EMA draft guidance points out challenges to biosimilar interferon beta developers
This article was originally published in SRA
The European Medicines Agency has issued a draft guideline for companies wanting to develop biosimilar versions of interferon beta for the treatment of multiple sclerosis1,2. As with all biosimilars, there will be a number of challenges for developers of interferon beta, not least the complexity of the disease and the substance, safety issues, and differences among the available reference products.
The draft guidance, which is out for consultation until 31 May, suggests the best way to go about developing interferon beta. It will clearly be important to choose the correct reference product and to conduct appropriate clinical trials.
The guideline says that non-clinical studies should be comparative in nature and designed to detect differences in the pharmaco-toxicological response between the biosimilar and the reference drug.
The clinical development programme should begin with pharmacokinetic and pharmacodynamic studies in healthy volunteers and continue with efficacy and safety trials. Comparative efficacy should be shown in an "adequately powered, randomised, parallel group equivalence clinical trial, preferably double-blind". Importantly, the route of administration must be that recommended for the reference product. Whatever the design of the trial, its duration should be sufficient to show comparable efficacy on magnetic resonance imaging endpoints and provide relevant information on clinical endpoints – ie not less than 12 months.
Comparative safety data from the efficacy trial should be enough to provide an adequate pre-market safety database, the guideline says, although given the immunogenic nature of interferon beta, a minimum of 12 months' comparative immunogenicity data should be submitted. Any impact of neutralising antibodies will need to be evaluated after approval as part of the risk management plan.
Recombinant interferon beta and MS
Recombinant interferon beta is currently the mainstay of disease-modifying therapies in MS, which is one of the most common causes of neurological disability in young and middle-aged adults, the EMA notes. The pathogenesis of the disease is still unclear, but it is believed to be predominantly an organ- or antigenic-specific autoimmune disease mediated by activated T-lymphocytes, which cross the blood brain barrier and initiate a series of inflammatory events that result in demyelination and irreversible axonal loss.
Similarly, the mechanism of action of interferon in MS is not well established, although it has been suggested that it acts as an immunomodulator by interfering with T-cell activation in a number of ways and by inhibiting permeability changes in the blood brain barrier and the infiltration of T-cells into the central nervous system.
The clinical effects of recombinant beta interferon are modest in relapsing MS, showing a 30% decrease in exacerbations compared with placebo, and inconsistent results on the progression of disability.
Moreover, all interferon beta products induce the development of antibodies, particularly neutralising antibodies (NAbs). In clinical trials, the incidence of NAbs has been shown to vary widely, and they have the potential to affect clinical outcomes after 18-24 months of treatment.
As if that were not enough to deter potential biosimilar developers, the products currently on the market that would act as reference products are themselves heterogeneous. There are two forms of the substance that differ from each other in a number of ways.
Interferon beta-1a is produced in Chinese hamster ovary cells as a single glycosylated polypeptide chain with 166 amino acids. Interferon beta-1b, by contrast, is produced in E coli as a non-glycosylated chain of 165 amino acids, and has about 10% of the specific activity of the CHO-derived substance.
There are differences between the branded drugs too: interferon beta-1a, marketed by Biogen Idec as Avonex, has a once-weekly intramuscular injection regimen, while Merck Serono's Rebif is given three times weekly subcutaneously. The beta interferon-1b product, Bayer Schering's Betaseron/Betaferon, is given subcutaneously every other day. A fourth product, Novartis' Extavia, is the same as Betaseron and came to Novartis via its acquisition of Chiron.
Comparability exercise
Despite the heterogeneity of these products, the EMA is stressing the need for a strictly conducted comparability exercise against the selected reference drug. An earlier attempt to secure EU approval without doing so met with failure in February 2009 when the agency's scientific committee, the CHMP, rejected Biferonex, a biosimilar interferon beta-1a product from BioPartners.
The company had compared its product with placebo, and had also used information relating to Avonex and data from the published literature on drugs containing interferon beta. But the CHMP said that there were differences between the active substance in Biferonex and other interferon beta-containing medicines on the market, that the use of these published studies was not justified, and that studies on Biferonex itself were required. It also said that the clinical study provided did not demonstrate sufficient effectiveness of the product.
It is not clear at this stage how many companies will be interested in biosimilar beta interferon. The EMA said that there seemed to be "some interest" in developing the product, and that it had received a "small number of requests for scientific advice"3.
Biosimilar MAbs
In the meantime, another EMA guideline on biosimilars is expected to be published soon: the development of biosimilar monoclonal antibodies. Interest in this document is likely to be high, given the number of originator MAbs on the market or in development. A draft of the guideline was released for consultation at the end of 2010, with a deadline for comments of 31 May4.
References
1. EMA press release, 20 January 2012, http://bit.ly/yONIwW
2. EMA, Guideline on similar biological medicinal products containing interferon beta (EMA/CHMP/BMWP/652000/2010), posted online 19 January 2012, www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/01/WC500120652.pdf
3. Personal communication, EMA, 20 January 2012
4. Biosimilar MAbs in EU will need extensive clinical trials and post-approval monitoring, Scrip Regulatory Affairs, 26 November 2010