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

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.