News Article | February 24, 2017
BEERSE, Belgium--(BUSINESS WIRE)--Janssen-Cilag International NV announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended broadening the existing marketing authorisation for DARZALEX®▼ (daratumumab).1 If approved by the European Commission, daratumumab can be used in combination with lenalidomide and dexamethasone; or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.1 Despite the incredible work of the oncology community over the past decade, MM remains an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.2 The Positive Opinion of the CHMP was based on a review of data from the Phase 3 MMY3003 (POLLUX) study, published in The New England Journal of Medicine in October 2016,3 and the Phase 3 MMY3004 (CASTOR) study, also published in The New England Journal of Medicine in August 2016.4 The safety profile of daratumumab in combination with standard-of-care regimens was consistent with monotherapy studies. In combination with lenalidomide, and dexamethasone (POLLUX) the most common adverse events of grade 3 or 4 during treatment were neutropenia (51.9%), thrombocytopenia (12.7%), and anaemia (12.4%).3 Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.3 In combination with bortezomib and dexamethasone (CASTOR) three of the most common grade 3 or 4 adverse events reported were thrombocytopenia (45.3%), anaemia (14.4%), and neutropenia (12.8%).4 Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of patients), and in 98.2% of these patients, they occurred during the first infusion.4 “This Positive Opinion recognises progress in the treatment of multiple myeloma and has the potential to offer new treatment options to eligible patients.” said Torben Plesner, M.D., Vejle Hospital, Vejle, Denmark, a daratumumab clinical trial investigator. “Daratumumab has already demonstrated single-agent efficacy in highly refractory patients. Now, consistent with these data, the results when used in combination with standard-of-care regimens after one prior line of therapy are also encouraging.” Daratumumab first received conditional approval from the European Commission (EC) in May 2016, indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent, and who have demonstrated disease progression on the last therapy.5,6 Daratumumab was the first CD38-directed monoclonal antibody approved for use worldwide. “Almost all patients with multiple myeloma have to endure relapses which typically become more aggressive,” said Dr Catherine Taylor, Haematology Therapeutic Area Lead, Janssen Europe, the Middle East and Africa (EMEA). “I am heartened by this important and rapid recommendation which recognises the progress in multiple myeloma treatment.” The CHMP’s Positive Opinion will now be reviewed by the European Commission, which has the authority to grant approval of the new indication. This milestone follows last year’s decision by the U.S. Food and Drug Administration (FDA) on 21 November 2016, to approve the expanded use of daratumumab in combination with bortezomib/dexamethasone or lenalidomide/dexamethasone in patients with multiple myeloma who have received at least 1 prior therapy.7 Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.2 MM is the second most common form of blood cancer, with around 39,000 new cases worldwide in 2012.8 MM most commonly affects people over the age of 65 and is more common in men than in women.9 The most recent five-year survival data for 2000-2007 show that across Europe, up to half of newly diagnosed patients do not reach five-year survival.10 Almost 29% of patients with MM will die within one year of diagnosis.11 Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure. While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.9 Patients who relapse after treatment with standard therapies, including PIs and immunomodulatory agents, have poor prognoses and few treatment options available.12 Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.13-15 Daratumumab induces rapid tumour cell death through apoptosis (programmed cell death)6,16 and multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).6,17,18 Daratumumab has also demonstrated immunomodulatory effects that contribute to tumour cell death via a decrease in immune suppressive cells including T-regs, B-regs and myeloid-derived suppressor cells.6,19 Daratumumab is being evaluated in a comprehensive clinical development programme that includes five Phase 3 studies across a range of treatment settings in multiple myeloma. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases in which CD38 is expressed. For more information, please see www.clinicaltrials.gov. For further information on daratumumab, please see the Summary of Product Characteristics at http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004077/human_med_001979.jsp&mid=WC0b01ac058001d124. In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab. At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science. We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at www.janssen.com/emea. Follow us at www.twitter.com/janssenEMEA. This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding the potential benefits of, and expanded indication for, DARZALEX® (daratumumab). