Therapeutic Use of Tadekinig Alfa in Adult-onset Still's Disease

Condition(s) targeted: Still's Disease, Adult-Onset

Intervention: Tadekinig alfa (recombinant human IL-18 binding protein) (Biological)

Phase: Phase 2

Status: Recruiting

Sponsored by: AB2 Bio Ltd.

Official(s) and/or principal investigator(s):
Eduardo Schiffrin, MD, Study Director, Affiliation: AB2 Bio Ltd.
Cem Gabay, Prof., Principal Investigator, Affiliation: Hospital University of Geneva

Overall contact:
Eduardo Schiffrin, MD, Phone: +41 21 693 82 83, Email: eduardo.schiffrin@ab2bio.com

The objective of this study is to assess safety, tolerability and early signs of efficacy of the investigational drug Tadekinig alfa in Adult-onset Still's disease, a rare polygenic auto-inflammatory disorder for which treatment remains empirical. This disease is characterized by a daily spiking fever, arthralgia / arthritis, and skin rashes with frequent components of sore throat, lymphadenopathies and neutrophilic leukocytosis. The etiology is unknown. In addition to the above-mentioned clinical features, the diagnosis includes some laboratory components that reflect the systemic inflammation: high erythro-sedimentation rate, C-reactive protein, high serum ferritin and high levels of interleukin 18 (IL-18). Tadekinig alfa is the drug name for recombinant human interleukin-18 binding protein (IL-18BP). This investigational drug was tested in healthy volunteers, psoriasis and rheumatoid arthritis patients in phase I studies. It demonstrated good safety and tolerability profile with only mild adverse events in the injection site. The hypothesis of this study considers high levels of IL-18 during active Adult-onset still's disease as the therapeutic target. Treatment with IL-18BP will permit to inhibit the pro-inflammatory cascade triggered by IL-18 and may help to manage the different components of the disease. This study is an open label, dose-finding study involving multiple centers in Europe. Three dose cohorts of 10 patients per cohort (80mg, 160mg, 320mg) will be treated during twelve weeks and followed-up for four more weeks.

Official title: Open-label, Multicenter, Dose-escalating Phase II Study to Investigate the Safety, Tolerability, and Early Signs of Efficacy of Subcutaneous Administrations of Tadekinig Alfa (IL-18BP) in Patients With Adult -Onset Still's Disease (AoSD) During 12 Weeks

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Safety (adverse events)

Secondary outcome: Efficacy 9 Efficacious dose at 3 weeks will be considered if normalisation of body temperature and decrease of C-reactive protein (CRP) by more or equal to 50 percent of baseline values are achieved.)

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients aged 18 years and older, diagnosed as AoSD based on the presence of the

Yamaguchi criteria with active disease, irrespective of the continuation of the permitted treatment mentioned below

- Patients with active disease will be considered if they exhibit at least two of the

Yamaguchi's major criteria (appendix 2 of the study protocol) at the screening visit plus at least either fever or elevation of markers of inflammation (CRP ≥ 10 mg/L and/or Erythrocyte Sedimentation Rate ESR ≥ 28 mm/h).

- Patients that have been exposed to non-steroidal anti-inflammatory drugs (NSAIDS),

prednisone (at least 5 mg/day) for ≥ 1 month) and/or synthetic disease modifying anti-rheumatic drugs (sDMARDs) such as methotrexate at a dose of at least 10mg/week) for ≥ 3 months without response to treatment or with incomplete response to treatment

- Women of childbearing potential with negative pregnancy test at screening, V3, V4, V5

and V6 and that agree to follow highly effective birth control recommendations during the study and until 1 month after the end of the treatment. Birth control methods that are considered as highly effective are either: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence. In each case of delayed menstrual period (over one month between menstruations, confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of child bearing potential with infrequent or irregular menstrual cycles. As regards the duration of contraception after the study, taking into account the median half-life of Tadekinig alfa of almost 40h, 5 half-lives represent duration of 200 hours. In order to be on the safe side, a post-study contraception duration of 4 weeks is recommended

- Patients can maintain treatment with stable doses of NSAIDs, prednisone (stable dose

of prednisone (of at least 5 mg/day), and sDMARDs during Tadekinig alfa treatment (methotrexate at a dose of at least 10mg/week). Specifically baseline levels of prednisone treatment can be maintained or tapered (due to patient improvement), any requirement for prednisone increase during treatment will be considered a treatment failure.

- Previous treatments with biologicals are allowed if the following wash-out periods

are respected: one week for anakinra, two weeks for etanercept, and 6 weeks for adalimumab, certolizumab, golimumab, tocilizumab, abatacept and 8 weeks for infliximab. Previous rituximab administration will require 6 months of washout and normal B-cell counts and previous treatment with canakinumab will require 6 months of washout. Exclusion Criteria:

- Patients with a first episode of AoSD with less than one month of therapy with

Prednisone or sDMARDs

- Patients with active or chronic infections (i. e. Tuberculosis (TB), HIV, HBV & HCV

(hepatitis B/C virus) )

- Patients suffering from inherited immunodeficiency diseases

- Patients with white blood cell counts below 2'500 cells/mm3

- Patients with Neutrophils below 1'000 cells/mm3

- Concomitantly treated with biologicals

- Women of childbearing potential who are unwilling to use adequate protection from

pregnancy

- Women of childbearing potential who are unwilling to use highly effective birth

control methods (see definition in Inclusion criteria above) up to 1 month after the end of her participation in the study.

