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Generics, Biosimilars and Follow-On Non-Biologic Complex Drugs for Multiple Sclerosis: A Narrative Review of the Regulatory and Clinical Implications for European Neurologists
No full textBackgroundMultiple sclerosis (MS) places substantial socioeconomic burden on patients due to its early onset and progressive nature, but healthcare systems are also impacted by the high costs of disease-modifying treatments (DMTs). The use of generics (for conventional drugs), biosimilars (for biologics) or follow-on versions of non-biologic complex drugs (NBCDs) can help to reduce the cost of MS care and improve patient access. This review describes the European regulatory processes for these DMT 'copies' and the available data in people with MS.MethodsA PubMed literature search was undertaken in March 2024, using the terms 'biosimilar', 'generic', 'non-biologic complex drug', 'NBCD' and 'follow-on' in association with 'multiple sclerosis'.ResultsOur literature search identified three clinical studies with generic treatments for MS (two with generic fingolimod and one with generic dimethyl fumarate), 11 studies with biosimilars (eight with biosimilar interferon formulations, one with natalizumab and two with rituximab biosimilars) and six studies with follow-on glatiramer acetate. The data showed that the generics, biosimilars and follow-on NBCDs had similar clinical efficacy and tolerability profiles to the originator drugs, although the quality and quantity of the research varied between DMTs.ConclusionsIn Europe, there are robust regulatory processes for generics, biosimilars and follow-on NBCDs, in order to ensure that these agents can be considered equally effective and safe as the originator DMT. Physicians caring for people with MS should familiarise themselves with the evidence so that they can have informed conversations about the potential use of these agents.We would like to thank Catherine Rees who wrote the outline and first draft of this manuscript on behalf of Springer Healthcare. This medical writing assistance was funded by ParadigMS Foundation. ParadigMS Foundation is an independent and non-profit group of European, Middle Eastern and North African neurologist experts in multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMO-SD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). The content of this publication is based upon in-depth discussions on this topic by the group members at Expert Meetings. The current list of group members can be consulted at ParadigMS's website
Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer
No full textBackground: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC.
Patients and methods: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R-2 >= 0.7 defined a priori as clinically relevant.
Results: A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R-2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R-2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81.
Conclusions: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.FUNDING
Funded by the Prostate Cancer Foundation Challenge Award, and grants from Astellas Pharma, Pfizer, Janssen Pharmaceuticals, Millennium Pharmaceuticals, SOTIO, Bayer, Dendreon, and Sanofi. No grant number is applicable.
ACKNOWLEDGEMENTS
This manuscript was prepared using data from datasets RTOG-0126, RTOG-9601, and RTOG-9902 from the NCTN Data Archive of the National Cancer Institute’s (NCI’s) National Clinical Trials Network (NCTN). Data were originally collected from clinical trials NCT00033631, NCT00002874, and NCT00004054, respectively. All analyses and conclusions in this manuscript are the sole responsibility of the authors and do not necessarily reflect the opinions or views of the clinical trial investigators, the NCTN, or the NCI
Omgeving en leefstijfactoren: al vroeg in het leven van invloed op telomeerlengte
No full textTelomeren zij n de beschermende uiteinden van chromosomen en nemen in lengte af naarmate we verouderen. Telomeren zij n een indicator voor de gevoeligheid om ouderdomsgerelateerde ziekten te ontwikkelen. Verschillen in telomeerlengtes worden voornamelij k verklaard door een complex samen-spel van genetische, leefstij l-en omgevingsfactoren. Eerdere studies toonden aan dat een gezonde leefstij l belangrij k is in termen van ziektepreventie. Recent onderzoek toont aan dat leefstij l ook in verband wordt gebracht met essentiële biologische processen die betrokken zij n bij veroudering, zoals telomeerverkorting. Dit kan gedeeltelij k verklaren waarom er een verband is tussen leefstij l en ontwik-keling van ziekten. Dit benadrukt dat een gezonde leefstij l niet alleen direct bij draagt aan het voorkomen