The Rebif new formulation story: it's not trials and error

Abstract

The rapid evolution of the biopharmaceutical industry and the development of innovative technologies have provided an opportunity to improve recombinant interferon (IFN)-beta formulations. A number of strategies have been developed to improve the stability, tolerability and immunogenicity of IFNbeta formulations that are used in the long-term treatment of patients with multiple sclerosis (MS). This review focuses on the production of recombinant IFNs and discusses the development of one such biopharmaceutical, Rebif New Formulation (RNF).RNF was developed with the aim of further improving the tolerability and immunogenicity of Rebif, an approved IFNbeta-1a formulation administered subcutaneously three times per week (sc tiw). To this end, numerous candidate drug vehicles and formulations were developed. However, unlike other formulations of IFNbeta, the new candidate formulations in this case were free from all serum-derived components. Specifically, each RNF candidate was free from human serum albumin and produced without fetal bovine serum. The physicochemical stability, injection-site tolerability, pharmacokinetic profile and immunogenic potential of each candidate formulation were systematically tested. This involved initial screening of a large pool of formulations for promising candidates. Two candidate formulations were selected and subjected to further, extensive evaluation.Ex vivo T-cell assays were used to compare the immunogenicity of RNF candidates with that of the current (at the time of writing) approved formulation and an IFNbeta standard. A single RNF candidate induced less T-cell activation, in terms of proliferation and proinflammatory cytokine secretion, than the other two formulations. The results provided ex vivo evidence of the improved immunogenic potential of RNF. A murine model was used to compare the relative immunogenicity of RNF in vivo with two approved formulations of IFNbeta-1a. Mice treated with RNF developed neutralising antibodies more slowly and produced lower titres than mice treated with equivalent doses of the current IFNbeta-1a sc tiw formulation or another approved IFNbeta-1a formulation administered intramuscularly once per week (Avonex). RNF also demonstrated better local tolerability than the current IFNbeta-1a sc tiw formulation after single subcutaneous doses in healthy volunteers. One RNF candidate was superior to the others in all preclinical and phase I studies, and was chosen as the final RNF. This formulation is currently undergoing assessment in a 96-week, phase IIIb clinical trial in patients with MS. This single-arm, open-label, multicentre study will compare the immunogenicity and tolerability of RNF with historical data on the current formulation; results of a 48-week, interim analysis indicate that RNF has improved local tolerability and immunogenicity compared with the current formulation. It is anticipated that the benefits of RNF will translate into an improved long-term benefit-to-risk profile. Further assessment of RNF and other MS drugs is ongoing with the aim of enhancing the therapeutic options available for patients with MS.