A phase I/IIa, single-centre, randomized, double-blind, placebo-controlled, parallel treated dose-ranging study with a safety run-in period to assess the safety and efficacy of topical XZ.700 in patients with mild to moderate atopic dermatitis

The pathophysiology of atopic dermatitis (AD) is complex and still not
completely understood. Genetic susceptibility, environmental factors, epidermal
barrier abnormalities, immunological disturbances and dysbiosis of the skin
microbiota all play a role in the disease and the variability of these
mechanisms may explain the heterogeneous character of AD. It remains hard to
discern which of these mechanisms are primary events (causing AD), secondary
events (resulting from AD), or both (Weidinger et al., 2018).
Staphylococcus aureus (S. aureus) is an important player regarding dysbiosis in
AD. Colonization with this pathogen combined with a lower general microbial
diversity is apparent in approximately 70-90% of the AD patients (Totte et al.,
2016). Several factors contribute to enhanced S. aureus adhesion to AD skin.
After adhesion S. aureus may cause or exacerbate inflammation by binding of its
superantigens (SAgs) to MHCII molecules which induces an excessive production
of T cell cytokines (Spaulding et al., 2013), next to being conventional
allergens that can generate an IgE response. In addition, S. aureus produces
alpha toxin, which causes lysis of keratinocytes and aureolysin which
inactivates antimicrobial peptides (Geoghegan et al., 2018).
Based on the hypothesis that dysbiosis plays an important role in the
pathogenesis of AD the microbiome and especially S. aureus might be a target
for novel therapies (Geoghegan et al., 2018, Nakatsuji et al., 2017). A novel
topical treatment targeting the perturbed microbiome is XZ.700. XZ.700 is a
recombinant chimeric endolysin that specifically targets S. aureus. Endolysins
are phage derived enzymes that are produced at the end of the reproduction
cycle of bacteriophages in the bacteria to lyse the peptidoglycan cell wall and
to allow the newly assembled phages to leave the host-cell. XZ.700 is produced
via recombinant technology. It is highly specific against the S. aureus species
(both MSSA and MRSA) and unlikely to induce bacterial resistance, allowing it
to be used for the long-term treatment of chronic skin diseases such as AD.
This first-in-human study is intended to evaluate the safety and tolerability
of XZ.700 as well as exploring the pharmacodynamic effects in patients with
mild to moderate AD. Clinical efficacy will be investigated by means of
clinical outcomes (i.e. clearance of the target lesion, target lesion oSCORAD,
target lesion TSS) and local biomarkers will be assessed.

Primary Objective
To evaluate the safety and tolerability of topical XZ.700 in patients with mild
to moderate atopic dermatitis

Secondary Objectives
To investigate the PD effects of XZ.700 in patients with mild to moderate
atopic dermatitis
To evaluate the efficacy of three dose levels of topical XZ.700 in patients
with mild to moderate atopic dermatitis

Phase I/IIa, single-centre, randomized, double blind, placebo controlled,
parallel treated dose-ranging study with a safety run-in period. The study will
entail two Parts. . The aim of part A is to closely observe the safety through
daily assessments of both the non lesional and lesional skin whereas Part B is
only focussing on lesional skin.

Part A (safety run-in):
- 12 atopic dermatitis patients with 2 treatment areas
- Treatment area 1: healthy appearing, uninvolved, non-lesional skin of
preferably the upper back, 20x20cm (approx. 2.3% body surface area (BSA)), 7
days twice per day (BID) in-clinic treatment (for Part A interim safety
analysis).
- Treatment area 2: lesional skin involvement of approximately 1%*BSA*10% for
14 days BID followed by an end of treatment (EOT) visit at Day 15 and an end of
study (EOS) visit at Day 22. One target lesion of BSA*0,5% (preferably elbow or
knee-fold) is selected for pharmacodynamic measurements. Treatment area two
will consist of all lesions.(for Part A interim safety analysis and, together
with Part B, overall safety, efficacy and pharmacodynamic analysis)

Safety will be assessed by the investigator on an ongoing basis and if needed
action will be taken to warrant the safety of the patients. After completion of
the D22 visit of the last patient of Part A, a unblinded interim analysis will
be performed. The full interim analysis together with the decision to proceed
to Part B of the study will be provided to the Ethics Committee for assessment.

The study may continue as planned when:
- There are no Serious Adverse Events (SAEs) assessed related to the study drug
by the investigator
- There are no adverse events graded severe and assessed as related to the
study drug by the investigator
- There are no assessments of more than 8 points on the local irritation
grading scale
- The criteria of section 8.11, interim analysis after Part A, have been
fulfilled

In case any of the foregoing events occur in Part A, the study will be
temporarily halted, treatment allocation of the subjects will be unblinded and
a critical review of the safety data will be performed. In that case, approval
from the Ethics Committee will be obtained prior to restarting the study with
Part B.

Part B:
- 24 atopic dermatitis patients (that will be grouped together with Part A for
overall safety, efficacy and pharmacodynamic analysis)
- Treatment of all lesions of 1%*BSA*15% for 14 days BID treatment followed by
an EOT visit at Day 15 and an EOS visit at Day 22. One target lesion of
BSA*0.5% (preferably elbow or knee-fold) is selected for pharmacodynamic
measurements. First treatment is in-clinic, all other treatments will be
performed by the subjects (at home or at clinic)

XZ.700 or placebo

The current study is the first investigation with XZ.700 in humans. The drug is
a large molecule with 52kDa in size and applied via the topical route of
administration. Hence only negligible exposure of the drug is expected in the
systemic circulation and mainly local effects are expected. XZ.700 is a very
similar endolysin to the EU marketed SA.100. Since its introduction 7 years ago
no major safety issues were reported. The patients in this trial do have a mild
to moderate disease where any safety or tolerability issues can be assessed in
a well-monitored manner, i.e. daily administration site inspections, vital
signs monitoring and in-house observation. After completion of Part A a blinded
safety evaluation will be performed to continue into the outpatient-clinic Part
B with administrations at home. This warrants additional measures to mitigate
the risks of potential safety or tolerability issues. A multiple dose design
will be performed, as explained in detail in section 1.4.6 of the protocol,
with frequent administration site assessment and negligible systemic exposure
to XZ.700 based on ample SA.100 experience as well as negligible XZ.700
penetration as observed in ex vivo experiments.
Measurements are predominantly non-invasive, the minimally invasive techniques
are venepuncture and 4mm small skin punch biopsies (no suture necessary).
No additional risk for infection to SARS-CoV-2 can be determined due to
participation in the trial due to the various extra measures applied.
In summary, the risk to participate in the trial can be assessed as acceptable.