Evaluation of Safety and Efficacy of Topical SXR1096 Cream in Patients with Netherton Syndrome: A Phase I/II Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-507743-11-00
Protocol: SXR001
Sponsor: Sixera Pharma AB

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Diseases & Conditions

Netherton's syndrome

Objectives

The primary objective of this study is to evaluate the clinical **safety** and **efficacy** of the investigational medicinal product (IMP), SXR1096 cream, compared to placebo in patients with **Netherton syndrome** (NS). This objective is clinically relevant as it aims to determine the potential therapeutic benefits and safety profile of SXR1096, a benzoxazinone derivative and selective inhibitor of skin kallikreins KLK5, which could offer a novel treatment option for individuals affected by this rare genetic disorder characterized by skin barrier defects and chronic inflammation.

Secondary objectives include: Part A) assessing the safety of multiple doses of SXR1096 over 7 days in five adults, and Part B) evaluating the safety and efficacy of a 4-week treatment with SXR1096 in both adults and adolescents aged 12-17 years. These objectives are crucial for understanding the broader safety and therapeutic implications of SXR1096 across different age groups and treatment durations.

Participants

The clinical trial involves participants diagnosed with **Netherton syndrome (NS)**, a rare genetic disorder. The study population includes both male and female subjects, with an age range of 12 to 65 years. Participants are required to have a clinical diagnosis of NS, characterized by specific clinical criteria such as neonatal erythroderma, bamboo hair or alopecia, chronic atopy, and ichthyosis linearis circumflexa. The trial does not involve a vulnerable population. Participants must have NS involvement of at least 20% of their body surface area and an Investigator Global Assessment score of moderate or severe in two target areas. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are capable of understanding and complying with study requirements, including the application of medication and completion of the study. Female participants of childbearing potential must adhere to strict contraceptive measures or commit to abstinence throughout the trial. The trial population was selected based on these criteria to ensure the safety and efficacy evaluation of the investigational medicinal product compared to a placebo.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the safety and efficacy of SXR1096 cream in patients with **Netherton syndrome**. This trial is structured as a phase I/II, multicenter, first-in-human proof of concept study. The primary objective is to assess the clinical safety and efficacy of the investigational medicinal product (IMP) compared to placebo. The trial is expected to conclude by April 30, 2024, with recruitment having commenced on August 10, 2021.

Participants will be involved in the study for a maximum treatment period of 28 days, during which they will apply the cream topically. The study includes several key visits: an initial screening visit to confirm eligibility, followed by baseline assessments, and subsequent follow-up visits to monitor safety and efficacy. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted. The primary endpoints include safety assessments through adverse events, physical examinations, and laboratory tests, as well as the change in the Investigator Global Assessment (IGA) score from baseline to the end of treatment. Secondary endpoints involve the evaluation of skin condition using the Ichthyosis Area Severity Index (IASI), assessment of skin itching, and measurements of skin surface pH and transepidermal water loss.

Participants are expected to be involved for the duration of the treatment period, with conditions for early termination including non-compliance with study requirements or the occurrence of significant adverse events. The study is open to male and female patients aged 18 to 65 years, with adolescents aged 12-17 years eligible after an initial cohort of adult patients has been treated. Inclusion criteria require a clinical diagnosis of Netherton syndrome, with specific clinical features and a minimum body surface area involvement. Female participants of childbearing potential must adhere to strict contraceptive measures throughout the study. The trial is not categorized as low intervention due to its inclusion of both adult and adolescent patients.

Treatment

The clinical trial involves the use of an **experimental medication** known as SXR1096 cream, developed by SIXERA PHARMA AB. SXR1096 is a benzoxazinone derivative and functions as a potent and selective inhibitor of skin kallikreins KLK5. The pharmaceutical form of the medication is a cream, intended for **topical administration**. The dosage regimen specifies a maximum daily dose of 10 ml, with a total maximum dose of 280 ml over a treatment period of 28 days. The active substance, SXR1096, is of chemical origin and is not formulated specifically for pediatric use. The cream is applied directly to the skin, and participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

In addition to the experimental treatment, the study employs a **placebo** as a comparator within a double-blind, placebo-controlled design. The placebo is administered in the same manner as the SXR1096 cream, ensuring that neither the participants nor the investigators are aware of the treatment allocation. This design allows for an unbiased evaluation of the safety and efficacy of the SXR1096 cream in patients with Netherton syndrome. Compliance with the placebo administration is similarly monitored to maintain the integrity of the study results.

Efficacy

The efficacy of the investigational medicinal product, SXR1096 cream, in patients with Netherton syndrome will be assessed using both primary and secondary endpoints. The primary efficacy endpoint is the change in the **Investigator Global Assessment (IGA)** score, which ranges from 0 to 4, at the end of treatment compared to baseline. This score will be used to evaluate the severity of the skin condition in the treated areas.

