmacokinetic profile of the study drug- Time to reach Cmax - Tmax | Tmax measurement (h) | up to 91 days | 
| Pharmacokinetic profile of the study drug- AUC | AUC measurement (mg*h/L) | up to 91 days | 
| Efficacy endpoint- Clinician Global Impression of Severity scoring | Percent of responders in Clinician Global Impression of Severity (CGI-S) scale on Day 84, compared to baseline (Day 0, Visit 2); a responder is defined to have an improvement of at least 2 points in disease severity on Day 84 compared to baseline (Day 0). 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 Lesions severity will be assessed using the CGI-S scale, which is a 5-point scale (from 0= none to 4= very severe) | up to 84 days | 
| Efficacy endpoint- Patient Global Impression of Change scoring | Mean score of Patient Global Impression of Change (PGI-C) on Day 84 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. | up to 84 days | 
| Efficacy endpoint- Patient Global Impression of Severity scoring | Mean change from baseline (Day 0, Visit 2) in Patient Global Impression of Severity (PGI-S) to Day 84 (Visit 14, EoT). 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. | up to 84 days | 
| Efficacy endpoint- Visual Analogue Scale | Mean change from baseline (Day 0, Visit 2) in pain, assessed by Visual Analogue Scale (VAS) score, to Day 84 (Visit 14, EoT). 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? | up to 84 days |