Interferon Beta: From Molecular Level to Therapeutic Effects.

Interferon beta (IFNß) is a cytokine that is naturally produced by the immune system in response to biological and chemical stimuli. It signals by binding to the heterodimeric type I IFN receptor composed of the IFNAR1 and IFNAR2 chains, and regulates the expression of a plethora of genes by means of the classical JAK/STAT and other pathways. IFNß is pleiotropic in that it elicits antiviral, antiproliferative, and immunomodulatory activities on numerous cell types. The biological activities underpin the mechanisms by which the protein is used to treat various diseases such as hepatitis C infection and multiple sclerosis. Despite the success of IFNß therapy, the drug may evoke the production of antidrug antibodies that may reduce treatment efficiency. Immunogenicity is related to many factors: among them, structural properties, particularly aggregation, and T-cell and B-cell epitopes in the structure of IFNß, appear to be important. Knowledge of the structural properties of IFNß and its relation to immunogenicity may help scientists to develop safer and more effective forms. Several methods have been used to predict and reduce the immunogenicity of certain IFNß drug products. In this chapter, we review the current knowledge on IFNß from its structure, dynamic conformation, signaling pathway, and mechanism of action to its therapeutic effects. Immunogenicity and its relation to structural properties of IFNß are also discussed.

The risk-based approach to ATMP development - generally accepted by regulators but infrequently used by companies.

Advanced therapy medicinal products (ATMPs) are the cutting edge of drug innovation. ATMPs have different challenges than other drug classes. To accommodate these challenges and facilitate science-driven development, flexibility in the requirements to demonstrate the safety and efficacy of this rapidly evolving drug class is necessary. To create flexibility, the European Union introduced the risk-based approach. This approach provides the possibility of omitting guideline-based studies based on risk analyses. To gain insight into the effect of the risk-based approach on the non-clinical development of ATMPs, two questions are addressed in this paper. Firstly, "Do companies use a risk-based approach for the non-clinical development of ATMPs?" and, secondly, "Does the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) accept non-clinical development programs based on the risk-based approach?" Scientific advice letters formulated by the CHMP were analyzed. The risk-based approach was used to justify deviations from the guidelines in the majority (75%) of the cases. The CHMP accepted 40% of the proposals to omit studies and stated that additional data was necessary to make an informed decision for 35% of the proposals. This indicates that the risk-based approach facilitates the science-driven development of ATMPs.

The cost-effectiveness of periodic safety update reports for biologicals in Europe.

We analyzed the cost-effectiveness of all Periodic Safety Update Reports (PSURs) submitted for biologicals in Europe from 1995 to 2009 by comparing two regulatory scenarios: full regulation (PSUR reporting) and limited regulation (no PSUR reporting, but all other parts of the pharmacovigilance framework remain in place). During this period, PSUR reporting resulted in the detection of 2 out of a total of 24 urgent safety issues for biologicals: (i) distant spread of botulinum toxin and (ii) edema/fluid collection associated with off-label use of dibotermin-alfa. We used Markov-chain life tables to calculate costs and health effects of PSURs. The incremental cost-effectiveness ratio (ICER) of full regulation (PSUR reporting) vs. limited regulation (no PSUR reporting) for the base-case scenario was \[euro]342,110 per quality-adjusted life year (QALY) gained. It is possible to assess the cost-effectiveness of regulatory requirements using the same methods as those used in assessing the cost-effectiveness of medical interventions.

The cost-effectiveness of drug regulation: the example of thorough QT/QTc studies.

We analyzed the cost-effectiveness of the International Conference on Harmonisation (ICH) E14 guideline that requires a thorough QT/QTc (TQT) study for all drugs under development. We compared two pharmacoeconomic scenarios: the health effects and costs resulting from implementing ICH E14 ("regulation" scenario) vs. not implementing ICH E14 ("no regulation" scenario). We used a dynamic population model to calculate the cost-effectiveness of ICH E14 for a prototype QT-prolonging antipsychotic drug entering the US and European markets. The incremental cost-effectiveness ratios of regulation vs. no regulation were ~€2.4 million per sudden cardiac death prevented and ~€187,000 per quality-adjusted life year (QALY) gained in users of antipsychotic drugs. The main driver of cost was the requirement for electrocardiogram (ECG) monitoring of users of QTc-prolonging drugs. Even when several of the assumptions in the model were varied, there were no results in favor of regulation. Our study shows that cost-effectiveness analysis of drug regulatory measures is feasible and should be considered before developing such measures.

