BackgroundAssessment of biosimilarity uses the “totality-of-the-evidence” concept, whereby a complete data package, comprising physicochemical, biological, nonclinical and clinical data, is used to ...evaluate and confirm biosimilarity between a proposed biosimilar and an approved originator (reference) product. A stepwise approach, using comparative analytical characterisation to inform next steps, is recommended. The totality-of-evidence derived from these data should demonstrate that the active substance of a biosimilar and its originator are essentially the same.ObjectivesTo describe the development of a proposed etanercept biosimilar (GP2015).MethodsTo define the development target, multiple batches of the originator were characterised over time to understand quality attributes relating to protein structure, function, and amino acid modifications. An iterative, target-directed development process was used to design and produce a potential biosimilar product (GP2015) that fell within the variability range of the originator. Biosimilarity between GP2015 and the originator was confirmed at analytical, functional, nonclinical, pharmacokinetic (PK) and clinical levels using a stepwise approach. Biochemical attributes and functional properties were assessed using a comprehensive and sensitive state-of-the-art panel of analytical tools. Bioequivalence between GP2015 and the originator was assessed in vivo and in four PK studies in healthy volunteers. To confirm there were no clinically meaningful differences between GP2015 and the originator, a study of efficacy, safety and immunogenicity was performed in patients with moderate-to-severe chronic plaque-type psoriasis. This confirmative study assessed the Psoriasis Area and Severity Index response rate at Week 12 and at long-term timepoints.ResultsGP2015 was developed at the same dosage and strength as the originator. Multiple orthogonal analytical methods showed high similarity between GP2015 and the originator. The amino acid sequence was confirmed to be identical and protein folding was indistinguishable. Other attributes, such as glycosylation and product-related impurities, were highly-comparable with the originator. In vitro assays reflecting mechanisms of action and pharmacological properties showed GP2015 and the originator had similar bioactivity. PK bioequivalence between GP2015 and the originator was established in nonclinical and human studies. The study in patients with psoriasis confirmed similar efficacy and safety and comparable immunogenicity in a highly-sensitive indication. In all studies, no clinically meaningful differences between GP2015 and the originator were observed.ConclusionsAnalytical, functional, nonclinical and clinical data provide a comprehensive understanding of both GP2015 and the originator and demonstrate a high level of similarity between the two products in accordance with regulatory requirements. The totality-of-the-evidence is therefore believed to justify the use of the biosimilar in the same indications as the originator.Disclosure of InterestM. McCamish Employee of: Hexal AG, A. DaSilva Employee of: Hexal AG, R. Ernst Mayer Employee of: Sandoz Biopharmaceuticals, C. Fritsch Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, M. Schiestl Employee of: Sandoz Biopharmaceuticals
Transcatheter aortic valve implantation (TAVI) is a new treatment option for patients with severe symptomatic aortic stenosis. Despite a lack of scientific evidence for a benefit of the procedure ...compared with surgical valve replacement or repair as the current gold standard and pending questions about safety and long-term results, a continuous and remarkable increase of its application in Germany can be observed.
In a systematic research, publications suitable for the deduction of criteria for indication and structural and process standards were identified.
No appropriate studies exist to define scientifically sound criteria for indication and structural and process standards for TAVI. Two randomized controlled trials give hints for potential patient selection criteria. However, several interdisciplinary position statements of the most relevant scientific societies in Europe and North America provide recommendations for indication criteria and minimum structural and process requirements. TAVI should be used only in patients with contraindications for open surgery or highest perioperative risk. Multidisciplinary heart teams comprising at least one cardiac surgeon and one cardiologist are mandatory for patient selection and performance of TAVI. Structural equipment to carry out immediate open heart surgery is mandatory. Most recommendations require performing TAVI only in hospitals with a cardiac surgery unit. Participation in a registry is recommended.
Currently, TAVI should be restricted to patients with severe symptomatic aortic valve stenosis and contraindications against open heart surgery or maximum perioperative risk. The surgical risk should be assessed by a multidisciplinary team. The procedure should be performed by interdisciplinary heart teams in hospitals with a cardiac surgery unit.
Objective: The aim of this review is to describe the inherent variability that is natural to biologics and, using the proposed etanercept biosimilar (GP2015) as an example, provide details on the ..."totality-of-the-evidence" concept, whereby all physicochemical, biologic, preclinical, and clinical data for a biosimilar and reference medicine are evaluated in an iterative, stepwise manner and shown to be highly similar.
Methods: This review was carried out by a search of published articles, reviews, abstracts and patents in PubMed/Medline and Google Scholar up to November 2016.
Results: Analytical, functional, preclinical, and clinical data provide a comprehensive understanding of both GP2015 and reference etanercept, and demonstrate a high level of similarity between the two products in accordance with regulatory requirements. The totality of the evidence from all analyses and performed trials provides a robust scientific bridge between the biosimilar and clinical experience with the reference medicine, and is used to justify the use of the biosimilar in all indications for which the reference medicine is approved.