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: the uncertainties inherent in product development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns or financial distress of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended January 3, 2016, including in Exhibit 99 thereto, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. 1. EMA. Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 20-23 February 2017. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/document_listing/document_listing_000378.jsp. Last accessed February 2017. 2. American Society of Clinical Oncology. Multiple myeloma: overview. Available at: http://www.cancer.net/cancer-types/multiple-myeloma/overview Last accessed November 2016. 3. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide and dexamethasone for multiple myeloma. New Eng J Med. 2016;375:1319–1331. 4. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib and dexamethasone for relapsed and refractory multiple myeloma. New Eng J Med. 2016;375:754–766. 5. Janssen. Janssen’s Single-Agent DARZALEX® (daratumumab) Approved by European Commission for Treatment of Multiple Myeloma (MM). Available at: http://www.janssen.com/janssen-s-single-agent-darzalex-daratumumab-approved-european-commission-treatment-multiple-myeloma. Last accessed November 2016. 6. European Medicines Agency. DARZALEX summary of product characteristics, May 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004077/WC500207296.pdf Last accessed August 2016. 7. DARZALEX® Prescribing Information November 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761036s004lbl.pdf. Last accessed January 2016. 8. GLOBOCAN 2012. Multiple myeloma. Available at: http://globocan.iarc.fr/old/burden.asp?selection_pop=62968&Textp=Europe&selection_cancer=17270&Text-c=Multiple+myeloma&pYear=13&type=0&window=1&submit=%C2%A0Execute Last accessed November 2016. 9. American Cancer Society. Multiple myeloma: detailed guide. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Last accessed November 2016. 10. De Angelis R, Minicozzi P, Sant M, et al. Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000-2007: results of EUROCARE-5 population-based study. Eur J Cancer. 2015;51:2254-68. 12. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26:149-57. 13. Fedele G, di Girolamo M, Recine U, et al. CD38 ligation in peripheral blood mononuclear cells of myeloma patients induces release of protumorigenic IL-6 and impaired secretion of IFNgamma cytokines and proliferation. Mediat Inflamm. 2013;2013:564687. 14. Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121:482-8. 15. Santoconito AM, Consoli U, Bagnato S et al. Flow cytometric detection of aneuploid CD38++ plasmacells and CD19+ B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res. 2004;28:469-77. 16. Overdijk MB, Jansen JH, Nederend M, et al. The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcy Receptor-Mediated Cross-Linking. J Immunol. 2016;197(3):807-13. 17. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186:1840-8. 18. Overdijk MB, Verploegen S, Bögels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7:311-21. 19. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384-94.
Christensen H.,Vejle Hospital
Telemedicine journal and e-health : the official journal of the American Telemedicine Association | Year: 2011
We have developed an expert computer system for the control of oral anticoagulation therapy, accessible by the patients via their own computer. To investigate if the weekly measurement and dosing of international normalized ratio (INR) at home using the online Internet-based system was superior to conventional treatment, we performed a randomized, controlled trial. All 669 patients in our anticoagulation clinic were asked to participate in the trial, providing that they had Internet access and could use the CoaguChek XS system. A total of 140 patients were included and randomized to (A) once weekly measurement and report online, (B) twice weekly measurement and report online, and (C) continued conventional treatment with INR measurement in the lab every 4 weeks and dose adjustment by letter. Group A had 79.7% (95% CI 79.0-80.3) of time in therapeutic range (TTR), group B 80.2% (95% CI 79.4-80.9) of TTR, and group C 72.7% (95% CI 71.9-73.4) TTR. Groups A and B perform statistically significantly better than the conventional group C, with a difference of TTR of 7% points (p<2.2×10(-16)), whereas no difference was seen between A and B. Home measurement of INR and the reporting and dosing of results online once a week increase TTR from 72% to 79% as compared to conventional computer-assisted monitoring in an anticoagulation clinic.
