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New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population. In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3–4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of “clear” or “almost clear” (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591. Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events. In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis. Pfizer Inc.

As of mid-2017, 10 tumour necrosis factor inhibitors (four for etanercept and three each for adalimumab and infliximab) and a first rituximab biosimilar are on the market, and a considerable number more are in various stages of development. The clinical trials of biosimilars, which have included long term extensions, have used various designs to look at switching between originator and biosimilar products, with reassuring results for clinical practice. For the infliximab biosimilar CT-P13 in particular, several studies have examined non-medical switching in real world practice. The results suggest that switching does not compromise safety, efficacy, or immunogenicity. However, additional data from clinical and real world switching studies, especially of switching between two or more biosimilars, are needed, as is continuing pharmacovigilance with larger databases to fill remaining gaps in the evidence. As biosimilar development continues, innovations in formulation and drug delivery technology may become of increasing interest.

Psoriasis is a chronic, inflammatory, lifelong disease with a high prevalence (afflicting approximately 1–5% of the population worldwide) and is associated with significant morbidity. The introduction of biologic therapies has improved the management of this disease. Multiple biologic medicines that block cytokine signaling, including tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, and infliximab) and inhibitors of interleukin (IL)-17 (brodalumab, ixekizumab, and secukinumab), IL-23 (guselkumab), or IL-12/23 (ustekinumab), are approved for the treatment of psoriasis. Despite the clinical benefits associated with use of biologics in psoriasis, many patients are not treated with biologic therapy, and access to treatment may be limited for various reasons, such as high treatment costs. Patents for many biologics have expired or will soon expire, and biosimilar versions of these agents are available or in development. A biosimilar is a biological product that is highly similar to an approved biologic (i.e., originator or reference) product, and has no clinically meaningful differences in safety, purity, or potency when compared with the reference product. Biosimilars may offer less expensive treatment options for patients with psoriasis; they also may increase access to and address problems with underutilization of biologic therapy. Biosimilar development and approval follows a well-regulated process in many countries, with guidelines developed by the European Medicines Agency, US Food and Drug Administration, and World Health Organization. Currently, several anti-TNF biosimilars are available for use in patients with psoriasis, and other monoclonal antibodies are in development. This review provides dermatologists and those who treat and/or manage psoriasis with a working knowledge of the scientific principles of biosimilar development and approval. It also examines real-world experience with biosimilars available for or used in dermatology that will enable physicians to make informed treatment decisions for their patients with psoriasis. Funding : Pfizer Inc.

With the projected expansion of the biosimilars market, there will be an increased propensity for the substitution of reference biological products with cheaper biosimilars for economic reasons (ie, non-medical switching). This will lower the cost per patient and should provide the benefit of wider access to biological therapies. However, it is essential that patients and clinicians fully understand the rationale for non-medical switching and its potential implications in terms of efficacy, safety, and immunogenicity. To date, clinical experience supports the use of biosimilars and a growing body of evidence from clinical trials and real world observational studies specifically supports clinical decision making around non-medical switching. Equally, as non-medical switching becomes more common, it is essential that pharmacovigilance systems adapt to handle the increasing volumes of data needed to effectively monitor the use of biosimilars and detect new signals. This will require a reduced reliance on registries, as well as streamlining and integration of existing systems to allow a frequent cycle of online reporting of adverse events by healthcare professionals, analysis by national authorities, and feedback to treating clinicians. This article considers the current use and future uptake of biosimilars from a clinical perspective.

Biosimilars are biotherapeutic products with similar efficacy, safety, and quality to a licensed bio-originator. Biosimilars include monoclonal antibodies, soluble receptors, growth factors, and hormones. The manufacture of biosimilars is a sophisticated multi-step process; factors at each stage, such as production cell line, culture conditions, and formulation, may each alter the final product through post-translational modifications. A vial of a therapeutic antibody contains multiple species with distinct glycosylation profiles (microheterogeneity), which are responsible, for example, for complement activation, pharmacokinetics, and structural stability. Whereas the focus for the manufacturer of the bio-originator is to show safety and efficacy in clinical trials, biosimilar development focuses predominantly on in-depth analyses to confirm that the product is identical to the originator in terms of structure, composition, and in vitro activity. Therefore, the critical quality attributes of a biological drug that influences clinical safety and efficacy should be carefully assessed. At least one clinical study is required to compare pharmacokinetics of bio-originator and biosimilar, and at least one sufficiently large randomised controlled trial to demonstrate clinical equivalence. Once biosimilarity is confirmed, regulators may allow extrapolation to other licensed bio-originator indications, provided efficacy relies on a similar mechanism of action in each one. Consequently, a biosimilar may be approved in all indications for which the bio-originator has been approved, without multiple clinical trials.

With the authorisation of an increasing number of biosimilars, and the prospect of multiple biosimilar switching, biosimilar naming and the importance of this for pharmacovigilance are coming into sharper focus. Current naming policies are not universal; neither are extrapolation criteria. Indeed, consideration of whether we can extrapolate information from one indication or disease to another continues to be a divisive topic. However, this is changing, as we strive for a more harmonised approach. Such a unified approach will be needed when considering future strategies to follow for multiple biosimilar switching, especially so because there is currently no uniform policy regarding interchangeability, switching, and automatic substitution. In this multiple biosimilar setting, the question as to whether we can be confident to move across indications will be increasingly important. The cost of biosimilar switching also needs to be considered—biosimilar use may mean that patients need more training and medical visits, with associated administrative costs. The biosimilars debate seems to be refocusing issues that have previously been extensively discussed but that have recently lost impetus, including the role of clinical pharmacology in internal medicine.

