BackgroundIxekizumab (IXE) is an interleukin (IL)-17A antagonist approved for the treatment of adults with moderate-to-severe psoriasis.ObjectiveThe objective of this study was to determine if the immune response to tetanus and pneumococcal vaccines in healthy subjects administered IXE was noninferior to control.MethodsIn a randomized, open-label, parallel-group study, adult subjects received vaccinations alone (N = 42, control) or in combination with 160 mg IXE subcutaneously 2 weeks prior to vaccination and 80 mg IXE on the day of vaccination (N = 41, IXE). Response to tetanus vaccination was defined as anti-tetanus antibodies ≥ 1.0 IU and a ≥ 1.5-fold increase if baseline was ≤ 1.0 IU or a ≥ 2.5-fold increase if baseline was > 1.0 IU. Response to pneumococcal vaccination was defined as a ≥ 2-fold increase from baseline in anti-pneumococcal antibodies against > 50% of the 23 serotypes. The primary outcomes were the percentages of patients with a response to the tetanus and pneumococcal vaccines 4 weeks after vaccination. A noninferiority analysis of IXE to control using a 40% margin was evaluated for the primary outcomes. Safety and pharmacokinetics were also assessed.ResultsIXE (38 completers) was noninferior to control (41 completers) based on the difference in the proportion of responders to tetanus [1.4%; 90% confidence interval (CI) − 16.6 to 19.2] and pneumococcal (− 0.8%; 90% CI − 12.9 to 11.0) vaccines. Twenty subjects (14 IXE, six control) reported 43 mild treatment-emergent adverse events.ConclusionIXE does not suppress the humoral immune response to non-live vaccines and was well tolerated in healthy subjects.ClinicalTrial.gov identifier: NCT02543918.Electronic supplementary materialThe online version of this article (doi:10.1007/s40259-017-0249-y) contains supplementary material, which is available to authorized users.

Zostavax(®) is a live attenuated shingles (herpes zoster) vaccine approved in the EU for the prevention of herpes zoster (HZ) and postherpetic neuralgia (PHN) in adults aged ≥50 years. Zoster vaccine protected against HZ in adults aged 50-59 years (ZEST trial) and ≥60 years [Shingles Prevention Study (SPS)], and also reduced the burden of illness associated with HZ and the risk of PHN in adults aged ≥60 years (SPS). A large amount of real-world data also supports the efficacy of zoster vaccine. Results of the SPS Short- and Long-Term Persistence Substudies and real-world studies indicate that zoster vaccine provided continued benefit in the longer term, albeit with a gradual decline in vaccine efficacy over time; long-term effectiveness studies are ongoing. The need for a booster dose is still unknown, but a study showed that, if necessary, a booster dose administered to adults aged ≥70 years who received their first dose of zoster vaccine ≥10 years previously was immunogenic. Zoster vaccine had a favourable safety and tolerability profile, with the most commonly reported adverse events being non-severe injection-site reactions. In conclusion, zoster vaccine reduces the incidence of HZ and PHN, thereby reducing the burden of illness associated with HZ; improved uptake of zoster vaccine is needed.

In recent years, remarkable advances in the ability to diagnose genetic disorders have been made. The identification of disease-causing genes allows the development of gene-specific therapies with the ultimate goal to develop personalized medicines for each patient according to their own specific genetic defect. In-depth genotyping of many different genes has revealed that ~12% of inherited genetic disorders are caused by in-frame nonsense mutations. Nonsense (non-coding) mutations are caused by point mutations, which generate premature termination codons (PTCs) that cause premature translational termination of the mRNA, and subsequently inhibit normal full-length protein expression. Recently, a gene-based therapeutic approach for genetic diseases caused by nonsense mutations has emerged, namely the so-called translational read-through (TR) therapy. Read-through therapy is based on the discovery that small molecules, known as TR-inducing drugs (TRIDs), allow the translation machinery to suppress a nonsense codon, elongate the nascent peptide chain, and consequently result in the synthesis of full-length protein. Several TRIDs are currently under investigation and research has been performed on several genetic disorders caused by nonsense mutations over the years. These findings have raised hope for the usage of TR therapy as a gene-based pharmacogenetic therapy for nonsense mutations in various genes responsible for a variety of genetic diseases.

