Safety, Tolerability, and Pharmacokinetics of Ascending Topical Doses of TCP-25 Applied to Epidermal Suction Blister Wounds, Non-Healing Leg Ulcers and Patients With Dystrophic Epidermolysis Bullosa.

This is a three-part, Phase I, first-in-human study designed to evaluate the safety, tolerability, and potential systemic exposure of multiple topical doses of TCP-25. Part I includes healthy volunteers with acute epidermal wounds formed by the suction blister technique. Part II includes patients with non-healing leg ulcers and Part III patients with dystrophic epidermolysis bullosa (DEB).


Eligibility Criteria:
Part I:

Inclusion Criteria:

1. Willing and able to give written informed consent for participation in the study.
2. Healthy male or female subject 18-60 years (inclusive) of age at the time of signing the informed consent.
3. Body Mass Index (BMI) ≥ 18.0 and ≤ 30.0 kg/m2.
4. Healthy and intact skin where the blister suction wounds will be induced.
5. Women of childbearing potential (WOCBP) must have a documented negative serum pregnancy test done at the screening visit, within 4 weeks prior to suction blister formation and the start of study treatment.

   WOCBP must practice abstinence (only allowed when this is the preferred and usual lifestyle of the subject) or must agree to use a highly effective method of contraception with a failure rate of \< 1% to prevent pregnancy (combined \[oestrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, implantable\], intrauterine device \[IUD\] or intrauterine hormone-releasing system \[IUS\]) from at least 4 weeks prior to dose to 4 weeks after last dose. Female subjects must refrain from donating eggs from the date of dosing until 3 months after dosing with the IMP. Their male partner must agree to use a condom during the same time frame if he has not undergone vasectomy.

   Women of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle stimulating hormone \[FSH\] 25-140 IE/L is confirmatory).

   Male subjects must be willing to use condom or be vasectomised or practice sexual abstinence to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of last dosing until 3 months after the last dosing with the IMP. Their female partner of child-bearing potential must use contraceptive methods with a failure rate of \< 1% to prevent pregnancy (see above).
6. Clinically relevant medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
2. Disease that may interfere with wound healing, e.g., diabetes type I/II, arterial-, renal-, liver, or cardiac insufficiency, chronic obstructive lung disease, cancer, autoimmune disease, edema at the study site, severe obesity, or previous known wound healing problems, as judged by the investigator.
3. Active skin disease, e.g., dermatitis, psoriasis and wounds, and/or tattoos in the areas where suction blister wounds will be induced, as judged by the investigator.
4. Any planned major surgery within the duration of the study.
5. After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges:

   * Systolic blood pressure \<90 or \>160 mmHg, or
   * Diastolic blood pressure \<50 or \>100 mmHg, or
   * Pulse \<40 or \>90 beats per minute (bpm)
6. Any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator.
7. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than three times per week is allowed before screening visit.
8. Female subjects who are pregnant or lactating or planning a pregnancy.
9. Systemic immunosuppressive treatment.
10. Subjects who are currently receiving or have received the following treatments within 2 weeks prior to screening are excluded from the study: - systemic corticosteroids or immunosuppressant agents; or - antibiotics via any route
11. Regular use of anticoagulants (i.e., heparin, warfarin, coumarins, other anticoagulants per Investigator's judgement) or non-steroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to the (first) administration of IMP, at the discretion of the Investigator.
12. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to TCP-25 or to any excipients of the hydrogel.
13. Planned treatment or treatment with another investigational drug within 3 months prior to Day -1.
14. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
15. Presence or history of drug abuse, as judged by the Investigator
16. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening.
17. Involvement in the planning and/or conduct of the study.
18. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

Part II:

Inclusion criteria:

1. Willing and able to give written informed consent for participation in the study.
2. Male patient, or female patient of non-childbearing potential, ≥40 years of age at the time of signing the informed consent.
3. Male subjects must be willing to use condom or be vasectomized or practice sexual abstinence to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of last dosing until 3 months after the last dosing with the IMP. Their female partner of child-bearing potential must use contraceptive methods with a failure rate of \< 1% to prevent pregnancy.

   Women of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle stimulating hormone \[FSH\] 25-140 IU/L is confirmatory).
4. Clinically relevant medical history, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator.
5. Patients diagnosed with venous insufficiency by relevant physiological tests including doppler or venous plethysmography or diagnosed by relevant clinical evaluations.
6. Systolic index \> 0.6 (Data from medical records from the last 2 years, or the assessment should be repeated at the screening visit).
7. Ulcer duration \> 6 weeks
8. Total target ulcer area applicable for treatment: ≤ 30 cm2 (as measured with the Silhouette imaging equipment at the screening visit). (The target ulcer area may not consist of \>2 separate ulcers.)
9. Ability to tolerate compression bandaging.
10. Willing to attend study site visits.

Exclusion criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
2. Disease that may interfere with wound healing, e.g., diabetes type I/II, arterial-, renal-, liver, or cardiac insufficiency, chronic obstructive lung disease, cancer, autoimmune disease, edema at the study site, severe obesity, or previous known wound healing problems, as judged by the Investigator.
3. Active skin disease, e.g., dermatitis, psoriasis and wounds, and/or tattoos in the areas where suction blister wounds will be induced, as judged by the Investigator.
4. Any planned major surgery within the duration of the study.
5. After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges:

   * Systolic blood pressure \<90 or \>160 mmHg, or
   * Diastolic blood pressure \<50 or \>100 mmHg, or
   * Pulse \<40 or \>90 beats per minute (bpm)
6. Any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator.
7. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than three times per week is allowed before screening visit.
8. Female subjects who are pregnant or lactating or planning a pregnancy.
9. Systemic immunosuppressive treatment.
10. Subjects who are currently receiving or have received the following treatments within 2 weeks prior to screening are excluded from the study:

