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Drug development; Non-alcoholic steatohepatitis; Study designs Desenvolupament de fàrmacs; Esteatohepatitis no alcohòlica; Dissenys d'estudi Desarrollo de fármacos; Esteatohepatitis no alcohólica; Diseños de estudio Background and Aims Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. Methods Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. Results Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. Conclusions PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, ‘proof-of-platform’ at a smaller scale needs to be provided. JMP reports having received consulting fees from Boehringer-Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898. NAdP works for Janssen. QMA is Coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. He reports research Grant Funding: Allergan/Tobira, AstraZeneca, Boehringer-Ingelheim, Glaxo SmithKline, Glympse Bio, Intercept, Novartis Pharma AG, Pfizer Ltd. Consultancy: 89Bio, Abbvie/Allergan, Akero, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer-Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company, Viking Therapeutics. Speaker: Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape. Royalties: Elsevier Ltd. PM works for Novartis. MSK is an employee of and a shareholder in Novo Nordisk A/S. JG has received consulting fees from Boehringer-Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. JRE has received speaking fees from Gilead. FT lab’ work has been supported by the German Research Foundation (DFG, CRC/TR 362) and research grants from Gilead, Allergan, Bristol-Myers Squibb and Inventiva. VR consults for and Intercept, Novo Nordisk, Galmed, Poxel, NGM, Madrigal, Enyo, Sagimet, 89 Bio, Prosciento, Terns, and Theratechnologies, and received grants from Intercept and Gilead.

Non-alcoholic steatohepatitis; Drug development; Non-invasive biomarkers Esteatohepatitis no alcohólica; Desarrollo de fármacos; Biomarcadores no invasivos Esteatohepatitis no alcohòlica; Desenvolupament de medicaments; Biomarcadors no invasius Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH. EU-PEARL has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Children’s Tumor Foundation, Global Alliance for TB Drug Development Non-profit Organisation, Springworks Therapeutics Inc.

PURPOSE There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders. METHODS After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved. RESULTS Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements. CONCLUSION An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer.

Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. The uncertainty about the product's benefit-risk balance at the time of approval, the limitations of nonclinical development, and the complex quality aspects of those highly individualized advanced therapies are playing a key role in the clinical development, approval, and post-marketing setting for these therapies. This article reviews the current landscape of clinical development of advanced therapies, its challenges, and some of the efforts several stakeholders are conducting to move forward within this field. Progressive iteration of the science, methodologically sound clinical developments, establishing new standards for ATMPs development with the aim to ensure consistency in clinical development, and the reproducibility of knowledge is required, not only to increase the evidence generation for approval but to set principles to achieve translational success in this field., Graphical abstract, Most authorized ATMPs are based on small, open-label, uncontrolled, and single-arm pivotal trials using single and intermediate variables to evaluate outcomes. Health authorities are demanding methodologically sound clinical development to guide higher-quality evidence generation and decision-making. New standards for ATMP development are required to ensure consistency in clinical development.

Endometrial cancer; Immunotherapy; Rectal cancer Càncer d'endometri; Immunoteràpia; Càncer de recte Cáncer de endometrio; Inmunoterapia; Cáncer de recto Immune checkpoint blockers (ICB) act by reverting the immunosuppressive phenotype of cancer cells, thus allowing host immune system to generate an immune response to the tumor. One of the key mechanisms targeted by ICB is the PD-1/PD-L1 axis, which lies onto the interaction between the programmed-cell death protein 1 and its ligand, overexpressed in several tumor types. This interaction leads to the inhibition of T-cell proliferation and their apoptosis and exhaustion. Anti-PD-1/PD-L1 monoclonal antibodies are now the mainstay of treatment for several advanced stage tumors. Dostarlimab is a novel IgG4 anti-PD-1 antibody which has yielded remarkable results in mismatch-repair deficient endometrial cancer and locally advanced rectal cancer. This product review will illustrate the preclinical development of dostarlimab and its pharmacological characteristics, the clinical trials published so far and the ongoing clinical investigations.

Antídots; Factors; Cooperació Antidotes; Factors; Cooperation Antídotos; Factores; Cooperación Aquest article analitza la disponibilitat qualitativa i quantitativa dels antídots ja que és un repte global i, malgrat que existeixen diferències importants entre països, s'observen deficiències en l'àmbit internacional. Este artículo analiza la disponibilidad cualitativa y cuantitativa de los antídotos al ser un reto global y, aunque existen diferencias importantes entre países, se observan deficiencias en el ámbito internacional.