An unusually high production of cytokines or chemokines as well as increased complement activation can drive development of chronic inflammatory autoimmune diseases. State-of-the-art biological therapies, recombinant receptors, or specific antibodies that target immune and inflammatory mediators are now effectively used. However, these newer drugs are not equally effective for all patients and can cause adverse effects, making the search for new immunomodulatory proteins of great importance. The poxviruses--first and foremost, the variola (smallpox) virus, which is highly pathogenic in man--code for numerous highly evolved and extraordinarily effective immunomodulatory proteins that bind cytokines, chemokines, and proteins of the complement system. The discovery of and investigation into immune modulators from the variola virus has great potential for guiding new and effective drugs for autoimmune diseases.

BackgroundThe acceptability of switching between reference drugs and their biosimilars is often disputed. It is unclear whether this concern is specific to the use of biosimilars or is relevant to the practice of switching between any biological drugs.ObjectiveThe objective of this study was to quantify the occurrence of switching between different erythropoiesis-stimulating agents.MethodsA retrospective drug utilization study was conducted in the Umbria region (Italy). The study population included all residents who received their first epoetin prescription between 1 July 2011 and 31 December 2014. The Umbria drug prescription database and the regional archive of residents were used to gather information. Switching was defined as any transition between different epoetins (different substances and/or different products of the same substance) in a series of two prescriptions. The probability of switching was described in relationship to the duration of treatment in a survival analysis.ResultsOverall, 3258 subjects received prescriptions of epoetins. Among the 2896 patients with at least two prescriptions, 354 (12.2 %) experienced one or more switches. The probability of switching depended on the duration of treatment: approximately 15 % of users switched within 12 months of observation and 25 % switched within 2 years. Switching was not limited to reference and biosimilar epoetins and it affected patent and off-patent epoetins equally.ConclusionsSwitching between different epoetins was related to the duration of use and most episodes of switching involved epoetins that have never been contrasted in a comparability exercise. The present level of switching may provide reassurance to physicians when taken together with other sources of comparative evidence.Electronic supplementary materialThe online version of this article (doi:10.1007/s40259-015-0155-0) contains supplementary material, which is available to authorized users.

In 2015, five or more biosimilars may be approved in the USA. Because no two biologic medicines are identical, postapproval safety monitoring will be critical to detect potential differences in safety signals between a biosimilar, its reference product, and other biosimilars. Postapproval safety monitoring in the USA uses two signal detection systems: spontaneous reporting systems (SRSs) and active surveillance (AS) systems. Both depend on accurate identification of the specific product(s) dispensed or administered to patients, which may be compromised when products from multiple manufacturers share common drug nomenclature or coding. Product identification can present challenges across different healthcare settings, including inpatient and ambulatory care. Common oral-dosage drugs are predominantly dispensed directly to patients by pharmacists, whereas most injectable drugs, including biologics, are administered to patients by healthcare professionals in outpatient clinics or hospitals. Thus, the effectiveness of SRS and AS mechanisms in both pharmacy and medical channels must be given greater consideration as biotechnology matures. In this article, we describe these systems and their limitations. We identify challenges and opportunities for product-specific safety surveillance of biologics in both the pharmacy and medical settings and provide recommendations to improve biologic safety surveillance under the current and future systems envisioned in the Drug Quality and Security Act. As biosimilars are integrated into existing pharmacovigilance systems, distinguishable nonproprietary names and codes for all biologics, as well as other opportunities to improve traceability (e.g., increased use of barcodes), must be considered to ensure patient safety and confidence in this new class of drugs.