van ziekten, maar ook indirect via biologische processen die de veroudering reguleren en daarbij de gevoeligheid voor het ontstaan van ziekte verminderen. Deze omgevings-en leefstij lfactoren kunnen al voor de geboorte aanzienlij k invloed uitoefenen op de variatie in telomeerlengte bij pasgeborenen. Hoewel bij de geboorte ieder kind even oud is, is dat niet zo als we kij ken naar de biologische leeftij d op basis van de lengte van de telomeren. Met andere woorden, de lengte van de telomeren bij de geboorte vormt één van de mechanismen die verschillen in veroudering en ziektegevoeligheid gedurende het le-ven mee bepalen. Dit benadrukt het belang van een gezonde leefstij l en omgeving voor het bevorderen van een lang en gezond leven vanaf de preconceptie, niet alleen voor onszelf, maar ook voor toekomstige generaties. (NED TIJ DSCHR LEEFSTIJ LGENEESKD 2025;3(2):69-75) 1 PhD-student, 2 hoogleraar faculteit Wetenschappen, 3 gast FWO postdoctoraal onderzoeker, 4 Centrum voor Milieukunde, Universiteit Hasselt, Hasselt, België, 5 departement Maatschappelij ke Gezondheidszorg en Eerstelij nszorg, KU Leuven, Leuven, België. Correspondentie graag richten aan: dhr. prof. dr. T.S. Nawrot, Universiteit Hasselt, Centrum voor Milieukunde, Agoralaan gebouw D, 3590 Diepenbeek, België, tel: +32 490 57 70 13, e-mailadres: [email protected] Belangenconflict: geen gemeld. Financiële ondersteuning: D.S. Martens is houder van een postdoctoraatbeurs bij het Fonds Wetenschap-pelij k Onderzoek-Vlaanderen (FWO 12X9623N). Trefwoorden: gezondheid, leefstij lfactoren, preventie, telomeerlengte, veroudering
European practices on antithrombotic management during percutaneous mechanical circulatory support in adults: a survey of the Association for Acute CardioVascular Care of the ESC and the European branch of the Extracorporeal Life Support Organization
No full textAims Bleeding and thrombotic complications compromise outcomes in patients undergoing percutaneous mechanical circulatory support (pMCS) with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and/or microaxial flow pumps like Impella (TM). Antithrombotic practices are an important determinant of the coagulopathic risk, but standardization in the antithrombotic management during pMCS is lacking. This survey outlines European practices in antithrombotic management in adults on pMCS, making an initial effort to standardize practices, inform future trials, and enhance outcomes.Methods and results This online cross-sectional survey was distributed through digital newsletters and social media platforms by the Association of Acute Cardiovascular Care and the European branch of the Extracorporeal Life Support Organization. The survey was available from 17 April 2023 to 23 May 2023. The target population were European clinicians involved in care for adults on pMCS. We included 105 responses from 26 European countries. Notably, 72.4% of the respondents adhered to locally established anticoagulation protocols, with unfractionated heparin (UFH) being the predominant anticoagulant (Impella (TM): 97.0% and V-A ECMO: 96.1%). A minority of the respondents, 10.8 and 14.5%, respectively, utilized the anti-factor-Xa assay in parallel with activated partial thromboplastin time for UFH monitoring during Impella (TM) and V-A ECMO support. Anticoagulant targets varied across institutions. Following acute coronary syndrome without percutaneous coronary intervention (PCI), 54.0 and 42.7% were administered dual antiplatelet therapy during Impella (TM) and V-A ECMO support, increasing to 93.7 and 84.0% after PCI.Conclusion Substantial heterogeneity in antithrombotic practices emerged from participants' responses, potentially contributing to variable device-associated bleeding and thrombotic complications.
Graphical Abstract AMICS, acute myocardial infarction-induced cardiogenic shock; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy; DAPT, dual antiplatelet therapy; APTT, activated partial thromboplastin time; ACT, activated clotting time; anti-Xa assay, heparin anti-factor-Xa assay; V-A ECMO, veno-arterial extracorporeal membrane oxygenation.Funding
C.J.V.E. is funded by a grant from Fonds Wetenschappelijk Onderzoek Flanders (11P6X24N) and a research grant from Abiomed (Danvers, MA, USA). C.V., F.P., H.S., and B.S. have reported receiving research and/or travel funding, as well as speaker fees, from Abiomed outside of this manuscript. K.H. received honoraria for consulting and lecturing from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Novartis, Pfizer, and Sanofi. B.S. and H.S. report speaker fees from AstraZeneca. P.V. reports personal fees from Bayer, Pfizer-Bristol Myers Squibb Alliance, Daiichi Sankyo, CSL Behring, and Novartis.
