Background DEKAVIL (F8-IL10) is a fully human anti-inflammatory immunocytokine, which has shown considerable activity in mouse models of rheumatoid arthritis and which is now being investigated in a Phase Ib clinical trial in combination with methotrexate (MTX). In a collagen-induced model of arthritis (CIA), DEKAVIL selectively accumulated at the site of disease and potently inhibited disease progression [1,2]. The immunocytokine consists of the F8 antibody (specific to the alternatively-spliced EDA domain of fibronectin, a marker of tissue remodeling) fused to human anti-inflammatory cytokine interleukin-10 (IL10) which has exhibited a potential for the therapy of patients with rheumatoid arthritis [3]. In randomized clinical trials,the administration of IL10 at doses of 8 and 20 μg/kg resulted in ACR20 responses in over 60% of the treated patients, but ACR50 responses were suboptimal [3]. In the mouse CIA model, DEKAVIL displayed a therapeutic activity which was dramatically superior compared to free IL10. Moreover, the F8 antibody mediated a selective and long-lasting accumulation in arthritic joints [1]. We report the promising results of the on-going Phase Ib clinical trial, involving the administration of DEKAVIL in combination with MTX to patients with rheumatoid arthritis who have previously failed at least one line of TNF blockers.

Objectives To establish the maximum tolerated dose (MTD) and the recommended dose (RD) of DEKAVIL when combined with MTX,to study the pharmacokinetic of the drug and to assess early signs of activity in patients.

Methods Cohorts of 3-6 patients with active RA are assigned to receive escalating doses of F8IL10 (6,15,30,60μg/kg) in combination with 15mg of MTX. The treatment is given as repeated once weekly subcutaneous injections for up 8 weeks. Safety evaluations performed on days 1 through 28 are used for determination of the dose limiting toxicity. Adverse events assessment is based on R-CTC. Response is assessed after 4 and 8 weeks of treatment according to ACR and DAS28 criteria.

Results The clinical trial is still on-going and has so far confirmed the excellent tolerability of DEKAVIL at the doses used. These safety data are in line with the ones which had previously been established for IL10 in patients with rheumatoid arthritis [3]. Surprisingly,already in the first cohort of patients treated with DEKAVIL at a dose of 6 μg/kg,ACR50 responses were observed already after 8 weeks of therapy,indicating a potential activity of the product at very low doses,in patients which did not respond anymore to MTX and failed at least 1 anti-TNF line of therapy. These promising therapeutic results may be the consequence of the targeted delivery of IL10 to the site of disease,mediated by the F8 antibody.

Conclusions The promising safety data about the clinical use of DEKAVIL, together with emerging signs of potent activity in heavily pre-treated patients, warrants future developments of the product in randomized clinical trials,which are currently in planning. An update of clinical data will be presented at the EULAR meeting.

1. Schwager (2009) Arthritis Res. Ther.,11,R142

2. Pasche & D. Neri (2012) Drug Discov. Today,in press

3. Asadullah (2003) Pharmacol.Rev.,55,241

Disclosure of Interest M. Galeazzi: None Declared, C. Baldi: None Declared, K. Schwager: None Declared, D. Neri: None Declared, L. Giovannoni Employee of: Philogen spa, E. Selvi: None Declared