Approved by the US Food and Drug Administration (FDA) in 2010, sipuleucel-T (Provenge(®)) was the first 'personalized' cancer vaccine for the treatment of prostate cancer in a metastatic, non-symptomatic population of 30,000 men in the USA. Sipuleucel-T is prepared individually for each patient and infused in three sessions over a period of 1 month. However, in 2015, Dendreon, the owner of sipuleucel-T, filed for bankruptcy. This opinion paper reviews the probable reasons this innovative product failed to achieve commercial success. PubMed and internet searches were performed focused on pricing, reimbursement, and market access. We found that sipuleucel-T's FDA approval was delayed by 3 years, reportedly because of the vaccine's new mechanism of action. Sipuleucel-T was cleared by the European Medicines Agency 2 years later, but other national agencies were not approached. It was priced at $US93,000 for a course of treatment, and this high price combined with the company's late securement of reimbursement for the vaccine by the US Centers for Medicare and Medicaid Services (CMS) resulted in another year's delay in accessing the market. Despite a positive recommendation by the National Comprehensive Cancer Network, sipuleucel-T's complex administration, high price, and uncertainty about the reimbursement status deterred doctors from prescribing the product. Furthermore, the vaccine's supply was limited during the first year of launch due to limited manufacturing capacity. In addition, two oral metastatic prostate cancer drugs with similar survival benefits reached the US market 1 and 2 years after sipuleucel-T. Also, even though Dendreon's market capitalization topped $US7.5 billion following the FDA's approval of sipuleucel-T, this value degraded gradually until the firm's bankruptcy 5 years later. We conclude that the bankruptcy of Dendreon was largely due to the delay in securing FDA approval and CMS coverage, as well as the high cost that had to be incurred by providers up-front. Licensing sipuleucel-T to a pharmaceutical company more experienced in the market access pathway may have saved the company and the product.

BackgroundAuthorization to market a biosimilar product by the appropriate institutions is expected based on biosimilarity with its originator product. The analogy between the originator and its biosimilar(s) is assessed through safety, purity, and potency analyses.ObjectiveIn this study, we proposed a useful quality control system for rapid and economic primary screening of potential biosimilar drugs. For this purpose, chemical and functional characterization of the originator rhEPO alfa and two of its biosimilars was discussed.MethodsQualitative and quantitative analyses of the originator rhEPO alfa and its biosimilars were performed using reversed-phase high-performance liquid chromatography (RP-HPLC). The identification of proteins and the separation of isoforms were studied using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF–MS) and two-dimensional gel electrophoresis (2D-PAGE), respectively. Furthermore, the biological activity of these drugs was measured both in vitro, evaluating the TF-1 cell proliferation rate, and in vivo, using the innovative experimental animal model of the zebrafish embryos.ResultsChemical analyses showed that the quantitative concentrations of rhEPO alfa were in agreement with the labeled claims by the corresponding manufacturers. The qualitative analyses performed demonstrated that the three drugs were pure and that they had the same amino acid sequence. Chemical differences were found only at the level of isoforms containing N-glycosylation; however, functional in vitro and in vivo studies did not show any significant differences from a biosimilar point of view.ConclusionThese rapid and economic structural and functional analyses were effective in the evaluation of the biosimilarity between the originator rhEPO alfa and the biosimilars analyzed.Electronic supplementary materialThe online version of this article (doi:10.1007/s40259-015-0136-3) contains supplementary material, which is available to authorized users.

Filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF), is efficacious in stimulating neutrophil production and maturation to prevent febrile neutropenia (FN) in response to chemotherapy. Because of its relatively short circulating half-life, daily filgrastim injections are required to stimulate neutrophil recovery. In an effort to develop a long-acting form of filgrastim that was as safe and efficacious as filgrastim but had a longer in vivo residence time, a number of strategies were considered. Ultimately, fusion of filgrastim to polyethylene glycol (PEG) was selected. Following extensive analysis of conjugation chemistries as well as in vitro and in vivo characterization of a panel of PEGylated proteins, a construct containing a 20 kDa PEG moiety covalently conjugated to the N-terminus of filgrastim was chosen for advancement as pegfilgrastim. Pegfilgrastim is primarily cleared by neutrophils and neutrophil precursors (rather than the kidneys), meaning that clearance from the circulation is self-regulating and pegfilgrastim is eliminated only after neutrophils start to recover. Importantly, addition of PEG did not alter the mechanism of action and safety profile compared to filgrastim. Clinical evaluation revealed that a single 6 mg dose effectively reduces the duration of neutropenia and risk of FN in patients receiving chemotherapy. This work demonstrates the benefit of using PEGylation to generate pegfilgrastim, which allows for once-per-chemotherapy cycle administration while maintaining similar safety and efficacy profiles as those for multiple daily administration of filgrastim. Approaches that may provide advances for therapeutic agonists of G-CSF receptor are also discussed.