Detlefsen S.,Vejle Hospital |
Detlefsen S.,University of Southern Denmark
Histology and Histopathology | Year: 2013
During the first decade of the 21st century, IgG4-related disease (IgG4-RD), a fibroinflammatory condition occurring at multiple sites of the body, has been newly recognized. As indicated by its name, elevation of IgG4 in the serum and tissue is a common denominator of IgG4-RD. Since the observation that many patients suffering from autoimmune pancreatitis (AIP), a specific type of chronic pancreatitis, had elevated serum levels of IgG4, it was reported that these patients also had increased numbers of IgG4-positive cells in the inflamed pancreatic tissue. In 2003, it was noted that a significant proportion of the AIP patients had a variety of extrapancreatic fibroinflammatory lesions, and that AIP therefore was the pancreatic manifestation of a systemic disease. Among these extrapancreatic manifestations, the extrahepatic bile ducts, salivary glands, thyroid, lymph nodes and retroperitoneum were most frequently reported, and infiltration of the tissue with IgG4-positive cells was also noted at these sites. During the following years, a multitude of other conditions have been added to the spectrum of IgG4-RD. While some of these organ manifestations were once believed to represent diseases on their own, others have been included under the umbrella of multifocal fibrosclerosis. Biopsies or resection specimens from affected organs in IgG4-RD reveal several common microscopic features irrespective of the site of the lesion. Cellular and storiform fibrosis, lymphoplasmacytic infiltration, increased numbers of IgG4-positive cells and obliterative phlebitis are among the most characteristic histological changes in IgG4-RD. The detailed etiology, pathophysiology, epidemiology and clinical long-term outcome have at present yet to be fully elucidated. This paper focuses on the microscopic features, diagnosis and differential diagnosis of the different organ manifestations of IgG4-RD, and the current concepts of its pathogenesis will also be addressed.
Nissen H.D.,Vejle Hospital |
Appelt A.L.,Vejle Hospital |
Appelt A.L.,University of Southern Denmark
Radiotherapy and Oncology | Year: 2013
Background and purpose: This study aims at evaluating the effect of deep-inspiration breath hold (DIBH) on target coverage and dose to organs at risk in a large series of breast cancer patients. Materials and methods: Clinical dose plans for 319 breast cancer patients were evaluated: 144 left-sided patients treated with DIBH and 175 free-breathing (FB) patients (83 left-sided and 92 right-sided). All patients received whole breast irradiation with tangential fields, based on a forward-planned intensity-modulated radiation therapy (IMRT) technique. Dose to heart, ipsi-lateral lung and ipsi-lateral breast were assessed and median values compared between patient groups. Results: Comparing group median values, DIBH plans show large reductions of dose to the heart compared with left-sided FB plans; V20Gy (relative volume receiving ≥20 Gy) for the heart is reduced from 7.8% to 2.3% (-70%, p < 0.0001), V40Gy from 3.4% to 0.3% (-91%, p < 0.0001) and mean dose from 5.2 to 2.7 Gy (-48%, p < 0.0001). Lung dose also shows a small reduction in V20Gy (p < 0.04), while median target coverage is slightly improved (p = 0.0002). Conclusions: In a large series of clinical patients we find that implementation of DIBH in daily clinical practice results in reduced irradiation of heart and lung, without compromising target coverage. © 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology.
Gimsing S.,Vejle Hospital
Journal of Laryngology and Otology | Year: 2010
Objectives: (1) To compare audiometric parameters in patients with vestibular schwannoma and in those with asymmetric hearing loss from other causes; and (2) to assess proposed screening criteria by comparing published protocols. Methods: Audiometric data from 199 vestibular schwannoma patients and 225 non-tumour patients were compared. Eight screening protocols were tested on these 424 patients. Results: Vestibular schwannoma and non-tumour patients with little or no hearing loss in the unaffected ear were inseparable; however, vestibular schwannoma patients with hearing loss in the unaffected ear had greater audiometric asymmetry, compared with non-tumour patients with the same pattern of hearing loss. The sensitivity of screening protocols varied from 73 to 100 per cent; parallelism was observed between sensitivity and screening rate. Conclusion: As regards vestibular schwannoma screening protocols, the best compromise between sensitivity and screening rate was offered by a criterion comprising either: (1) 20dB asymmetry at two neighbouring frequencies, or unilateral tinnitus, or (2) 15dB asymmetry at two frequencies between 2 and 8kHz. Copyright © JLO (1984) Limited 2009.