Acknowledgements
We would like to sincerely thank the following experts for their valuable input during the preparation of the survey: Alaide Chieffo, Dieter Dauwe, Diana Gorog, Johannes Grand, Greet Hermans, Matthias Lubnow, Bart
Meyns, Alexandre Mebazaa, Maria Monteagudo Vela, Caroline Ozment, Sascha Ott, Amin Polzin, Marius Szymanski, Thomas Vanassche, and Lorenz Van der Linden. Furthermore, we would like to express our deepest gratitude to the respondents of the survey. A list of survey respondents who included their full name and affiliation can be found in the Supplementary material online, Supplement S8
Dissolved air flotation of Chlorella sp. using chitosan: influence of algal organic matter and growth phase on coagulant dose
No full textThis study investigates the efficient separation of Chlorella sp. microalgae using dissolved air flotation with chitosan as a coagulant. Improving the harvesting process, which significantly contributes to total costs and carbon footprint, could lead to competitive microalgae products and commodities. The exponential phase required 0.20 mg⋅mg 1 1 chitosan, which is almost two times more than the chitosan dose of 0.12 mg⋅mg required for the stationary phase of growth, although the algal biomass concentration had increased from 0.26 ± 0.06 to 0.53 ± 0.01 mg⋅L and the concentration of algal organic matter from 8 to 32 mg C⋅L 1 1 in dissolved organic carbon, respectively. It is also shown, via Microscope Force Spectroscopy, that the cell measured directly from the culture had bound algal organic matter to their surface at pH 8.5, increasing their softness (Young’s Modulus = 8.1 ± 10 kPa), roughness (4.2 ± 2.4 nm) and interaction with bubbles (2.5 ± 2.1 nN, adhesion 64.4 %), compared to the washed cells in PBS buffer at pH 7.4 (1474 ± 1053 kPa; 1.3 ± 0.4 nm; 0.8 ± 0.5 nN, adhesion 9.1 %, respectively). Polysaccharides, mainly containing arabinose (29.2 ± 6.9 % and 33.0 ± 1.7 % dw polysaccharide) and galactose (34.2 ± 8.1 % and 17.43 ± 1.3 % dw), while acidic residues of the polysaccharides (6.7 ± 2.1 % and 13.1 ± 5.8 % Area) were also present along with protein (9.1 ± 2.2 % and 0.9 ± 0.2 % dw AOM) in exponential and stationary growth phase, respectively. Nevertheless, the relationship between AOM composition and its underlying structure and functionality is not yet fully understood.This work was supported by Research Foundation Flanders (FWO junior fundamental research project - G050220N, FWO scientific exchange program Tournesol - VS01322N).
Acknowledgements We would like to acknowledge the technicians’ support of Guy Reggers, Jenny Put, Elsy Thijssen, Martine Vanhamel, Bernard Noppen for TGA analyses, Ion Chromatography, HPAEC-PAD, FTIR, and PY-GC/ MS
Multilevel governance and strategic planning: supralocal governments influencing local circular economy adoption
No full textLocal governments use strategic planning (SP) to address grand challenges like climate change. More and more local governments adopt the circular economy (CE) into their climate strategies to reduce their impact. The CE requires collaboration among different levels of government. However, there is little research considering multiple government levels in the CE transition. At the same time, the SP literature has ignored the multilevel governance (MLG) setting in which local SP takes place. Therefore, we study if supralocal governments influence the adoption of the CE in local SP for climate change and, if so, how they influence the local SP. Supralocal governments are found to have influenced the CE adoption in climate strategies of Flemish local governments. Moreover, interviews showed their influence on both the SP content, process, and implementation. These results highlight the importance of considering the MLG context in which local SP takes place and the influence of supralocal governments
automated multi-patient planning for VMAT prostate planning using fine-tuning process through dynamic adjustment of optimization parameters
No full textElucidating Carrier Dynamics and Interface Engineering in Sb2S3: Toward Efficient Photoanode for Water Oxidation
