Background

Pyogenic sterile Arthritis Pyoderma gangrenosum and Acne (PAPA) syndrome is a rare autosomal dominant inherited autoinflammatory disease due to mutations of proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene. The manifestations of this disorder are pyoderma gangrenosum, cystic acne and pyogenic sterile arthritis, which is the most common symptom of the disease. The disease has a great impact on the quality of life. No specific treatments are available so far. Anecdotal reports suggest the efficacy of IL-1 blockade, especially with the IL-1beta monoclonal antibody (canakinumab).

Objectives

Primary objective: To determine whether canakinumab administered every 4 weeks is able to maintain disease remission compared to placebo in canakinumab-responder patients.

Secondary objectives



1) To determine the efficacy of canakinumab to achieve a complete or almost complete response after 24 weeks .

2) To evaluate optimal dose of canakinumab to induce disease remission.

3) To assess the profile over time in each of the 4 key PAPA signs and symptoms (arthritis, furunculosis, pyoderma gangrenosum, hidradenitis suppurativa) from baseline to end of study.

4) To assess the profile over time in physician’s and patients’ global assessment score from baseline to end of study.

5) To assess the profile over time in acute phase reactants (ESR, CRP, SAA) from baseline to end of study.



Methods

Twenty-four PAPA patients will be enrolled in a withdrawn study at the moment of disease flare. All patients will receive 150 mg s.c. (or 2 mg/kg) every 4 weeks for 6 months. Patients with a partial response could receive an up-titration to 300 mg (or 4 mg/kg) or 450 mg (or 6 mg/kg) every four weeks after 1 or 3 months, respectively.

After 6 months (Part 1), all responder patients will be randomized to receive canakinumab at the last effective dose or placebo (Part 2). The time to disease flare will be registered after randomization in both groups.

A 6 months open label phase (Part 3) will follow the efficacy and safety of the drug at the most effective dose.



Expected results

1. To provide the first evidence of the actual efficacy of IL-1 blockade in a potentially devastating inflammatory condition, using canakinumab

2. To identify the best dosage able to achieve remission in the absence of severe adverse events

3. To evaluate the long-term efficacy and safety of canakinumab in PAPA syndrome