Oncology; Transcriptomics; Tumor biopsies Oncologia; Transcriptòmica; Biòpsies tumorals Oncología; Transcriptómica; Biopsias tumorales Background: The current model of clinical drug development in oncology displays major limitations due to a high attrition rate in patient enrollment in early phase trials and a high failure rate of drugs in phase III studies. Objective: Integrating transcriptomics for selection of patients has the potential to achieve enhanced speed and efficacy of precision oncology trials for any targeted therapies or immunotherapies. Methods: Relative gene expression level in the metastasis and normal organ-matched tissues from the WINTHER database was used to estimate in silico the potential clinical benefit of specific treatments in a variety of metastatic solid tumors. Results: As example, high mRNA expression in tumor tissue compared to analogous normal tissue of c-MET and its ligand HGF correlated in silico with shorter overall survival (OS; p

Fibrosis; Drug research and development; Decision making Fibrosis; Investigación y desarrollo de medicamentos; Toma de decisiones Fibrosi; Recerca i desenvolupament de medicaments; Presa de decisions Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and a disease with high unmet medical need. Platform trials provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. In this article, we describe some of the activities of the EU-PEARL consortium (EU Patient-cEntric clinicAl tRial pLatforms) regarding the use of platform trials in NASH, in particular the proposed trial design, decision rules and simulation results. For a set of assumptions, we present the results of a simulation study recently discussed with two health authorities and the learnings from these meetings from a trial design perspective. Since the proposed design uses co-primary binary endpoints, we furthermore discuss the different options and practical considerations for simulating correlated binary endpoints. EU-PEARL has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and CHILDREN’S TUMOR FOUNDATION, GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT NON PROFIT ORGANISATION, SPRINGWORKS THERAPEUTICS INC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Breast cancer subtypes; Neoadjuvant therapy; Surrogate markers Subtipos de cáncer de mama; Terapia neoadyuvante; Marcadores sustitutos Subtipus de càncer de mama; Teràpia neoadjuvant; Marcadors substituts Drug approval for early-stage breast cancer (EBC) has been historically granted in the context of registration trials based on adequate outcomes such as disease-free survival and overall survival. Improvements in long-term outcomes have made it more difficult to demonstrate the clinical benefit of a new cancer drug in large, randomized, comparative clinical trials. Therefore, the use of surrogate endpoints rather than traditional measures allows for cancer drug trials to proceed with smaller sample sizes and shorter follow-up periods, which reduces drug development time. Among surrogate endpoints for breast cancer, the increase in pathological complete response (pCR) rates was considered appropriate for accelerated drug approval. The association between pCR and long-term outcomes was strongest in patients with aggressive tumor subtypes, such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor-negative breast cancers. Whereas in hormone receptor-positive/HER2-negative EBC, the most accepted surrogate markers for endocrine therapy–based trials include changes in Ki67 and the preoperative endocrine prognostic index. Beyond the classic endpoints, further prognostic tools are required to provide EBC patients with individualized and effective therapies, and the neoadjuvant setting provides an excellent platform for drug development and biomarker discovery. Nowadays, the availability of multigene signatures is offering a standardized quantitative and reproducible tool to potentiate the efficacy of standard treatment for high-risk patients and develop de-escalated treatments for patients at lower risk of relapse. In this article, we first evaluate the surrogacies used for long-term outcomes and the underlying evidence supporting the use of each surrogate endpoint for the accelerated or regular drug approval process in EBC. Next, we provide an overview of the most recent studies and innovative strategies in a (neo)adjuvant setting as a platform to accelerate new drug approval. Finally, we highlight some clinical trials aimed at tailoring systemic treatment of EBC using prognosis-related factors or early biomarkers of drug sensitivity or resistance.

