MSC EVs in Dystrophic Epidermolysis Bullosa

Study Overview
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Brief Summary
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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, ascending dose, study to assess the effectiveness and safety of AGLE-102 on lesions in subjects with EB.

Detailed Description
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STUDY DESIGN: This is a phase 1/2A, non randomized, multi-center, ascending dose, study to assess the effectiveness and safety of AGLE-102 on lesions in subjects with EB. Eligible subjects will undergo a one-month observation period to confirm that the targeted wound is chronic (only single wounds with evidence of less than 20% closure over that period will be eligible for treatment). Once this has been established, up to 6 administrations of BM-MSC EVs will occur, at each to be given over a period of no more than 3 months. A maximum of 50 cm2 in total wound surface will be treated, and each administration will occur 14 days (+/- 7 days) but no less than 7 days apart. If the wound closes prior to 6 administrations, no additional doses will be given. Wound closure will be 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). After the 6 doses of BM-MSC EVs are given, the wound will be followed monthly for a period of 4 months to the termination of the study at 8 months or, in the event the wound closes before receiving all 6 doses, for 4 month after the wound closes. The ARANZ SilhouetteStarTM will be used to measure the target lesion at all visits. STUDY OBJECTIVES: Primary Objective: The primary objective is to determine the safety of applying single administrations of 2 ascending dose levels of EVs derived from allogeneic MSCs to DEB wounds between 10 and 50 cm2 that have persisted for more than one month Secondary Objectives: The secondary objectives are to determine the safety of applying multiple administrations of 2 ascending dose levels of EVs derived from allogeneic MSCs to DEB wounds between 10 and 50 cm2 that have persisted for more than one month and to determine if there is clinical benefit (>50% closure) of applying BM-MSC EVs to DEB wounds PLANNED SAMPLE SIZE: 10 subjects will be treated on the protocol with AGLE-102.

Official Title
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A Safety Study of the Administration of Mesenchymal Stem Cell Extracellular Vesicles in the Treatment of Dystrophic Epidermolysis Bullosa Wounds

Conditions
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Dystrophic Epidermolysis Bullosa

Intervention / Treatment
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* Drug: AGLE 102


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. Subjects who have one or more active wounds (unroofed EB erosions) each between 10 and 50 cm2 on arms, legs, or trunk. 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. 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. Subjects must be willing to comply with the protocol requirements. Subjects must be accessible for wound treatments and assessment visits. Subjects must have a negative urine test for drugs of abuse at the screening visit. Female subjects willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period. 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: Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 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: The subject has clinical evidence of systemic infection. The subject has a history or bone marrow transplantation. The subject has evidence of autoimmune disease, including insulin-dependent diabetes. The subject has wounds that are considered by the investigator as likely to heal within 1 month after standard therapy. The subject has clinical evidence of an active infection at the wound site. The subject has evidence of significant wound healing before treatment (i.e., ≥ 20% closure of wound during the first month observation period treatment). The subject has a wound that extends across the fingers, toes, pubic or perineum region. 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. The subject has a history of coagulopathy. The subject currently uses systemic steroids or immunosuppressive agents. The subject is allergic to human albumin, streptomycin, or penicillin. The subject is a potential recipient of tissue or organ transplantation. 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. The subject has a positive test result for human immunodeficiency virus (HIV) at screening. The subject has a history of poor compliance or unreliability. Females who are pregnant, nursing, or planning a pregnancy during their participation in the study.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a phase 1/2A, non-randomized, multicenter, ascending dose, study to assess the effectiveness and safety of AGLE-102 on lesions in subjects with EB.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGLE 102<br>Treatment arm | Drug: AGLE 102<br>* Exosomes from MSCs<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity | This study examines a dose escalation, Dose Limiting Toxicity (as defined in the NCI/CTCAE v4.0 grading scale) | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wound size evaluation | 1. Wound Size Evaluation Target wounds will be measured using Silhouette® (Aranz Medical Direct wound tracings will also be performed. | 8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exosomes