    * systemic corticosteroids or immunosuppressant agents; or
    * antibiotics via any route
11. Regular use of anticoagulants (i.e., heparin, warfarin, coumarins, other anticoagulants per Investigator's judgement) or non-steroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to the (first) administration of IMP, at the discretion of the Investigator.
12. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to TCP-25 or to any excipients of the hydrogel.
13. Planned treatment or treatment with another investigational drug within 3 months prior to Day -1.
14. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
15. Presence or history of drug abuse, as judged by the Investigator.
16. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening.
17. Involvement in the planning and/or conduct of the study.
18. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

9.5.2 Part II: Exclusion criteria

Patients must not enter the study if any of the following exclusion criteria are fulfilled:

1. Presence or documented illness, which in the Investigator's opinion may negatively affect wound healing or interfere with the study conduct.
2. Target wound present for more than 5 years.
3. Clinical signs of infection in or around the wound in need of antibiotic treatment.
4. Albumin \<25 g/L or capillary Hb \<90 g/L, or HbA1c \> 70 mmol/mol at the time of the screening visit.
5. Any planned major surgery within the duration of the study.
6. Patients who are currently receiving or have received the following treatments within 2 weeks prior to screening are excluded from the study:

   * systemic corticosteroids above 5 mg prednisolone or equivalent, or
   * immunosuppressant agents; or
   * antibiotics via any route.
7. Regular use of anticoagulants (i.e., heparin, warfarin, coumarins, other anticoagulants affecting APTT and/or PK/INR per Investigator's judgement) within 2 weeks prior to the (first) administration of IMP, at the discretion of the Investigator.
8. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to TCP-25 or to any excipients of the hydrogel.
9. Planned treatment or treatment with another investigational drug within 3 months prior to Day -1.
10. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening.
11. Involvement in the planning and/or conduct of the study.
12. Investigator considers the patient unlikely to comply with study procedures, restrictions and requirements.

Part III:

Inclusion criteria:

1. Willing and able to give written informed consent for participation in the study. For 15 to 17-year-olds: A separate consent is required from both (if applicable) the patient's parents/legal guardians.
2. Male or female patient with documented diagnosis of inherited DEB, ≥15 years of age at the time of signing the informed consent.
3. Male patients must be willing to use condom or be vasectomized or practice sexual abstinence to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of last dosing until 3 months after the last dosing with the IMP. Their female partner of child-bearing potential must use contraceptive methods with a failure rate of \< 1% to prevent pregnancy.

   WOCBP must practice abstinence (only allowed when this is the preferred and usual lifestyle of the patient) or must agree to use a highly effective method of contraception with a failure rate of \< 1% to prevent pregnancy (combined \[oestrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, implantable\], intrauterine device \[IUD\] or intrauterine hormone-releasing system \[IUS\]) from at least 4 weeks prior to dose to 4 weeks after last dose. Female patients must refrain from donating eggs from the date of dosing until 3 months after dosing with the IMP. Their male partner must agree to use a condom during the same time frame if he has not undergone vasectomy.

   Women of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle stimulating hormone \[FSH\] 25-140 IU/L is confirmatory).
4. Clinically relevant medical history at the time of screening, as judged by the Investigator.
5. Presence of two target wound areas of 50 cm2. The primary wound area should not be located at anatomical sites with high likelihood of accidental trauma (e.g., knee, elbow). The secondary wound area could be located at anatomical sites with high likelihood of accidental trauma or be within the higher age span. Both wound areas should meet all the following characteristics:

   1. Including open wound with a surface area of ≤ 30 cm2 (as measured with the Silhouette imaging equipment at the screening visit).
   2. At Visit 2 (first IMP treatment), each target wound should not present a surface reduction ≥ 30 % from the Screening visit.
   3. Wound aged ≥ 3 weeks to \< 9 months at the Screening visit.
6. Presence of a reference wound area of 50 cm2 to be treated with standard of care only and to be included in the exploratory assessment. The wound area should match the primary wound area for following characteristics:

   1. Including open wound with a surface area of ≤ 30 cm2 (as measured with the Silhouette imaging equipment at the screening visit).
   2. At Visit 2 (first IMP treatment), the wound should not present a surface reduction ≥ 30 % from the Screening visit.
   3. Wound aged ≥ 3 weeks to \< 9 months at the Screening visit.
   4. Not located at anatomical sites with high likelihood of accidental trauma (e.g., knee, elbow).
7. Willing to attend study site visits.

Exclusion criteria

1. Any subtype of EB other than DEB.
2. EB index wounds that have infection in need of systemic antibiotic treatment.
3. Presence of or documented illness, which in the Investigator's opinion may negatively affect wound healing or interfere with the study conduct.
4. Subject has evidence of a systemic infection or has used systemic antibiotics for EB-related infections within 7 days before the screening visit (Visit 1).
5. Administration of systemic corticosteroids within 30 days (\> 10 mg daily of prednisolone or corresponding) or of topical corticosteroids on target wound areas (primary, secondary and reference wound areas) within 14 days before the screening visit (Visit 1). Corticosteroids for inhalation, ophthalmic, or intranasal use are permitted.
6. Subject has undergone stem cell transplant or gene therapy for the treatment of EB with an effect on target wounds.
7. History of malignancy, including basal cell carcinomas or squamous cell carcinomas in the wound areas that will be included in the study.
8. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to TCP-25 or to any excipients of the hydrogel.
9. Planned treatment or treatment with another investigational drug within 3 months prior to Day -1.
10. Involvement in the planning and/or conduct of the study.
11. Investigator considers the patient unlikely to comply with study procedures, restrictions and requirements.