Conclusion: Biologic therapies have revolutionized the treatment of immune-mediated inflammatory diseases. The availability of biosimilars has the potential to improve patient access to biologic medicines and stimulate innovation. Physicians may be unfamiliar with the totality-of-the-evidence concept; therefore education and information on this unique approach to developing biosimilars is required to facilitate the use of biosimilars in clinical practice and allow physicians to make informed treatment decisions.
Etanercept is a TNFα receptor Fc fusion protein used for the treatment of rheumatic disease and psoriasis. Physicochemical and functional investigation of process fractions during development of the ...etanercept biosimilar GP2015 (Erelzi
) revealed a correlation between reduced potency and incorrect disulfide bridging between specific cysteines in the receptor domain. This novel structure-function relationship was found to be the molecular basis for reduced potency in recent Enbrel
batches, which exhibit higher levels of incorrect disulfide bridging. Interestingly, incorrect disulfide bridging was found to be reversible under serum-like redox conditions, restoring potency to normal levels. This redox dependent reversibility suggests that these variants are likely not relevant for clinical efficacy once the drug enters the bloodstream. Nonetheless, incorrect disulfide bridging in etanercept represents a new quality attribute that is critical for biopharmaceutical functionality and should thus be carefully monitored and controlled to guarantee patient safety.
The twenty-fourth Fermat number is composite CRANDALL, Richard E; MAYER, Ernst W; PAPADOPOULOS, Jason S
Mathematics of computation,
07/2003, Letnik:
72, Številka:
243
Journal Article
Recenzirano
Odprti dostop
We have shown by machine proof that F_{24} = 2^{2^{24}} + 1 is composite. The rigorous Pépin primality test was performed using independently developed programs running simultaneously on two ...different, physically separated processors. Each program employed a floating-point, FFT-based discrete weighted transform (DWT) to effect multiplication modulo F_{24}. The final, respective Pépin residues obtained by these two machines were in complete agreement. Using intermediate residues stored periodically during one of the floating-point runs, a separate algorithm for pure-integer negacyclic convolution verified the result in a ``wavefront'' paradigm, by running simultaneously on numerous additional machines, to effect piecewise verification of a saturating set of deterministic links for the Pépin chain. We deposited a final Pépin residue for possible use by future investigators in the event that a proper factor of F_{24} should be discovered; herein we report the more compact, traditional Selfridge-Hurwitz residues. For the sake of completeness, we also generated a Pépin residue for F_{23}, and via the Suyama test determined that the known cofactor of this number is composite.
In contrast to other Indian exports, black pepper was widely available throughout the Roman World, and affordable for ordinary working people. The relatively low price of black pepper indicates that ...Indo-Roman trade goods was not just pitched at the very wealthy, but benefited a much broader segment of the population. This throws new light on the scale and cultural impact of Indo-Roman trade, which appears to have exploited Rome's burgeoning non-elite "consumer culture" in the early imperial period. The scale and cultural impact of Indo-Roman pepper and other trade is evidenced by a wide variety of Western sources and ancient Indian texts.
Ruptured Aneurysms of the Sinus of Valsalva Mayer, Ernst-Dietrich; Ruffmann, Kai; Saggau, Werner ...
The Annals of thoracic surgery,
07/1986, Letnik:
42, Številka:
1
Journal Article
Recenzirano
From 1964 to 1984, 10 male and 5 female patients with ruptured aneurysms of the sinus of Valsalva (ASVs) underwent surgical correction. These procedures constituted 0.23% of the 6,350 surgical ...procedures that used cardiopulmonary bypass during this period. Five patients had an inflammatory condition (bacterial endocarditis, 4; syphilis, 1), and 1 had an ASV relapse 5 years after her first operation. Coexistent lesions included aortic valve regurgitation in 5 patients, ventricular septal defect in 3 (1 of whom had mitral insufficiency), patent foramen ovale in 2, and atrial septal defect in 1. Ninety-three percent were symptomatic (sudden onset of symptoms, 5 patients; gradual onset, 9 patients), commonly with shortness of breath, fatigability, chest pain, and tachycardia. The following connections occurred: noncoronary sinus to right atrium (RA) (5 patients); right coronary sinus (RCS) to RA (5 patients); and RCS to right ventricle (5 patients). There were no early or late postoperative deaths. One patient underwent reoperation after an ASV relapse. The mean follow-up period (± standard deviation) was 7.9 years (range, 10 months to 20.1 years). Eighty percent of the patients were found to be in New York Heart Association class I, and 20% were in class II. Apart from ASV relapse, late complications are determined by prosthetic valve dysfunction or evidence of valve disease. Early surgical intervention is justified in patients with ruptured ASV.
Our image of the Roman world is shaped by the writings of upper-class intellectuals. Yet most of the material evidence we have--art, architecture, household artifacts--belonged to artisans, ...merchants, and professionals. Roman culture as we have seen it with our own eyes is distinctly middle-class and requires a radically new framework of analysis.
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