- Inability to understand and unwilling to sign a written informed consent

- Active Macrophage Activating Syndrome (MAS)

- Any acute or chronic life-threatening disease (such as cancer, and irreversible organ

failures of heart, liver, lung and kidney (creatinine not higher than 1. 5 X upper limit of normal)

- Patients having received adalimumab, certolizumab, golimumab, tocilizumab and

abatacept within 6 weeks, infliximab within 8 weeks, canakinumab within 6 months, etanercept within 2 weeks, or anakinra 1 week prior to the start of Tadekinig alfa will not be enrolled into the study. Patients that have received rituximab within 6 months and/or have persistent low B-cell counts will not be eligible for enrolment.

- Subject who cannot be expected to comply with the study procedures

- Currently participating or having participated in another clinical trial during the

last 4 weeks prior to the beginning of this study.

- Patients with no social security coverage

- Patients with a history of severe hypersensitivity reactions

Eduardo Schiffrin, MD, Phone: +41 21 693 82 83, Email: eduardo.schiffrin@ab2bio.com

Hôpital Pellegrin, Bordeaux 33076, France; Not yet recruiting
Thierry SCHAEVERBEKE, Prof. Dr.
Thierry SCHAEVERBEKE, Prof. Dr., Principal Investigator

CHRU de Lille - Hôpital Claude Huriez, Lille 59037, France; Not yet recruiting
Eric HACHULLA, Prof. Dr.
Eric HACHULLA, Prof. Dr., Principal Investigator

Hôpital de la Croix Rousse, Lyon 69317, France; Not yet recruiting
Pascal SEVE, Prof. Dr.
Pascal SEVE, Prof. Dr., Principal Investigator

CHRU de Montpellier, Montpellier 34090, France; Not yet recruiting
Jacques MOREL, Prof. Dr.
Jacques MOREL, Prof. Dr., Principal Investigator

CHU de Nantes - Hôtel Dieu, Nantes 44093, France; Not yet recruiting
Mohamed HAMIDOU
Mohamed HAMIDOU, Prof. Dr., Principal Investigator

CHU Paris-GH La Pitié Salpêtrière-Charles Foix - Hôpital Pitié-Salpêtrière, Paris 75651, France; Not yet recruiting
FAUTREL Bruno, Pr. Dr.
Bruno Fautrel, Prof. Dr., Principal Investigator

Innere Medizin II - Rheumatologie Schlosspark-Klinik, Berlin 14059, Germany; Not yet recruiting
Rieke Alten, Dr.

Medizinische Klinik - Rheumatologie und Klinische, Berlin, Germany; Recruiting
Eugen FEIST, Pr. Dr.
Eugen FEIST, Pr. Dr., Principal Investigator

Universitätsklinikum Erlangen, Erlangen 91054, Germany; Recruiting
Juergen RECH, Dr. med.
Juergen RECH, Dr. med., Principal Investigator

Asklepios Klinik Altona, Hamburg 22763, Germany; Recruiting
Ina KÖTTER, Prof. Dr.
Ina KÖTTER, Prof. Dr., Principal Investigator

St. Elisabeth Gruppe GmbH Katholische Kliniken Rhein-Ruhr Rheumazentrum Ruhrgebiet, Herne 44649, Germany; Recruiting
Jürgen Braun, Prof. Dr.

Universitätsklinikum Jena Klinik für Innere Medizin III Rheumatologie/Osteologie, Jena 07747, Germany; Not yet recruiting
Thomas Neumann, MD

Klinik Kirchheim, Kirchheim Unter Teck 73230, Germany; Recruiting
Bernhard HELLMICH, Pr. Dr.
Bernhard HELLMICH, Pr. Dr., Principal Investigator

Universitätsklinikum Schleswig-Holstein - Campus Lübeck, Lübeck 23538, Germany; Not yet recruiting
Peter LAMPRECHT, Pr. Dr. med.
Peter LAMPRECHT, Pr. Dr. med., Principal Investigator

UNIVERSITÄTSMEDIZIN der Johannes-Gutenberg-Universität Mainz I. Medizinische Klinik und Poliklinik Rheumatologie, Mainz 55131, Germany; Not yet recruiting
Schwarting, Prof. Dr.

LMU München, München 80336, Germany; Not yet recruiting
Hendrik Schulze-Koops, Prof. Dr.
Hendrik Schulze-Koops, Prof. Dr., Principal Investigator

Hôpitaux Universitaires de Genève - HUG, Genève, Switzerland; Active, not recruiting

CHUV hospital, Lausanne, Switzerland; Recruiting
Eduardo Schiffrin, MD
Lalla Myriam Lamrani-Mercier
François Spertini, MD, Principal Investigator

Immunologie-Zentrum de Zürich, Zürich, Switzerland; Active, not recruiting

Related publications:

Bagnari V, Colina M, Ciancio G, Govoni M, Trotta F. Adult-onset Still's disease. Rheumatol Int. 2010 May;30(7):855-62. doi: 10.1007/s00296-009-1291-y. Epub 2009 Dec 18. Review.

Bywaters EG. Still's disease in the adult. Ann Rheum Dis. 1971 Mar;30(2):121-33.

Efthimiou P, Kontzias A, Ward CM, Ogden NS. Adult-onset Still's disease: can recent advances in our understanding of its pathogenesis lead to targeted therapy? Nat Clin Pract Rheumatol. 2007 Jun;3(6):328-35. Review.

Fautrel B. Adult-onset Still disease. Best Pract Res Clin Rheumatol. 2008 Oct;22(5):773-92. doi: 10.1016/j.berh.2008.08.006. Review.

Kawashima M, Yamamura M, Taniai M, Yamauchi H, Tanimoto T, Kurimoto M, Miyawaki S, Amano T, Takeuchi T, Makino H. Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease. Arthritis Rheum. 2001 Mar;44(3):550-60.

Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, Kashiwazaki S, Tanimoto K, Matsumoto Y, Ota T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992 Mar;19(3):424-30.

Starting date: February 2015
Last updated: July 6, 2015