Advanced therapies; Clinical trials; Drug development Teràpies avançades; Assaigs clínics; Desenvolupament de fàrmacs Terapias avanzadas; Ensayos clínicos; Desarrollo de fármacos Several advanced therapy medicinal products (ATMPs) have been approved in the European Union (EU). The aim of this study is to analyse the methodological features of the clinical trials (CT) that supported the marketing authorization (MA) of the approved ATMPs in the EU. A systematic review of the characteristics of pivotal CT of ATMPs approved in the EU until January 31st, 2021 was carried out. A total of 17 ATMPs were approved and 23 CT were conducted to support the MA (median, 1, range, 1–3). Of those studies, 8 (34.78%) were non-controlled and 7 (30.43%) used historical controls. Only 7 (30.4%) were placebo or active-controlled studies. Among all CT, 21 (91.3%) were open-label and 13 (56.52%) had a single-arm design. To evaluate the primary endpoint, 18 (78.26%) studies used an intermediate and single variable. The median (IQR) number of patients enrolled in the studies was 75 (22–118). To date, ATMPs’ approval in the EU is mainly supported by uncontrolled, single-arm pivotal CT. Although there is a trend toward an adaptive or a life cycle approach, a switch to more robust clinical trial designs is expected to better define the benefit and the therapeutic added value of ATMPs.

Medicament de teràpia avançada; Medicament en investigació; Translacional (regulació) Medicamento de terapia avanzada; Medicamento en investigación; Traslacional (regulación) Advanced therapy medicinal product; Investigational medicinal product; Translational (regulation) A systematic and ordered product development program, in compliance with current quality and regulatory standards, increases the likelihood of yielding a successful advanced therapy medicinal product (ATMP) for clinical use as safe and effective therapy. As this is a novel field, little accurate information is available regarding the steps to be followed, and the information to be produced to support the development and use of an ATMP. Notably, successful clinical translation can be somewhat cumbersome for academic researchers. In this article, we have provided a summary of the available information, supported by our experience in Spain throughout the development of an ATMP for myocardial infarction, from the pre-clinical stage to phase I clinical trial approval. This work was supported by the Spanish Cell Therapy Network (TerCel) [RD16/0011/0006 and RD16/0011/0028]; and CIBER Cardiovascular [CB16/11/00403] projects, as a part of the National R&D&I Plan, and was co-funded by the ISCIII-Sub-Directorate General for Research Assessment and Promotion and the European Regional Development Fund (ERDF); the Government of Catalonia: Agency for Management of University and Research Grants (AGAUR) [2017-SGR-483 and 2017-SGR-719], PERIS Program (Health Department) [SLT002/16/00234 and SLT002/16/00209] and CERCA Program; La Caixa Banking Foundation; grants from the Spanish Ministry of Science, Innovation and Universities (MICINN) [SAF2017-84324-C2-1-R]; Institute of Health Carlos III (ISCIII) [PI18/00256, PIC18/00014, ICI19/00039, and PI19/01788], and cofunded by European Union (ERDF/ESF) - A way to build Europe. This work has also been funded by the Sociedad Española de Cardiología and by the Call for Expression of Interest (EoI) for Collaborative Projects on Regenerative Medicine 2019 of Center for Regenerative Medicine of Barcelona (CMR[B]). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Treball de fi de grau en Bioinformàtica. Curs 2020-2021 Tutora: Mireia Olivella Desenvolupament d'un algoritme basat en la similitud entre molècules i l'anàlisi de compostos per identificar molècules principals pel procés de desenvolupament de medicaments. El mètode està combinat amb simulacions de creixement de fragments utilitzant FragPELE, un programa pel desenvolupament in silico de fàrmacs, i iteracions de cerques a bases de dades externes. Desarrollo de un algoritmo basado en la similitud entre moléculas y el análisis de compuestos para identificar moléculas principales para el proceso de desarrollo de fármacos. El método está combinado con simulaciones de crecimiento de fragmentos usando FragPELE, un programa para el desarrollo in silico de medicamentos, e iteraciones de búsquedas en bases de datos externas. Development of a similarity-based algorithm for the analysis of compounds to identify promising leads for the drug discovery process. The method is based on the combination of fragment growing simulations using FragPELE, a tool for in-silico hit-to-lead drug design, and feed forward fragment searches on an external database.