Secondary efficacy endpoints include the characterization of the skin condition using the **Ichthyosis Area Severity Index (IASI)**, which integrates erythema and scaling. This index has been validated for use in patients with Netherton syndrome. Additionally, skin itching will be assessed using a Visual Analog Scale (VAS) and a multidimensional 5-D pruritus scale. Measurements of skin surface pH and transepidermal water loss (TEWL) will also be conducted on the treated areas to provide further insights into the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients aged 18 to 65 years at the screening visit and also adolescents (12-17 years) only after initial cohort of 5 adult patients have been treated for at least 7 days (Part A). 2. Patients must be willing to provide written informed consent. Adolescents (as applicable in Part B) are eligible if all inclusion/exclusion criteria are met, benefits outweigh risks, are irreplaceable as a participant, and a legal guardian has conveyed and clarified the Informed Consent information to ascertain the subject’s understanding of it as adequate for the decision. 3. Clinical diagnosis of NS including at least 3 out of the 4 following clinical criteria; a. Neonatal erythroderma b. Bamboo hair and/or alopecia c. Chronic atopy specified as food allergy, asthma, rhino conjunctivitis and/or eczema for at least 2 years d. Ichthyosis linearis circumflexa 4. Patients must be willing and able to understand and can comply with study requirements, apply the medication as instructed and be able to complete the study. 5. Absent LEKTI on immunohistochemistry of skin biopsy and/or confirmed mutation in SPINK5 gene 6. NS involvement ≥ 20% of Body Surface Area (BSA) required at both the screening and baseline visits. 7. Investigator Global Assessment (IGA) of two areas to be treated, score ≥3, i.e. moderate or severe for each area required. Each target area approx. 9% of BSA. i.e. equal to one arm. 8. Female of childbearing potential must either commit true abstinence (as defined as refraining from heterosexual intercourse) during the complete trial when this is in line with the preferred and usual lifestyle of the subject, or use an adequate and approved highly effective method of contraception throughout the study and for 4 weeks after the last study drug application. This criterion also applies to a prepubertal female subject who begins menses during the study. Adequate and approved highly effective methods of contraception applicable for the subject and/or her partner are defined below: • Progestogen-only (oral, transdermal, injectable or implantable) hormonal contraception associated with inhibition of ovulation • Combined (oestrogen- and progestogen-containing) oral, , or transdermal hormonal contraception • Injectable or implanted hormonal contraception • Intrauterine devices or intrauterine hormone-releasing system • Bilateral tubal ligation or tube insert (such as the Essure system) at least 3 months before the study • Vasectomy of partner, confirmed to be the sole sexual partner, at least 3 months before the study with confirmed surgical success. • Female subjects 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, bilateral salpingectomy, or bilateral oophorectomy at least 3 months before screening • In adolescents who are not yet post-pubertal, eligibility demands the childbearing potential to have been evaluated by a suitably qualified medical practitioner and use of an acceptable sexual maturity rating scale (e.g. Tanner)

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Exclusion Criteria

Female patient who is pregnant, nursing an infant or planning a pregnancy throughout the course of the study or is unwilling or unable to adhere to the contraception methods described herein 2. Patient with any uncontrolled systemic disease. A potential patient in whom therapy for a systemic disease is not yet stabile for at least 3 months will not be considered for entry into the study. 3. Patient with positive serology tests like HIV, HCV & HBsAg. 4. Patient with presence of any skin disease that might interfere with the diagnosis or evaluation of the test medications. Cutaneous infection within 1 week before the baseline visit or, any infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics, or antifungals within 2 weeks before the baseline visit. 5. Patient that has a condition or is in a situation, which in the investigator's opinion may put the patient at significant risk, may confound the study results, or may interfere significantly with the patient's participation in the study. 6. Use of topical drugs that might alter the course of NS (e.g., topical corticosteroids and topical calcineurin inhibitors) within two weeks before baseline visit. 7. Patient with a known sensitivity to any of the study treatments and/or their components (detailed in Appendix E herein). 8. Patients with contact dermatitis-like reactions to the vehicle cream (placebo) evaluated at Screening (Appendix I) 9. Patient who anticipates a need to use other topical or systemic therapy that might alter the course of NS. Emollients/creams can be used on remaining skin area but not the test areas. Use of topical prescription treatment within 2 weeks prior to initial dosing of study drug. Recent systemic treatment for NS (e.g. systemic corticosteroids, antibiotics, immunosuppressant, biologic and biosimilars treatments). A washout period of 4 weeks will be required for such patients to be eligible to participate in the trial. 10. Patient who anticipates the need for surgery or hospitalization during the study. 11. Concurrent involvement in any other clinical study/expanded access program with an investigational drug or device, or participation in a clinical study within 30 days prior to entering the study. 12. Suspected or confirmed COVID-19 infection within 4 weeks before the screening or baseline visit. Unresolved COVID-19 infection. Planned vaccination for COVID-19 during screening, treatment period or before the follow-up visit.