Bei Patienten mit chronischen Wunden sollte neben einer ursächlichen Therapie auch immer eine Wundbehandlung erfolgen. Wiederholt wurde in diesem Kontext über die unzureichende Evidenz von Wundheilungsprodukten diskutiert. An dem Beispiel von TLC(„technology lipido-colloid“)-Sucrose Octasulfat wird in der vorliegenden Übersichtsarbeit gezeigt, dass auch in diesem Bereich eine aussagekräftige Datenlage mit guter Evidenz und Vergleichbarkeit vorliegt. Ein therapeutischer Ansatzpunkt, die Wundheilung zu fördern, ist die Hemmung von Matrixmetalloproteinasen beispielsweise durch Sucrose Octasulfat. Für Wundprodukte mit TLC-Sucrose Octasulfat wurden in den letzten Jahren mehrere, aufeinander aufbauende klinische Studien durchgeführt. Die WHAT-Studie war eine offene RCT (randomisierte kontrollierte Studie) mit 117 Patienten mit Ulcus cruris venosum. Bei der CHALLENGE-Studie handelte es ich um eine doppelblind durchgeführte RCT mit 187 Patienten mit Ulcus cruris venosum. Die SPID-Studie war eine Pilotstudie mit 33 Patienten mit diabetischem Fußulkus (DFU). In 2 prospektiven, multizentrischen klinischen Pilotstudien NEREIDES und CASSIOPEE wurden insgesamt 88 Patienten mit Ulcera crurum in verschiedenen Heilungsphasen untersucht. In der REALITY-Studie erfolgte eine gepoolte Datenanalyse über 8 Anwenderbeobachtungen mit 10.220 Patienten mit chronischen Wunden unterschiedlicher Genese. In der doppelblinden, zweiarmigen EXPLORER-RCT wurden 240 Patienten mit neuroischämischem DFU erstmalig bis zur vollständigen Abheilung untersucht. In allen Studien konnte eine signifikante Förderung der Wundheilung durch den Einsatz von Wundheilungsprodukten mit TLC-Sucrose Octasulfat gezeigt werden.

We retrospectively compared the efficacy of razoxane and radiotherapy with radiotherapy alone or in combination with a non-razoxane based medication in patients with melanoma brain metastases. From 19 assessable patients receiving whole brain irradiation with or without a boost (mean total dose 40.5 Gy) for measurable brain metastases, 8 patients underwent an additional razoxane therapy with 125 mg per os twice daily started 5 days before radiotherapy and given throughout the whole radiation period. The median razoxane dose was 6.25 g (range 3.2-8.0 g). Endpoints included radiation response rates, median survival time and 1-year survival rates. To generate reliable prognostic parameters for this non-randomized study population, the Score Index for Stereotactic Radiosurgery and the Radiation Therapy Oncology Group Recursive Partitioning Analysis score were applied. Radiotherapy with razoxane led to higher response rates (62% vs. 27%) and a lower percentage of progressive disease (12.5% vs. 36%) if compared with radiotherapy alone or with a non-razoxane based medication. This combination was associated with a longer median survival (5 months vs. 2.2 months; P=0.052) and a 1-year survival rate of 37.5% vs. 0% (P=0.027). Both treatment groups belonged to similar prognosis subsets. The treatment was well tolerated. Taken together our data support the therapeutic concept of a combined razoxane radiation therapy in melanoma patients with brain metastases. The favorable treatment effects are probably due to the radiosensitizing and the cytorallentaric mode of action of razoxane. Since the patient numbers are low, confirmatory studies are certainly necessary.

Objective: To evaluate the efficacy and safety of continuous and paused etanercept regimens in psoriasis patients. Methods: Patients with moderate-to-severe plaque psoriasis were randomized to receive continuous etanercept 25 mg twice weekly or paused etanercept for 54 weeks. The paused group received etanercept 50 mg twice weekly for no more than 12 weeks until reaching a Physician Global Assessment (PGA) of 2 or less (mild or better), when treatment was paused; upon relapse (PGA ≥ 3), etanercept was resumed at 25 mg twice weekly until a PGA of 2 or less was regained. The primary efficacy end point was mean PGA over 54 weeks, which was compared between the continuous and paused groups. Secondary efficacy end points included changes from baseline in mean PGA score, Psoriasis Area and Severity Index (PASI) and patient satisfaction with current psoriasis treatment. Results: Among 711 patients evaluable for efficacy, the mean PGA score averaged over 54 weeks (primary end point) was significantly lower in the continuous etanercept therapy group than in the paused etanercept therapy group (1.98 vs 2.51, respectively; p < 0.001). Mean PGA was significantly reduced from baseline (3.6, both groups) to week 54 in the continuous (1.9) and paused groups (2.4; p < 0.01, within-group comparisons). Mean PASI was significantly decreased from baseline (21.9 and 22.8, respectively) to week 54 with continuous (7.1) and paused therapy (9.5; p < 0.01, within-group comparisons). PASI improved by 68 and 59% from baseline to week 54 in patients receiving continuous and paused etanercept, respectively. Patient satisfaction rates improved from 20.2 and 22.5% in continuous and paused groups, respectively, at baseline to 83.5 and 83.0% at week 12; 83.3 and 78.3% at week 24; and 81.3 and 72.6% at week 54, respectively. Overall, 7.5% (54 out of 720) of patients had serious adverse events (6.4 and 8.5%, continuous and paused groups, respectively); four patients (two per group) had serious infections. No cases of tuberculosis or demyelinating diseases were observed. Conclusion: Both continuous and paused etanercept therapies improved PGA and PASI scores and patient satisfaction rates; patients receiving continuous etanercept therapy showed a greater level of improvement, although those who paused and resumed active treatment generally recaptured response and experienced sustained benefit.