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

NCT05435638 | Completed Phase 1 DMC

• 1 other identifier: KM-001B1
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Punctate Palmoplantar Keratoderma Type 1; Pachyonychia Congenita

Outcome Measures

Primary Outcomes (7)

• Safety endpoint 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 for arm 1 and 126 days for arm 2

• Safety endpoint-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 for arm 1 and 126 days for arm 2

• 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 for arm 1 and 126 days for arm 2

• Safety endpoint-Vital signs- Heart rate

  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 for arm 1 and 126 days for arm 2

• Safety endpoint-Vital signs- Blood Pressure

  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 for arm 1 and 126 days for arm 2

• Safety endpoint-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 for arm 1 and 126 days for arm 2

• Safety endpoint- 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 for arm 1 and 126 days for arm 2

Secondary Outcomes (7)

• Pharmacokinetic profile of the study drug- maximal concentartion- Cmax

  up to 91 days for arm 1 and 126 days for arm 2

• Pharmacokinetic profile of the study drug- Time to reach Cmax - Tmax

  up to 91 days for arm 1 and 126 days for arm 2

• Pharmacokinetic profile of the study drug- AUC

  up to 91 days for arm 1 and 126 days for arm 2

• Efficacy endpoint- Investigator's Global Impression (IGA) score.

  up to 84 days for arm 1 and 112 days for arm 2

• Efficacy endpoint- Patient Global Impression of Change scoring

  up to 84 days for arm 1 and 112 days for arm 2

Study Arms (2)

KM-001 1% cream 12 weeks treatment

EXPERIMENTAL

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; 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% cream 12 weeks treatment; 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

KM-001 1% cream 16 weeks treatment

EXPERIMENTAL

KM-001 1% cream will be applied to the affected area, twice daily for 16 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; 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; 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; Drug: KM-001 1% cream 16 weeks treatment

Interventions

Serum chemistry DIAGNOSTIC_TEST

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.

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

Hematology DIAGNOSTIC_TEST

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.).

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

Urinalysis DIAGNOSTIC_TEST

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.

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

Physical Examination DIAGNOSTIC_TEST

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.

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

Vital Signs DIAGNOSTIC_TEST

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.

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

ECG Test DIAGNOSTIC_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.

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

PK DIAGNOSTIC_TEST

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).

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

IGA scoring DIAGNOSTIC_TEST

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 12 weeks treatment; KM-001 1% cream 16 weeks treatment

KM-001 1% cream 12 weeks treatment DRUG

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.

Also known as: Cohort 1

KM-001 1% cream 12 weeks treatment

Clinician global impression of severity (CGI-S) DIAGNOSTIC_TEST

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"

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

Visual Analogue Scale (VAS) DIAGNOSTIC_TEST

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?"

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

Patient global impression of change (PGI-C) scoring DIAGNOSTIC_TEST

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.

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

Patient global impression of severity (PGI-S) scoring DIAGNOSTIC_TEST

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.

KM-001 1% cream 12 weeks treatment; KM-001 1% cream 16 weeks treatment

Lesion photography DIAGNOSTIC_TEST

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 12 weeks treatment; KM-001 1% cream 16 weeks treatment

KM-001 1% cream 16 weeks treatment DRUG

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.

Also known as: Cohort 2

KM-001 1% cream 16 weeks treatment

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Known hypersensitivity or any suspected cross-allergy to the active pharmaceutical ingredient and/or excipients.
• Regular alcohol consumption for males \>21 units per week and for females \>14 units per week (1 unit = 8gr of alcohol; e.g., 200 mL of 5% beer, 25 mL of 40% spirits or 125 mL 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.
• Note: patients who have participated in Cohort 1 of this study may be enrolled to Cohort 2 after a minimum of 4 weeks from last KM-001 dose.
• Cutaneous infection or another active underlying skin condition, regardless of location.
• Cutaneous infection of the area to be applied with KM-001, requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals, or any topical treatments 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 4 (Section 5.8) within the specified timeframe before baseline.

Sponsors & Collaborators

• Kamari Pharma Ltd: lead

Study Sites (3)

Soroka Medical Center

Beersheba, Israel

Location

Rabin Medical Center (Beilinson, Hasharon)

Petah Tikva, Israel

Location

Sourasky Medical Center - Ichilov Hospital

Tel Aviv, 6423906, Israel

Location

MeSH Terms

Conditions

Keratosis palmoplantaris papulosa; Pachyonychia Congenita

Interventions

Hematologic Tests; Urinalysis; Physical Examination; Vital Signs; Therapeutics; Pain Measurement; KPNA1 protein, human

Condition Hierarchy (Ancestors)

Ectodermal Dysplasia; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Nail Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Clinical Chemistry Tests; Diagnostic Techniques, Urological; Neurologic Examination

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Patients with type I punctate palmoplantar keratoderma or pachyonychia congenita will be recruited to be treated, with 1% topical KM-001. Arm 1: up to 10 eligible patients will be treated twice daily for 12 weeks. Treatment safety and efficacy will be assessed in the clinic visits up to day 84. In between, safety will also be assessed by phone. PK blood samples will be collected. 1 week after the end of treatment visit, patients will return to the clinic for final safety, efficacy and PK evaluations. Arm 2: up to 8 eligible patients, will be treated twice daily, for 16 weeks, with 1% topical KM-001. Treatment safety and efficacy will be assessed in the clinic visits up to day 112. PK blood samples will be collected. In between visits, safety will also be assessed by phone. 2 weeks after the end of treatment visit, patients will return to the clinic for final safety, efficacy, and PK evaluations.

Study Record Dates

• First Submitted: May 11, 2022
• First Posted: June 28, 2022
• Study Start: July 17, 2022
• Primary Completion: September 5, 2024
• Study Completion: September 5, 2024
• Last Updated: January 7, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

IL (3)