Background Expanded adipose-derived stem cells (eASCs) are shown to have immune-modulatory effects in vitro and in animal models of arthritis. eASCs are currently under investigation as potential treatments targeting auto-immune and inflammatory diseases.
Objectives Determine the tolerance, safety and feasibility of intravenous (IV) administration of allogeneic eASCs in Rheumatoid Arthritis (RA) patients.
Methods A 24-week, single blind dose-escalating study in refractory RA patients, defined as patients treated with at least one non-biological DMARD and who previously failed to treatment with at least two biologicals, was conducted in 23 centers in Spain. Fifty-three patients with moderate to high disease activity (DAS28>3.2) were assigned to 1x106 eASCs/kg (cohort A: 20 patients), 2x106 eASCs/kg (cohort B: 20 patients), 4x106 eASCs/kg (cohort C: 6 patients) or placebo (Ringer's lactate solution: 7 patients).
All patients received 3 IV eASC or placebo infusions at day 1, 8 and 15. Tolerability and treatment emergent adverse events such as Dose Limiting Toxicities (DLTs), serious adverse events (SAEs) and non-serious adverse events (AEs) were primary endpoints. Efficacy measures such as ACR20/50/70, DAS 28, and SF-36 were secondary endpoints.
Results Patient and disease characteristics were comparable for all three dose groups. 85.7% were females, the age ranged between 33 years and 78 years (median 56 years, mean 55 years). Time since onset of the disease was between 3.3 and 69.9 years (mean 15.6 years, median 13 years). DAS28 (PCR) disease activity scores at baseline ranged between 3.2 and 7.9. Repeated IV infusion of eASCs did not show any major safety signals and no dose-limiting safety signal was identified. One possibly related SAE, a lacunar infarction in cohort A, lead to discontinuation but the patient recovered. Non-serious related AEs (threshold: >4%) occurring in patients treated with eASCs and more frequently than with placebo, included pyrexia (15%), headache (9%) and malaise, influenza-like illness, pruritus, rash, and respiratory tract infection (4% each).
In secondary endpoints, no clinically relevant differences were observed among the three dose regimens. Overall ACR20/50/70 responses were observed in 45/20/5% of patients receiving 1x106 eASCs/kg versus 25/10/0% of patients on placebo at month 1. The DAS 28 remission (<2.6) for the eASC treated group and placebo was 7% versus 0% at month 1 and 11% versus 0% at month 2 respectively.
Conclusions These early clinical results are the first evidence suggesting that IV infusion of eASCs may be well tolerated for the treatment of refractory RA. Encouraging results include the absence of major safety signals within 24 weeks and the larger improvement in secondary endpoints in the eASC arms versus placebo.
Acknowledgements The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under the grant agreement no. 279174.
Disclosure of Interest J.M. Alvaro-Gracia: None declared, J.Ά. Jover Grant/research support: Pfizer Inc, R. García-Vicuña: None declared, L. Carreño: None declared, A. Alonso: None declared, S. Marsal: None declared, F. J. Blanco: None declared, V. M. Martinez-Taboada: None declared, P. Taylor: None declared, F. Díaz-Gonzalez: None declared, L. Dorrego Employee of: TiGenix SAU