MSC EVs in Dystrophic Epidermolysis Bullosa

INVESTIGATIONAL PRODUCT: AGLE-102 is an allogeneic derived extracellular vesicle (EV) product derived from normal donor mesenchymal stem cells (MSCs).

INDICATION AND RATIONALE: The aim of the study is to assess the safety and efficacy of AGLE-102 in the treatment of lesions in subjects with Epidermolysis Bullosa (EB).

STUDY DESIGN: This is a phase 1/2A, non randomized, multi-center, study to assess the effectiveness and safety of AGLE-102 on lesions in subjects with EB.

STUDY DESIGN: This trial is a prospective, open label, randomized, multi-center study, with intra-subject paired- wound control, intended to assess the safety and preliminary efficacy of administering EVs derived from allogeneic MSCs to 10-50 cm2 wounds in RDEB subjects with wounds persisting for at least four weeks.

After providing written informed consent (assent with parental written consent for pediatric subjects) and undergoing screening evaluations, eligible subjects have a single set of paired wounds identified that are determined by either subject/caregiver reporting, medical history or other reliable sources to have been present for a minimum of four weeks. One of each pair is randomized to treatment with EVs in conjunction with standard of care. The other wound of each pair receives standard of care alone, without EV treatment. All wounds on study continue to receive standard of care throughout the study. For the EV treated wounds, up to six administrations of EVs occur approximately two weeks apart over a period of 10 weeks. If the treated wound closes prior to six administrations, and remains closed for at least two weeks, no additional doses are given. Wound closure is determined by complete re-epithelialization that is not subject to re-injury during dressing changes or as a result of normal daily activities (e.g., wearing clothing, eating, sleeping). This is confirmed by the investigator at least two weeks after initial closure. After the initial 10- week treatment period, or from the time of closure of the treated wound if prior to the end of the treatment period, the wounds are followed every four weeks for a period of 12 additional weeks, for a total of up to 22 weeks of observation from the start of treatment. Regardless of the closure status of wounds or the timing of the last EV treatment, all subjects must present 10 weeks after the initial treatment to ascertain closure status of both the control and EV treated wounds. At no time during the study does closure status of the control wound influence the EV treatment or visit schedule.

STUDY OBJECTIVES:

Primary Objectives:

Determine the safety of applying multiple administrations of EVs derived from allogeneic MSCs to 10-50 cm2 RDEB wounds that have persisted for at least four weeks

Determine if EVs plus standard of care can promote wound healing in RDEB subjects compared to standard of care alone control

Secondary Objectives: Determine if there is clinical benefit of applying EVs to RDEB wounds

PLANNED SAMPLE SIZE: 8 subjects will be treated on the protocol with AGLE-102.

Eligibility Criteria:
Inclusion Criteria:

1. The first 2 subjects must be 18 years or older at the time of signing the informed consent. If approved by the SRC, additional subjects (after the first 2 subjects) may be 6 years or older at the time of signing the informed consent; otherwise additional subjects must be 18 years or older until such time it is considered by the SRC as appropriate to lower the age limit to 6 years.
2. Subjects who have a confirmed diagnosis of DEB as determined by electron microscopy, immunomapping, or genetic testing. Subjects with severe DEB (e.g., RDEB patients with absent Col VII/no anchoring fibrils) and milder forms of DEB (e.g., RDEB patients with reduced Col VII and/or anchoring fibril levels) will be eligible.
3. Subjects who have one or more active wounds (unroofed EB erosions) each between 10 and 50 cm2 on arms, legs, or trunk.
4. Females of childbearing potential must have a negative urine or serum pregnancy test at screening and agree to continue use of an acceptable form of birth control throughout the duration of the study. Acceptable forms of birth control include oral, implant, injectable, and transdermal contraceptives; an intrauterine device; or other forms considered acceptable by the investigator.
5. Subjects or guardian of subjects who are under the age of 18 years must be capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
6. Subjects must be willing to comply with the protocol requirements.
7. Subjects must be accessible for wound treatments and assessment visits.
8. Subjects must have a negative urine test for drugs of abuse at the screening visit.
9. Female subjects willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period.
10. A female subject is eligible to participate if she is not pregnant (i.e. has a negative urine pregnancy result at the Screening Visit and on Day 1), and at least one of the following conditions applies:
11. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
12. Or a WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the intervention and follow-up period

Note: Reference to Appendix 3 can be located in the protocol

Exclusion Criteria:

1. The subject has clinical evidence of systemic infection.
2. The subject has a history or bone marrow transplantation.
3. The subject has evidence of autoimmune disease, including insulin-dependent diabetes.
4. The subject has wounds that are considered by the investigator as likely to heal within 1 month after standard therapy.
5. The subject has clinical evidence of an active infection at the wound site.
6. The subject has evidence of significant wound healing before treatment (i.e., ≥ 20% closure of wound during the first month observation period treatment).
7. The subject has a wound that extends across the fingers, toes, pubic or perineum region.
8. The subject has a severe medical condition, such as malignancy (including skin cancer), a life expectancy of \< 2 years, or severe cardiopulmonary disease that restricts ambulation to the clinical facility.
9. The subject has a history of coagulopathy.
10. The subject currently uses systemic steroids or immunosuppressive agents.
11. The subject is allergic to human albumin, streptomycin, or penicillin.
12. The subject is a potential recipient of tissue or organ transplantation.
13. The subject has a current history of alcohol or substance abuse or has a history of alcohol or substance abuse that required treatment within the previous 12 months.
14. The subject has a positive test result for human immunodeficiency virus (HIV) at screening.
15. The subject has a history of poor compliance or unreliability.
16. Females who are pregnant, nursing, or planning a pregnancy during their participation in the study.