The sponsored pandemic of the Mexican flu?

The first reports of the New Influenza A (H1N1) spoke of a markedly increased morbidity and mortality. Later it turned out that this flu was a very mild flu. Gradually the role of the WHO was questioned. The definition of a pandemic flu had been changed and there rose doubts about the independency of the experts advising the WHO. It showed that some of these experts had a conflict of interest with the pharmaceutical industry, especially with those producing vaccines and neuraminidase inhibitors. As of june 2010 the WHO declared the outbreak to be a pandemic. This provided the momentum to produce vaccines. At the outbreak of the pandemic in the northern hemisphere, there was sufficient evidence that the pandemic would not be so serious, that a single vaccination was sufficient, that there were strong doubts about the efficacy of oseltamivir and that the drug, although rarely, could have serious side effects. With the stockpiling of neuraminidase inhibitors and with the recommendation of the vaccination political decisions were involved. These decisions should be driven and supported by independent scientific advisory bodies with no room for even the semblance of conflicts of interest. Stronger measures to limit the impact of experts with conflicts of interest on the development of, among others, guidelines are necessary.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.

Conditional approval and approval under exceptional circumstances as regulatory instruments for stimulating responsible drug innovation in Europe.

The need for fast drug innovation and the public demand for risk-free drugs creates a dilemma for regulatory authorities: less restrictive procedures involve uncertainties about benefit/risk profiles of new drugs. The European Union has introduced two instruments that regulate early market access: conditional approvals (CAs) and approvals under exceptional circumstances (ECs). We have studied whether these instruments compromise the safety of new drugs and whether they lead to earlier access to innovative drugs. Our study shows that neither of these regulatory pathways accelerates the approval process for innovative drugs. However, the CA pathway shortens the clinical development period. Approvals under ECs are associated with longer clinical development periods, but this regulatory pathway may open up opportunities for specific drugs to be admitted into the market because less comprehensive data are required. Despite the fact that these advanced approvals are based on limited safety databases, there are no special safety issues associated with using these pathways.

Assessing the bioequivalence of biosimilars The Retacrit case.

This first phase of the first generation of modern biotechnology-derived protein drugs is now coming to an end with the expiration of their patents and consequently the possibility of the marketing of copies. The generic paradigm used for classical drugs cannot, however, be applied to therapeutic proteins because of their complexity. The European regulatory system issued its first comprehensive guidelines for the development of the so-called biosimilars. A number of these products have now been introduced to the European market. The case of Retacrit, one of the biosimilar epoetines, is being discussed as an example of the challenges encountered when assessing the bioequivalence of therapeutic proteins.

Recombinant human erythropoietins, biosimilars and immunogenicity.

Biopharmaceutical agents have revolutionised the treatment and management of medical conditions such as diabetes, Gaucher disease, cancer and infertility. From the introduction of the first products of nonhuman origin some 100 years ago, to the more recent addition within the last 2 decades of human recombinant DNA products (e.g., recombinant human erythropoietin and growth hormone), millions of patients have benefited from treatment using these complex medicinal products. With many of the developed biopharmaceuticals reaching their patent expiry, increasing interest has been expressed in the almost inevitable introduction of biosimilars, or follow-on biopharmaceuticals. In particular, concerns have been raised regarding the safety of biosimilars in light of the complex production methods necessary for the generation of biopharmaceutical products. This review explores some of the safety issues applicable to biosimilars, with a focus on immunogenicity.

Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: expert opinions based on the Proceedings of an International Consensus Conference.

On August 30, 2002, an international panel of neurologists who specialize in the treatment of multiple sclerosis (MS) was convened in Paris (France) to discuss the issue of neutralizing antibodies (NAb) to interferon beta (IFN-beta) therapy in patients with MS. The goals of this meeting were to: (i) review the most recent clinical information on NAb, (ii) come to a consensus on the clinical relevance of NAb in the management of patients with MS receiving IFN-beta therapy, and (iii) establish a framework for the development of patient management guidelines based on scientific consensus. The meeting was chaired by Hans-Peter Hartung (Heinrich-Heine University, Düsseldorf, Germany) and Huub Schellekens (Utrecht University, Utrecht, the Netherlands). This article summarizes the opinions of the expert panel on a number of key issues raised at the meeting.

