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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
KM-001 1% will be supplied in glass jars (30 ml) and will be provided to patients with spatulas and polyethylene gloves on all the clinical visits. The patient will use IMP twice a day for 84 days. IMP will be applied on the plantar surfaces.
A complete physical examination will be performed as follows at screening and baseline, abbreviated after that (i.e., on Days 7, 28, 42, 63, 84, 112, 140, and at ET visit - where applicable, per cohort): * The complete physical examination will cover a careful assessment of all body systems, including the head, eyes, ears, nose, and throat and the respiratory, cardiovascular, gastrointestinal (GI), 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 trial visits. * Height and weight measurement will be performed at screening only. An abbreviated examination including a comprehensive skin examination.
Vital sign measurements (oral body temperature, pulse, and resting systolic and diastolic blood pressure) will be measured at screening, on Days 1, 7, 28, 42, 63, 84, 112, 140, and at ET visit - where applicable, per cohort. Vital signs will be measured in supine position after at least 5 minutes of rest.
Approx. 5 mL whole blood will be collected after an ≥8 h fast for serum biochemistry assessments during screening, and on Days 1 (baseline), 7, 84 112, 140 or at an ET visit - where applicable, per cohort. Serum chemistry will include assessments of total and direct bilirubin, ALT, AST, gamma-glutamyl transferase (GGT), alkaline phosphatase, glucose (fasting), sodium, potassium, blood urea nitrogen (BUN/Urea), creatinine, chloride, calcium, uric acid, albumin, and total protein.
Approx. 5 mL whole blood will be collected for complete blood count (CBC) during screening, and on Days 1 (baseline), 7, 84, 112, 140 or at an ET visit - where applicable, per cohort. The CBC assessments will include red blood cells (RBC), haemoglobin, haematocrit, reticulocyte count, platelet count, mean corpuscular haemoglobin (MCH), mean platelet volume (MCV), white blood cells (WBC), neutrophils (absolute \[abs.\]), lymphocytes (abs.), monocytes (abs.), eosinophils (abs.), and basophils (abs.).
Approx. 5 mL whole blood will be collected for serology assessments during screening. Serology will include HbsAg, HbcAb, hepatitis C antibody, and HIV antibody.
General urinalysis will be performed, by dipstick, during screening, and on Days 1 (baseline), 7, and 84, 112, and 140, or at an ET visit - where applicable, per cohort. At least 7 to 10 mL of 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.
A 12-lead, resting, ECG will be taken for each patient at screening, on Days 1 (baseline), 84, 112, and at day 140 (for Cohort 2), or at an ET visit - Where applicable. The measurement will be taken 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 QTc interval and QRS complex. The report will be printed out and signed by the investigator, who will record in the eCRF whether it is normal, abnormal but not clinically significant, or abnormal AND clinically significant. In the latter case the eligibility of the patients will be reviewed.
Blood samples for PK will be collected during screening (Days -14 to 0) at any time during the visit, or on Day 1 (up to 30 minutes prior to the first dose, if not performed during Screening) and on Day 7 and at End of Treatment (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, on Days 28, 42, and 84 (for Cohort 2): 1 sample after the first dose, before the second dose, as late as possible in the visit, at End of Study (EoS, Cohort 1: Day 112; Cohort 2: Day 140), or at an ET visit: at any time during the visit. * Altogether up to 15 samples, and approx. 30 mL of blood will be drawn for PK at screening or Day 1 and on Days 7, 28, 42, 84, EoT (84/112), and EoS (112/140), or at an ET visit, if applicable. * Overall, up to a total of 85 mL of blood will be drawn during the trial for blood and PK assessments per patient in Cohort 1, and 95 mL of blood per patient in Cohort 2.
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 during screening and on Days 1 (baseline, prior to first dosing), 7, 28, 42, 63, 84, 112, 140, and at ET visit - where applicable, per cohort). 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"
The patient will enter the PPPK- or PC-related pain score (not any pain) using a VAS pain scale in the patient-reported diary, on a weekly basis starting on Day 1 through ET visit, prior to the second administration of the IMP (evening dose) at the same time every time (±1 hour) except for Day 1 (Visit 2, in-clinic visit), where the assessment will be performed pre-dose during the visit. The score will be collected on every in-clinic visit during the treatment and follow up periods (Days 1, 7, 28, 42, 63, 84, 112, 140, and at an ET visit - where applicable, per cohort). 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?"