No full textConjugation of low-cost and high-performance semiconductors is essential in solar-driven photoelectrochemical (PEC) energy conversion. Sb2S3 is a wide-bandgap (approximate to 1.7 eV) semiconductor with the potential to deliver a maximum photocurrent density of 24.5 mA cm-2, making it highly attractive for PEC water splitting applications. However, bulk Sb2S3 exhibits intrinsic recombination issues and low electron-hole separation, posing a limit to photocurrent generation. This study clarifies the carrier dynamics by ultrafast spectroscopy measurements and proposes the design of a heterojunction between Sb2S3 and SnO2, with suitable band-edge energy offset. The SnO2/Sb2S3 heterojunction enhances the charge separation efficiency, resulting in improvement of the photocurrent. The SnO2/Sb2S3 photoanode, fabricated entirely by vapor deposition processes, demonstrates photoelectrochemical water oxidation with a photocurrent density up to approximate to 3 mA cm-2 at 1.38 V versus RHE.I.D.T. and A.S. are first authors and equally contributed to this work. S.S. acknowledges European Union’s Horizon Europe program for funding under the Marie Skłodowska-Curie Grant Agreement No. 101067667. S.S. and B.V. acknowledge Catalisti VLAIO (Vlaanderen Agentschap Innoveren & Ondernemen) through the Moonshot SYN-CAT project (HBC.2020.2614), KESPER (M-ERA.NET), and Interreg FOTON project. S.S., B.V., and V.K.S. acknowledge support from Belgian federal government through the Energy Transition Fund for T-REX project. A.S. acknowledges CeSAR (Centro Servizi Ateneo per la Ricerca) at University of Cagliari and Dr. Marco Marceddu for technical
assistance. A.S. was supported by PON R&I 2014-2020 CCI2014IT16M2OP005 Azione IV.4. Green—CUP F35F21002390008. I.D.T. thanks FWO for the funding through the Fundamental Research Ph.D. Fellowship (11PNM24N) and Travel Grant for a short stay abroad (V434524N)
Rectal organoid morphology analysis (ROMA) as a novel physiological assay for diagnostic classification in cystic fibrosis
No full textBackground Diagnosing cystic fibrosis (CF) is not always straightforward, in particular when sweat chloride concentration (SCC) is intermediate and <2 CF-causing CFTR variants are identified. The physiological CFTR assays proposed in the guidelines, nasal potential difference and intestinal current measurement, are not readily available nor feasible at all ages. Rectal organoid morphology analysis (ROMA) was previously shown to discriminate between organoids from subjects with and without CF based on a distinct phenotypical difference: compared with non-CF organoids, CF organoids have an irregular shape and lack a visible lumen. The current study serves to further explore the role of ROMA when a CF diagnosis is inconclusive. Methods Organoid morphology was analysed using the previously established ROMA protocol. Two indices were calculated: the circularity index to quantify the roundness of organoids and the intensity ratio as a measure of the presence of a central lumen. Results Rectal organoids from 116 subjects were cultured and analysed together with the 189 subjects from the previous study. ROMA almost completely discriminated between CF and non-CF. ROMA indices correlated with SCC, pancreatic status and genetics, demonstrating convergent validity. For cases with an inconclusive diagnosis according to current guidelines, ROMA provided additional diagnostic information, with a diagnostic ROMA classification for 18 of 24 (75%). Discussion ROMA provides additional information to support a CF diagnosis when SCC and genetics are insufficient for diagnostic classification. ROMA is standardised and can be centralised, allowing future inclusion in the diagnostic work-up as first-choice physiological assay in case of an unclear diagnosis.This work was supported by a grant from the Belgian cystic fibrosis patient association ’Association Muco/Mucovereniging’ to the Belgian Organoid Project and the CF research centre at KU Leuven, by the Research Grant of the
Belgian Society of Paediatrics (BVK-SBP 2019), by a grant from the UZ Leuven Fund for Translational Biomedical Research and by the Klosterfrau Group Award for research in Paediatric Pulmonology awarded by the Klosterfrau Healthcare Group (no award/grant numbers).
Acknowledgements
We thank all people who participated in this study. We thank Abida Bibi and Yoline Soeffers for the technical work involving the rectal organoids. We thank the team at the UZ Leuven CF reference centre for supporting this research, particularly Linda Boulanger, Nathalie Feyaerts, Marianne Schulte and Els Aertgeerts