Planned safety, efficacy and proof of mechanism obtained

The goal of this study is to determine the safety and effects of ENS-002, a live biotherapeutic product (LBP) consisting of commensal, clonal, non-pathogenic bacteria in participants with atopic dermatitis.

This is a Phase 1, open-label, non-randomized, study investigating ENS-002, a live biotherapeutic product (LBP) consisting of commensal, clonal non-pathogenic bacteria

The purpose of this dose escalation study is to determine the recommended Phase 2 dose (RP2D) of ENS-002 in participants with mild, moderate or severe atopic dermatitis.

Participation in this study will continue until dose limiting toxicity or therapy intolerance, or participant withdrawal.

Inclusion Criteria:

1. Able to understand and sign an informed consent form (ICF).

2. Age 18 years or older on the day of signing the ICF.

3. Diagnosis of AD according to Hanifin and Rajka

4. Atopic dermatitis has been diagnosed and present for ≥ 6 months prior to the first planned ENS-002 administration.

5. EASI (Eczema Area and Severity Index) score of 5 to 7 (mild) or 7.1 to 21 (moderate), or ≥ 21.1 or severe at screening.

6. Mild, moderate or severe AD as scored by the IGA at screening and baseline For Cohort 1, in which only a single antecubital fossa or other body site lesion will be administered ENS-002, a target lesion IGA will be performed.

7. Body surface area involvement must be ≥ 2% for mild AD and >10% for moderate to severe AD (excluding scalp, face, groin, and genitalia) at both screening and baseline as estimated based on the rule of nines and/or the palmar rule. Participants who have only one or a limited number of areas affected by AD (eg, neck, antecubital fossa, hands/feet, or popliteal involvement), as long as these sites have at least moderate severity, may also be eligible even if they do not meet the minimum BSA required - these participants will need to be approved by the Concerto Medical Monitor.

8. Presence of specific bacteria via qPCR. Two affected skin sites will be sampled as part of the screening tests; if at least one of the affected skin sites contains the specified bacteria, the participant is eligible pending eligibility in all the other inclusion/exclusion criteria. If the qPCR test does not detect the specified bacteria, the participant is not eligible, but the bacteria skin swabs may be repeated. No more than 2 attempts to detect the specified bacterial colonization over 28 days may be made.

9. Acceptable screening laboratory values that are within normal limits or are not clinically significantly abnormal. If clinical significance is unclear, the investigator must consult with Concerto's medical monitor.

   • Complete blood count with WBC differential (including absolute values).
   • Chemistry panel including hepatic transaminases.
   • CRP.
   • Urinalysis.
   • 12-lead electrocardiogram.
   • For women of childbearing potential (WOCBP), serum and/or urine test consistent with a non-pregnant state.

10. If using an oral and/or topical H1 antihistamine for pruritus and/or insomnia, must have been on a stable dose and frequency for at least 14 days prior to screening and must continue at the same dose and frequency throughout the study.

11. Willing and able to complete once-daily electronic diary entries for the duration of the study.

Exclusion Criteria:

1. Has only facial AD.

2. Has more than 20 Geographic Body Site Areas (GBSA) if to be enrolled into Cohort 2 or more than 10 GBSA if to be enrolled in Cohort 3 that are affected by AD. These GBSA restrictions exclude face, scalp, genitalia, and groin lesions. If the total number of allowable GBSAs is exceeded, the participant may be allowed to enroll after discussion with the Concerto Medical Monitor, but these additional sites must not have ENS-002 applied.

3. Presence of non-AD dermatologic disorder(s) including, but not limited to, the following dermatitides: photodermatitis, allergic contact, infestations (including scabies), eczematous eruption (eg, secondary to calcium channel blockers), nummular, stasis, dermatitis herpetiformis, xerotic, widespread seborrheic, bullous pemphigoid (prodromal phase), eczematous psoriasis, or mycosis fungoides (Sezary syndrome).

4. Presence of idiopathic chronic eczematous eruption of aging - defined as new-onset, atopic-like dermatitis presenting in people > 50 years old with no history of childhood AD.

5. Presence of indwelling arterial or venous catheters.

6. Cardiac valve disease history or artificial valve or pacemaker in place.

7. Implanted devices/prostheses including, but not limited to, eye lens, knee, hip, dental implants (but not caps or crowns), etc. replacements.

8. History of Grade 2 or higher neutropenia or leukopenia (except for known benign neutropenia typical for Fy(a-b-) status [formerly known as benign ethnic neutropenia or BEN]).

9. Unwilling to stop hair removal by any method (including shaving, waxing, or depilatory creams) in ENS-002 administration body sites for 7 days prior to the first ENS-002 administration and for at least 7 days after the last ENS-002 administration.

10. Any significant breaks or cracks in the skin in the target areas of ENS-002 administration, including severe excoriations or open or weeping wounds suggestive of an active infection/increased susceptibility to infection.

11. Clinically significant immunodeficiency (congenital or acquired [including a history of treated or untreated HIV, malnutrition, chronic viral infection]).

12. Netherton syndrome or other genodermatoses resulting in a defective epidermal barrier.

13. Active malignancy or history of malignancy in the past 3 years (Exceptions: superficial skin cancers - squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the skin, curatively treated with cryosurgery or surgical excision only and indolent prostate cancer).