The peak pruritus severity will be assessed using the PP-NRS, an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The PP-NRS will be entered by the patients on a weekly basis starting on Day 1 through ET visit, preferably after the evening dose, at the same time every time (±1 hour) except for Day 1 (Visit 2, in-clinic visit), where the assessment will be performed pre-dose during the visit. The scores will be collected on every in-clinic visit during the treatment and follow up periods (Days 1, 7, 28, 42, 63, 84, 112, and 140, or at an ET visit - where applicable, per cohort). The PP-NRS was designed to measure peak pruritus, or "worst" itch, over the previous 24 hours based on the following question: "On scale from 0 (no itch) to 10 (worst imaginable itch) how was your worst itch in the past 24 hours?"
The PGI will be evaluated on Days 1, 7, 28, 42, 63, 84, 112, and 140, or at an ET visit - where applicable, per cohort. The PGI-C will be evaluated using a 7-point scale from 1 (very much improved) to 7 (very much worse) as follows: Since the start of the trial, my overall status has: from, 1= "very much improved" to 7= "very much worse"
The PGI will be evaluated on Days 1, 7, 28, 42, 63, 84, 112, and 140, or at an ET visit - where applicable, per cohort. The PGI-S will be evaluated using a 5-point scale from 1 (none) to 5 (very severe) as follows: Please rate the severity of your disease right now, from 1= "none" to 5= "very severe"
High quality photographic documentation of the treated lesions will be performed during Screening and on Days 1, 7, 42, 63, 84, 112, and 140, or at an ET visit before treatment - where applicable, per cohort. The photographs will be taken under standardised conditions, using imitoMeasure (Ⓒ imito AG 2016-2022).
KM-001 1% will be supplied in glass jars (30 ml) and will be provided to patients with spatulas and polyethylene gloves on all the clinical visits. The patient will use IMP twice a day for 112 days. IMP will be applied on the plantar surfaces.
Royal London Hospital-Clinical Research Facility-11D (11th Floor) Whitechapel, London, E1 1FR,
London, Whitechapel Rd, United Kingdom
Safety endpoint will be assessed through collection and analysis of adverse events.
Incidence rate of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) grouped by body system up to the patient´s end of trial (Day 112 \[Visit 12\]) or early termination \[ET\] visit\]).
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of Hematology- laboratory blood test profile.
Safety will be assessed by the % of change from normal range in clinical Hematology blood test profile from baseline (Day 1) up to day 112. Data management team will assess and review the laboratory blood test results (Hematology). Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: WBC (K/µl) and platelet count (K/µl), neutrophils (absolute \[abs.\])(K/µl), lymphocytes (abs.)(K/µl), monocytes (abs.) (K/µl), eosinophiles (abs.)(K/µl) and basophiles (abs.) (K/µl) and reticulocyte count (K/µl).
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of MCH result in laboratory blood test.
Safety will be assessed by the % of change from normal range in MCH (pg) blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the MCH lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of MCV result in laboratory blood test.
Safety will be assessed by the % of change from normal range in MCV(fl) laboratory blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the MCV lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of haematocrit result in laboratory blood test.
Safety will be assessed by the % of change from normal range in haematocrit (%) laboratory blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the haematocrit lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of hemoglobin result in laboratory blood test.
Safety will be assessed by the % of change from normal range in hemoglobin (g/dL) laboratory blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the hemoglobin lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of RBC result in laboratory blood test.
Safety will be assessed by the % of change from normal range in RBC (M/µl) laboratory blood test result, from baseline (Day 1) up to day 112. Data management team will assess and review the RBC lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition.
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of Sodium, potassium and chloride results in chemistry laboratory blood test.
Safety will be assessed by the % of change from normal range in chemistry laboratory blood test profile, from baseline (Day 1) up to day 112. Data management team will assess and review the chemistry lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Sodium (mmol/L), potassium (mmol/L) and chloride (mmol/L).
