A randomized, double-blind, placebo controlled, parallel group, proof of concept study evaluating the efficacy, safety, pharmacokinetics and pharmacodynamics of QGE031 in the treatment of patients with moderate to severe atopic dermatitis (CQGE031X2201)

Atopic dermatitis (AD) is a chronic atopic skin condition with a prevalence of
at least 10-15% of children in Europe and it has continuously increased in
recent decades. The persistence after puberty is approximately up to 50%.
Topical corticosteroids are the current mainstay of therapy but their value in
patients with extensive disease is limited. Long-term use of topical
corticosteroids is not recommended due to the potential to cause local and
systemic side effects. Treatment options for patients who are not controlled
with topical drugs include phototherapy, systemic steroids, methotrexate, and
cyclosporine.
Patients with AD often have elevated levels of serum IgE; however, the role of
IgE and specific allergens in driving AD has not been fully characterized. Case
series have been published demonstrating efficacy with omalizumab (Xolair®; the
first registered therapeutic antibody against IgE), although a randomized
placebo-controlled trial did not demonstrate clinical efficacy in AD patients.
In this study, an observed response in skin biomarkers suggests that clinical
efficacy in AD might be achieved with improved suppression of IgE.
QGE031 is a humanized monoclonal antibody directed against human IgE and is a
highly potent inhibitor of human IgE binding to the IgE receptor. It is
designed to overcome some of the limitations associated with omalizumab.
Clinical efficacy in treating patients with AD is expected due to the increased
affinity of QGE031 relative to omalizumab which allows for dosing of patients
with higher baseline IgE levels and suppression of free IgE to lower levels
than achievable with omalizumab.
This proof of concept study will assess the safety and efficacy of QGE031 in
patients with AD.

During the EC-assessment abroad it was requested to ajust the selction criteria
for the study in such a way that they would better reflect the approved
indication for cyclosporin, i.e. make them more stringent. Because in the mean
time in Austria 2 patiënts had been randomized to cyclosporin and 9 to either
QGE031 or placebo, and because amendment of the selction criteria would result
in a study population with 2 different grade of severity of the disease, it was
decided to ammend the randomization scheme in such a way that only 2 (instead
of 4) patients would be randomized to cyclosporin and 14 to QGE031 and 14 to
placebo (amendment 5). This means that no new cyclosporin-patients will be
enrolled.
In the Netherland no cyclosporin-patient will therefore be enrolled.
Cyclosporin will, however, remain in the protocol description in the ABR-form.

Primary: To demonstrate the efficacy of QGE031 relative to placebo at 12 weeks
in patients with
atopic dermatitis (AD) as assessed by Eczema Area and Severity Index (EASI).
Secondary: efficacy assessed by Investigator Global Assessment (IGA, 12 weeks),
EASI and IGA (6 weeks), safety, PK, PD, immunogenicity, specific IgE, IgE
autoantibodies and free IgE, Patient Reported Outcomes.

Multicenter randomized double-blind parallel-group placebo-controlled proof of
concept study.
Randomisation (7:7:1) to:
* 280 mg QGE031 s.c. every 2 weeks (double-blind).
* Placebo s.c. every 2 weeks (double-blind).
* 2.5 * 5.0 mg/kg oral cyclosporin daily (open-label). Cyclosporin-arm has been
closed in the mean time.
Continuation of current medication.
Screening period up to 4 weeks. Treatment period 12 weeks. Follow-up period 12
weeks.
Interim-analyses planned (see protocol paragraph 9.8, page 70).
Approx. 30 patients.

Treatment with QGE031, placebo or cyclosporin.

Risk: Adverse effects of study medication and prick test.
Burden: Study duration 24-28 weeks. 14 visits. Duration 1-4 h.
During 12 weeks every 2 weeks sc injection of study medication (2 injections of
1 ml each per occasion).
Physical examination 5 times.
Blood tests during every visit, 15-25 ml/occasion.
Pregnancy test (if relevant) 6 times.
Stool sample at screening.
ECG 4 times.
Photographs of affected skin 7 times.
Prick test 4 times.
Skin biopsy 2 times.
Questionnaires (2) 3 times.
Optional pharmacogenetic blood test (10 ml).