When biotech proteins go off-patent.

The patents of the first generation of biopharmaceuticals derived from recombinant DNA such as interferons, growth hormone and epoietins are expiring, opening up the possibility for competitors to introduce biosimilar products. The concept of generics that applies to classical drugs and allows market admission on limited documentation cannot be extrapolated to these "off-patent biologics". Physicochemical characterization, bioassays and animals studies do not predict completely the efficacy and safety of therapeutic proteins. Clinical studies will nearly always be necessary to obtain marketing authorization for off-patent biologics. Immunogenicity is considered to be the main problem with therapeutic proteins. The recent upsurge of pure red cell aplasia (PRCA), a severe form of anemia associated with the use of epoietin-alpha, highlights both the unpredictability and the severe consequences of immunogenicity. A risk-based approach can be used to evaluate the potential induction of antibodies by off-patent biologics.

Immunogenicity of biopharmaceuticals. The European perspective.

In 1993 a Concerted EU Action was started to coordinate research concerning the immunogenicity of biopharmaceuticals bringing together researchers from academia and industry. The main topic of this concerted action has been interferon alpha. The factors influencing its immunogenicity were studied. Blind panel testing of patients' sera showed large differences in reported titres as an important variable in different studies. The EMEA has requested the three marketing authorization holders of interferon beta to develop a common assay for antibodies to this product. The status of this project will be discussed. The occurrence of about 30 cases of pure red cell aplasia related to antibodies induced by erythropoietin treatment will also be reported.

The immunogenicity of biopharmaceuticals. Lessons learned and consequences for protein drug development.

Most biopharmaceuticals, including those proteins that are more or less identical to native human proteins, induce antibodies in a significant fraction of patients. The main factors contributing to immunogenicity are impurities and the presence of aggregates. Sequence divergence from the native proteins only plays a minor role except in proteins from microbial, plant or distant vertebrate origin. In the majority of cases the antibodies have no biological or clinical effects. The most common clinical effect is the loss of efficacy of the biopharmaceutical. Serious complications of immunogenicity are rare. The best method to prevent immunogenicity is optimizing production, purification and formulation of the biopharmaceutical protein to generate soluble, non-aggregated, native protein free of contaminating adjuvants. The best way to predict immunogenicity in humans is evaluation in immune tolerant transgenic mice.

[Genetic modification of animals]. / Genetische modificatie van dieren.

Genetic modificated animals are an essential part of modern biotechnology since the years of the seventies of last century. In the past selective crossbreeding of plants and animals took place in order to obtain the desired characteristics but nowadays this is done with the aid of biotechnology i.e. through transgenese, knock-out animals and cloning. A number of fields of application of genetic modification of animals are listed. In order to limit the risks that genetic modificated animals may carry with them the necessary legislation is formulated. A number of risks and the main rules are mentioned.

Oromucosal interferon therapy: relationship between antiviral activity and viral load.

Intraperitoneal (i.p.) administration of 20,000 IU recombinant murine IFN-alpha (rMuIFN-alpha) was highly effective in protecting mice challenged i.p. with doses of encephalomyocarditis virus (EMCV) ranging from 44 to 440 LD(50) (p<0.001). Oromucosal (o.m.) IFN therapy was also found to be effective in protecting mice challenged with a lethal dose of EMCV. Thus, 40% of animals infected with 44 LD(50) of EMCV and treated o.m. with 20,000 IU rMuIFN-alpha survived infection with a mean survival time of 12.0 +/- 2.46 days relative to a mean of 6.11 +/- 0.38 days in the control group (p<0.05). Oromucosal IFN therapy was found to be ineffective, however, in animals infected with higher doses of EMCV (88-440 LD(50)), even though intraperitoneal administration of the same dose of rMuIFN-alpha resulted in the survival of 90%, 50%, and 60% of animals infected with 88, 220, and 440 LD(50) of EMCV, respectively. These results suggest that oromucosal IFN therapy is effective at relatively low viral load only and that the mechanism of action of oromucosal IFN therapy may be different from that of parenterally administered IFN. Our results suggest that oromucosal IFN therapy may be most effective in chronic viral infections as an alternative to parenterally administered IFN, which is clinically effective but poorly tolerated.