Background Dekavil is an “armed antibody”, composed of the human F8 antibody (specific to the EDA domain of fibronectin) fused to the human immunoregulatory cytokine interleukin-10 (IL10). This approach allows the selective delivery and accumulation of the cytokine to sites of inflammation[1,2]. Unlike traditional medicines that suppress the immune system, DEKAVIL selectively modulates anti-inflammatory effects at sites of disease. A potent inhibition of arthritis progression, using DEKAVIL in combination with MTX, has previously been reported in a model of collagen induced arthritis. A Phase Ib clinical trial is now on-going, which features the subcutaneous administration of weekly doses of DEKAVIL, in combination with MTX, to patients with RA who have previously failed at least one line of anti-TNF therapy. We now report the results obtained within the first three dose levels.
Objectives To establish the maximum tolerated dose of the combined treatment, to study safety and tolerability, and to obtain preliminary information on efficacy.
Methods Cohorts of 3-6 patients with active RA were scheduled to receive escalating doses of DEKAVIL (6, 15, 30, 60 µg/kg respectively) in combination with 15mg of MTX. The treatment was given as once weekly sc injection for up to 8 weeks. Safety evaluations based on RCTC were performed on days 1 through 28, including AEs, SAEs and were used to determine the recommended dose and dose-limiting toxicity, if any. Response was assessed after 4 and 8 weeks of treatment, according to ACR and DAS28 criteria. The pharmacokinetic profile and formation of human anti-fusion protein antibodies were measured using standard methods.
Results All three patients enrolled in the first cohort (6 µg/kg weekly of F8-IL10) achieved ACR 50 responses at more than one evaluation time point. In cohort 2 (15 µg/kg weekly of F8-IL10), patient 5 enjoyed an ACR 70 response, whereas patient 4 did not reach ACR20 despite achieving a moderate EULAR response. In cohort 3 (30 µg/kg weekly of F8-IL10) patients 8 and 9 achieved an ACR50 and ACR20 at late evaluation time point. Patient 7 did not achieve any ACR response. Trends of CRP and ESR values have also been plotted. An excellent tolerability of F8-IL10, was observed in all treated patients, since no grade ≥2 adverse drug reactions have been reported. A low-titer transient formation of human anti-fusion protein antibodies has been detected only for one of the patients treated so far, using a BIAcore methodology and DEKAVIL immobilized on a microsensor chip. Two additional patients are being treated in cohort 4 (60 µg/kg weekly) at the time of writing.
Conclusions The promising safety data regarding the clinical use of F8-IL10, together with preliminary positive signs of activity, suggest that the targeted delivery of IL10 to the site of inflammation may be beneficial to patients with RA. These results also warrant future developments of the product in randomized clinical trials. An update of clinical data will be presented.
K. Schwager et al. (2009) Arthritis Res. Ther., 11, R142
N. Pasche & D. Neri (2012) Drug Discov. Today, 17, 583-90.
T. Woodworth et al. (2007) J. Rheumatol., 34: 1401-14.
Disclosure of Interest M. Galeazzi: None Declared, L. Bazzichi: None Declared, E. Prisco: None Declared, G. D. Sebastiani: None Declared, D. Neri Shareholder of: Philogen S.p.A., L. Giovannoni Employee of: Philogen S.p.A., M. Bardelli: None Declared, C. Baldi: None Declared, E. Selvi: None Declared, G. Minisola: None Declared, R. Caporali: None Declared, S. Bombardieri: None Declared