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

"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."

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.).

"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."

"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."

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.

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.

"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)."

"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."

"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."

"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"

"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?"

"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."

"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."

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.

"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."