A Pilot, Open-Label, Phase 2, Single-Center, Repeat Dose, Proof-of-Concept Safety, Pharmacodynamics and Efficacy Study of Orally Administered Dapansutrile Capsules in Subjects with Schnitzler*s Syndrome

Schnitzler*s syndrome is a rare autoinflammatory disorder characterized by
chronic urticaria, bone pain, monoclonal immunoglobulin M gammopathy and
intermittent fever. Treatment of Schnitzler*s syndrome remains a challenge
although many therapeutic approaches, including corticosteroids, NSAIDs,
colchicine, dapsone, thalidomide, interferon-α, rituximab, immunoglobulins and
methotrexate, have all been described in the literature. Dependency on high
doses of corticosteroids is common, entailing steroid toxicity.
Immunosuppressive drugs are generally ineffective or fail to provide long-term
remission despite short-term improvement.

Although the etiology of Schnitzler*s syndrome is unknown and the
pathophysiology has yet to be fully elucidated, a case report by Pizzirani et
al (2009) suggested that dysfunction of the inflammasome and IL-1β processing
contributes to the underlying pathogenesis. In fact, peripheral blood
mononuclear cells (PBMCs) or monocytes from patients with symptomatic
Schnitzler*s syndrome produced more IL-1β and IL-6 upon stimulation with LPS
relative to control PBMCs (Ryan 2008, Pizzirani 2009, de Koning 2015). Since
IL-1β activity is modulated by the IL-1 receptor antagonist (IL-1Ra), which
blocks binding of IL-1α and IL-1β to IL-1R1, the recombinant IL-1Ra anakinra
was evaluated as a potential treatment and found to rapidly control all the
symptoms of this syndrome. Clinical benefit of anakinra treatment is observed
often within a few hours on urticaria and within a few days on C-reactive
protein levels and leukocytosis. As there are no approved treatments for
Schnitzler*s syndrome, anakinra has been used off-label.

The results of this proof-of-concept study will provide evidence on the
potential utility of dapansutrile capsules in the treatment of Schnitzler's
syndrome. Results from the study will guide the design for future clinical
studies.

The objectives of this clinical trial are as follows:
1. To assess the safety, tolerability, and pharmacokinetics of dapansutrile
capsules after oral administration in subjects with chronic, well-controlled
Schnitzler*s syndrome
2. To assess the clinical activity of dapansutrile capsules, including the
change in symptoms of Schnitzler*s syndrome, upon withdrawal of anakinra therapy
3. To assess the pharmacodynamics and changes in inflammatory biomarkers after
oral administration of dapansutrile capsules, upon withdrawal of anakinra
therapy, and after all therapy has ende

This is a pilot, open-label Phase 2, single-center, repeat dose, single cohort,
proof-of-concept, safety, pharmacodynamics and efficacy study of dapansutrile
capsules to be conducted in subjects with Schnitzler*s syndrome (SchS)
currently well controlled by anakinra therapy. At least 5 but no more than 10
subjects will be enrolled.

Subjects who are responsive to anakinra (Kineret®) for at least 6 weeks will be
screened for eligibility at the Screening / Baseline (Day 1) visit. Following
confirmation of eligibility, subjects will be enrolled, the first dose of
dapansutrile will be administered at the clinical site and safety and efficacy
assessments will be completed. Subjects will self-administer dapansutrile
twice a day by mouth for 14 consecutive days. Subjects will continue their
standard dose of anakinra for Days 1, 2 and 3 of the 14-day Treatment Period
and will then cease taking anakinra. At the end of the 14-day Treatment Period
subjects will remain off all medication for Schnitzler*s syndrome. Subjects
will return to the study clinic on Days 5, 9, 14, 15, 16, 18, 21 for follow-up
visits and will be contacted by telephone on Day 42 (± 3 days) for additional
follow-up. Additionally, at the first signs of a relapse or worsening of SchS
symptoms, subjects will visit the study clinic for assessments (the *Symptom
Onset* visit or SOV) and to discuss with the Investigator when injections of
anakinra should be resumed. The Day 15, 16 and 18 visits will only occur in
the event that anakinra therapy has not been resumed.

Subjects will be given the option to remain in the Nijmegen area after the Day
14 visit and return to the study clinic for the Day 15, 16 and 18 visits.
Alternatively, subjects will be given the option to have these visits conducted
at their home by a trained study nurse.

Safety assessments will be conducted at each visit and subjects will capture
the frequency and intensity of symptoms, including body temperature, using a
paper diary. Safety and tolerability will be evaluated by monitoring the
occurrence of AEs and changes in abbreviated physical examination findings,
vital signs and clinical safety laboratory test results (chemistry, hematology
and urinalysis) and inflammatory biomarkers. Clinical activity will be
evaluated by: Subject Diary (completed daily), Subject Global Evaluation of
Disease Activity, Investigator Global Assessment of Disease Activity, and
analysis of biomarkers of inflammation, including changes in C-reactive protein
(CRP). Daily diary assessments will be captured starting at the Screening /
Baseline (Day 1) visit and will continue until Symptom Onset visit or Day 21
visit (whichever occurs latest).

Dapansutrile capsules (100 mg each) will be self-administered for the duration
of the Treatment Period beginning at the Baseline visit on Day 1 and will
continue for 14 days. The dose will consist of five 100 mg dapansutrile
capsules taken by mouth twice each day (BID) approximately 12 hours apart for a
total of 1 g of dapansutrile per day. If prior to the Day 14 visit, a subject
experiences a worsening of symptoms, an increase in the dose or dose frequency
of investigational drug up to a maximum of 2 g per day may be implemented at
the discretion of the Investigator.

During the study blood draws will be performed for determination of
pharmacokinetics, clinical chemistry and hematology and blood will be drawn and
urine collected for PD biomarker analysis. Patients will need to keep a diary
starting on the day of the Screening / Baseline (Day 1) visit until Symptom
Onset visit or Day 21 visit (whichever occurs latest)

As there are no approved treatments for Schnitzler*s syndrome, anakinra has
been used off-label and the clinical benefit of anakinra treatment is observed
often within a few hours on urticaria and within a few days on C-reactive
protein levels and leukocytosis. The short half-life of anakinra (4 to 6 hours)
requires daily subcutaneous injections, which can be painful and occasionally
lead to strong local injection site reactions. The study medication,
dapansutrile capsules, is in clinical development for the treatment of
Schnitzler*s syndrome and may reduce the inflammation caused by Schnitzler's
syndrome.

The burden and risks associated with participation in this study are summarized
as follows:
- the time it will take to attend study visits and fill out the study diary
- withdrawal or postponement of standard care
- intake of 10 capsules per day (up to 20 if the dose is increased)
- undergoing study-related tests such as blood draws, physical examinations,
and measurement of vital signs
- possible side effects of the study drug (diarrhea, back pain, migraine,
contact dermatitis, eczema, headache or allergic reaction)
- possible adverse effects/discomforts caused by the evaluations in the study
(blood draws)
- possible aggravation of your symptoms.