14. Clinically significant cardiovascular, liver, pulmonary, neurologic, metabolic, or kidney disease or any other comorbid medical, surgical, social, or psychiatric condition, that, in the opinion of the investigator, puts the participant at increased risk, might lead to study noncompliance, and/or confounds interpretation of safety and efficacy data.

15. Required to take immunosuppressive drugs (eg, including but not limited to chemotherapy, systemic corticosteroids [≥ 10 mg prednisone equivalent/day; allowed corticosteroids: inhaled, intra-articular, topical low- to mid-potency creams (and lotions, gels, foams, etc.); use of allowed topical corticosteroids only after discussion and agreement with Medical Monitor, or if systemic, permitted at doses intended only for adrenal replacement, or if ≥ 5 days prior to first ENS-002 administration, on a one-time basis as a prophylaxis for imaging procedures], anti-tumor necrosis factor, colchicine, hydroxychloroquine, sulfasalazine, dapsone, methotrexate, mycophenylate mofetil, azathioprine, anti-interluekin-6 (anti-IL-6) antibody, anti-IL-1 antibody, or anti-CD20 antibody).

16. Lives with or has frequent contact with individual(s) with implantable medical devices including, but not limited to, artificial eye lens, artificial joint, cardiac stents, indwelling venous or arterial catheters, cardiac valvular disease, or artificial valve in place; or who have severe skin barrier defects or known immunodeficiency (congenital or acquired [eg, treated or untreated HIV, malnutrition, chronic viral infections]). If there is any question on this exclusion criterion contact the Concerto medical monitor.

17. Received oral or systemic antibiotics within 21 days prior to screening.

18. Inability to tolerate > 7 days without topical AD treatments and topical antibiotics (prescription or over-the-counter [OTC]) or has had topical antibiotics ≤ 7 days prior to screening.

    Exceptions:

    allowed emollients and low- and mid-potency corticosteroid creams. Low- and mid-potency corticosteroid creams may be allowed without a washout, but only after discussion and agreement with Concerto Medical Monitor. Allowed emollients may be substituted for disallowed emollients during screening as long as this occurs at least 7 days before the planned first ENS-002 administration.

19. Therapy prior to the first planned dose of ENS-002 with one or more of the following:

    1. Systemic corticosteroids within 28 days
    2. Topical high-potency corticosteroids within 28 days
    3. Low- and mid-potency corticosteroid creams within 14 days. These may be allowed if the participant is on a stable dose and after discussion and agreement with the Concerto Medical Monitor.
    4. Topical phosphodiesterase inhibitors within 7 days
    5. Emollients within 7 days, other than those emollients allowed in this study. If a participant has used a product with a 7-, 14-, or 28-day eligibility limit, a minimum of a 7-, 14-, or 28-day washout, respectively, is required before the first planned dose of ENS-002.

20. Treatment with systemic therapies with anti-pruritic (eg, tricyclic antidepressants, sedatives, tranquilizers, marijuana or other cannabinoids, opioid receptor agonists/antagonists) or pruritus- inducing (eg, opioids, angiotensin-converting enzyme inhibitors, cocaine, antimalarials) potential within 28 days prior to the first planned dose of ENS-002.

21. Therapy within 28 days prior to the first planned dose of ENS-002 with any immuno-modulating agents (eg, cyclosporine, azathioprine, methotrexate), phototherapy, or indoor tanning.

22. Therapy within 56 days or 5 half-lives (whichever is longer) prior to the first planned dose of ENS-002 with investigational drugs or any Janus kinase inhibitors (JAKs).

23. Concurrent therapy with dupilumab, tralokinumab, or lebrikizumab is allowed as long as participant has been on a stable dose for

    ≥ 16 weeks prior to the first planned dose of ENS-002. If a participant was taking any of these agents but has stopped, then a 56-day or five half-lives (whichever is longer) period is required before the first planned dose of ENS-002.

24. Bleach baths within 30 days prior to the first planned dose of ENS-002.

25. Use of any live topical bacterial product (OTC products within 4 weeks or investigational bacteria within 365 days) prior to the first planned dose of ENS-002.

26. Allergic to any of the excipients in ENS-002 (pea hydrolysate, potassium phosphate dibasic, sodium chloride, yeast extract, water for injection, glycerol, and methylcellulose).

27. Unable to use at least 2 of the 6 rescue antibiotics that cover all 3 bacteria in ENS-002.

28. Pregnant or planning to attempt to become pregnant during this study, breast feeding, breast pumping, or planning to breast feed.

29. Participant with a pregnant or breastfeeding partner or a partner planning to attempt to become pregnant during the study.

30. Unable to demonstrate proper ENS-002 application technique despite proficiency training.

31. Any prior exposure to ENS-002.

32. Is biologically a WOCBP; eg, has not had a hysterectomy, has not been in menopause for at least one year, and cannot or is unable or unwilling to use highly effective birth control measures during this study and for 90 days after the last administration of ENS-002.

33. If biologically male and fertile, cannot donate sperm and must adhere to highly effective birth control measures during this study and for 90 days after the last administration of ENS-002.