Purpose The Spanish Society of Medical Oncology (SEOM) has carried out a study to analyse the conditions of access to oncology drugs in clinical practice in Spain. For the first time, the access of predictive biomarkers has also been analyzed. Methods A questionnaire was sent to 146 hospitals in Spain to collect information on the process of approval of 11 oncology drugs of an unquestionable clinical benefit and five predictive biomarkers of mandatory determination for specific treatments. Results Results highlight the still existing differences in the access of oncology drugs, as well as the newly identified differences in the access to predictive biomarkers between Autonomous Communities (AACC) in Spain, as well as between different hospitals within the same Autonomous Community. Conclusions The SEOM considers it necessary to reduce the differences identified, increase homogeneity, and improve conditions of access to oncology drugs and biomarkers, and makes proposals to address these issues.

Myc; descobriment de fàrmacs; Interaccions proteïna-ADN Myc; Descubrimiento de fármacos; Interacciones proteína-ADN Myc; Drug discovery; Protein–DNA interactions Myc is a transcription factor driving growth and proliferation of cells and involved in the majority of human tumors. Despite a huge body of literature on this critical oncogene, our understanding of the exact molecular determinants and mechanisms that underlie its function is still surprisingly limited. Indubitably though, its crucial and non-redundant role in cancer biology makes it an attractive target. However, achieving successful clinical Myc inhibition has proven challenging so far, as this nuclear protein is an intrinsically disordered polypeptide devoid of any classical ligand binding pockets. Indeed, Myc only adopts a (partially) folded structure in some contexts and upon interacting with some protein partners, for instance when dimerizing with MAX to bind DNA. Here, we review the cumulative knowledge on Myc structure and biophysics and discuss the implications for its biological function and the development of improved Myc inhibitors. We focus this biophysical walkthrough mainly on the basic region helix–loop–helix leucine zipper motif (bHLHLZ), as it has been the principal target for inhibitory approaches so far. This research was funded by the European Commission (SME Instrument, Grant no. 872212) and European Research Council (CoG grant no. 617473).

Estudis postautorització; Avaluació del medicament; Pràctica clínica Studies after approval; Drug evaluation; Clinical practice Estudios post autorización; Evaluación del medicamento; Práctica clínica Els estudis postautorització amb medicaments han demostrat constituir una eina molt útil en l’obtenció de nova informació sobre medicaments utilitzats en condicions de pràctica clínica habitual. Alhora, complementen a bastament la informació sobre aquests medicaments que s’havia obtingut en el desenvolupament clínic. Aquesta guia pretén ser un document pràctic i clarificador per dur a terme estudis postautorització a Catalunya i que respecta en tot moment les directrius sobre aquests estudis publicades a la legislació vigent

Novetats terapèutiques; Medicaments autoritzats; Targeta groga Novedades terapéuticas; Medicamentos autorizados; Tarjeta amarilla Therapeutic novelties; Authorized medications; Yellow card Durant els últims anys s’ha produït un increment del nombre de nous medicaments autoritzats. Concretament, durant l’any 2018 l’Agència Europea del Medicament (EMA) va emetre 84 opinions positives de les quals 42 corresponien a noves molècules comercialitzades per primera vegada. Tot i que aquesta xifra és inferior a les 59 molècules aprovades per la Food and Drug Administration durant l’any 2018, és superior a les aprovacions realitzades durant l’any 201735, 201627 i 201539. Aquestes novetats s’han centrat principalment en el tractament del càncer i les malalties infeccioses i en el camp de la neurologia i l’hematologia. Un cop aprovats els medicaments acostumen a trigar uns mesos a comercialitzar-se. És per aquest motiu que en aquest Butlletí es revisen diferents medicaments considerats d’interès general que han estat autoritzats abans del 2018: el brodalumab, un nou agent biològic per a la psoriasis; el lesinurad, el primer d’una nova família d’uricosúrics per al tractament de la gota; l’ozenoxacina, una quinolona tòpica per al tractament de l’impetigen, i la propiverina, un antiespasmòdic urinari. Tot i que l’EMA autoritza la comercialització d’aquells medicaments eficaços i segurs, cal tenir en compte que les autoritzacions es realitzen d’acord amb la informació disponible als assajos clínics i que el perfil de seguretat del medicament s’acaba de matisar amb l’exposició poblacional. Per tal de garantir el balanç benefici-risc dels medicaments comercialitzats, l’EMA realitza un seguiment continuat que s’intensifica durant els cinc primers anys de vida del medicament. Per això, és essencial notificar totes les sospites de reaccions adverses a través del sistema de targeta groga i així contribuir a la millora del coneixement sobre la seguretat dels medicaments