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of: Glucose fasting , BUN/Ur, creatinine, bilirubin total and direct, calcium, uric acid, and bilirubin result, in chemistry laboratory blood test.
Safety will be assessed by the % of change from normal range in chemistry laboratory blood test profile, from baseline (Day 1) up to day 112. Data management team will assess and review the chemistry lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Glucose fasting (mg/dL), BUN/Ur (mg/dL), creatinine (mg/dL), bilirubin total (mg/dL) and direct (mg/dL), calcium (mg/dL), uric acid (mg/dL), and bilirubin (mg/dL).
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of Alkaline phosphatase, AST, ALT and GGT result in chemistry- laboratory blood test.
Safety will be assessed by the % of change from normal range in chemistry laboratory blood test profile, from baseline (Day 1) up to day 112. Data management team will assess and review the chemistry lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Alkaline phosphatase (U/L), AST (U/L), ALT (U/L) and GGT (U/L).
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of Albumin and total protein result in chemistry- laboratory blood test.
Safety will be assessed by the % of change from normal range in chemistry blood test profile, from baseline (Day 1) up to day 112. Data management team will assess and review the chemistry lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Albumin (g/dL) and total protein (g/dL).
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of Serology -in laboratory blood test profile.
Safety will be assessed by the % of change from normal range in serology clinical blood test profile, from baseline (Day 1) up to Day 112. Data management team will assess and review the serology lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: HBsAg (positive/negative), HBcAb (positive/negative), hepatitis C antibody (positive/negative), or HIV antibody (positive/negative).
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of urine laboratory profile.
Safety will be assessed by the % of change in clinical urine laboratory profile from baseline (Day 1) up to Day 112. Data management team will assess and review the urine lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. the following values will be assessed: Glucose (mg/dl), protein (mg/ml),urobilinogen (mg/ml) and ketones (mg/ml).
Time frame: Up to 112 days
Safety endpoint-will be assessed by the % of change from normal range in the collection of Specific gravity , pH, blood and nitrites result in urine laboratory profile.
Safety will be assessed by the % of change in clinical urine laboratory profile from baseline (Day 1) up to Day 112. Data management team will assess and review the urine lab test results. Exceptional values above the norm or below the norm indicate an aggravation of the participant's condition. The following values will be assessed: Specific gravity , pH, blood and nitrites.
Time frame: Up to 112 days
Safety endpoint-Mean change in body temperature measurement from baseline.
Mean changes in body temperature from baseline (Day 1) up to Day 112.
Time frame: Up to 112 days
Safety endpoint-Mean change in pulse measurement from baseline.
Mean changes in pulse (unites: beats per minute) measurements from baseline (Day 1)up to Day 112.
Time frame: Up to 112 days
Safety endpoint- Mean change in blood pressure measurement from baseline.
Mean changes in blood pressure (systolic and diastolic blood pressure \[unites: mm Hg\]) measurements from baseline (Day 1) up to Day 112.
Time frame: Up to 112 days
Safety endpoint-ECG
Mean changes in ECG parameters from baseline (Day 1) up to Day 112. the following ECG parameters will be recorded: heart rate (HR), PR, QT, and QTC interval and QRS complex.
Time frame: Up to 112 days
Efficacy end point - will be assessed by Clinical global impression of severity (CGI-S) questionaries
Percent responders in CGI-S scale (0= "none" to 4= "very severe") on Day 84 \[Visit 10, EoT\] compared to baseline (Day 1); a responder is defined to have an improvement of at least 2 points in disease severity on Day 84 \[Visit 10, EoT\] compared to baseline (Day 1).
Time frame: Up to 84 days
Efficacy end point - will be assessed by Patient global impression of change (PGI-S) questionaries
Mean change from baseline (Day 1 \[Visit 2\] to Day 84 \[Visit 10, EoT\]) in PGI-S. scale: 1= "none" 5="very severe"
Time frame: Up to 84 days
Efficacy end point - will be assessed by Patient global impression of change (PGI-C) questionaries
Mean change from baseline (Day 1 \[Visit 2\] to Day 84 \[Visit 10, EoT\]) in PGI-C. scale: 1="very much improved" 7="very much worse"
Time frame: Up to 84 days
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