Groth K.A.,Aarhus University Hospital |
Skakkebaek A.,Aarhus University Hospital |
Host C.,Aarhus University Hospital |
Gravholt C.H.,Aarhus University Hospital |
Bojesen A.,Vejle Hospital
Journal of Clinical Endocrinology and Metabolism | Year: 2013
Context: Recently, new clinically important information regarding Klinefelter syndrome (KS) has been published. We review aspects of epidemiology, endocrinology, metabolism, body composition, and neuropsychology with reference to recent genetic discoveries. Evidence Acquisition: PubMed was searched for "Klinefelter," "Klinefelter's," and "XXY" in titles and abstracts. Relevant papers were obtained and reviewed, as well as other articles selected by the authors. Evidence Synthesis: KS is the most common sex chromosome disorder in males, affecting one in 660 men. The genetic background is the extra X-chromosome, which may be inherited from either parent. Most genes from the extra X undergo inactivation, but some escape and serve as the putative genetic cause of the syndrome. KS is severely underdiagnosed or is diagnosed late in life, roughly 25% are diagnosed, and the mean age of diagnosis is in the mid-30s. KS is associated with an increased morbidity resulting in loss of approximately 2 yr in life span with an increased mortality from many different diseases. The key findings in KS are small testes, hypergonadotropic hypogonadism, and cognitive impairment. The hypogonadism may lead to changes in body composition and a risk of developing metabolic syndrome and type 2 diabetes. The cognitive impairmentis mainly in the area of language processing. Boys with KS are often in need of speech therapy, and many suffer from learning disability and may benefit from special education. Medical treatment is mainly testosterone replacement therapy to alleviate acute and long-term consequences of hypogonadism as well as treating or preventing the frequent comorbidity. Conclusions: More emphasis should be placed on increasing the rate of diagnosis and generating evidence for timing and dose of testosterone replacement. Treatment of KS should be a multidisciplinary task including pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists, and endocrinologists. Copyright © 2013 by The Endocrine Society.
Hansen L.K.,Vejle Hospital
Danish medical journal | Year: 2014
Ulcerative Colitis (UC) is a chronic inflammatory bowel disease located in the mucosa of the large bowel. UC often affects young adults between 15 and 40 years of age with no pre-dominant sex. Over time, incidence rates are steadily increasing and the cause of the disease remains unknown. Symptoms are general discomfort and bloody diarrhea. UC is diagnosed by endoscopic examination of the large bowel, where different hallmarks are found. It is of great importance that attacks/relapses are treated medically, as flares may cause death due to inflammatory destruction of the mucosa and perforation of the colon leading to extreme infection of the abdominal cavity. UC often affects the social life of the patients, as they feel that they must be in the immediate vicinity of toilets. Therefore, many patients prefer to stay at home during active disease. For society, UC is a costly disease due to patients reporting in sick and expensive medications. When medical treatment fails, UC patients must undergo surgery and have their colon removed (colectomy). This PhD project focused on the immune system of the body. Specifically, we looked into T cells (the chairmen of the immune system) that we believe play an important role in disease activity. When T cells are activated in inflammatory diseases, they produce several signaling substances (cytokines) that attract and activate the other parts of the immune system. T cells regulate their effector functions through calcium regulation. Upon activation, calcium is released from intracellular stores, which causes calcium channels to be embedded in the cell membrane (CRAC channels). As long as the T cells are stimulated, the two potassium channels KV1.3 and KCa3.1 maintain the driving force for calcium influx, thus keeping the T cells activated. Our aims were to investigate whether the two potassium channels KV1.3 and KCa3.1 were upregulated in mucosal biopsies from patients with active UC and whether there were correlations between the expression of the channels and the disease severity assessed by endoscopic and histological evaluation. Moreover, we used a rat colitis model (dextran sodium sulphate-induced) to examine the effect of pharmacological inhibition of KV1.3 and KCa3.1 on inflammation. We found that the expression of T cell potassium channel, KV1.3, was increased in active UC and a higher expression correlated well with both the endoscopic and the histological degree of inflammation. This suggests KV1.3 to be involved in the inflammatory process of UC. We did not find an increase of the other potassium channel, KCa3.1, at the gene expression level, but the channels were definitely present in the infiltrating T cells as examined by immunostaining. Preliminary gene expression data showed similar changes of gene expression in biopsies from Crohns disease (CD) patients. In addition, we conducted first pilot studies investigating whether pharmacological blockade of the channels ameliorates colitis in the rat DSS-model. We found a tendency towards less endoscopic inflammation in the acute phase (at day 7 and 10). However, at study termination, the improvement of inflammation failed to reach a significant level, presumably because of insufficient compound absorption from the intestine (based on low plasma concentration and previously reported amelioration of colitis by inhibiting KCa3.1). Based on these findings in our target identification study, it is suggested that both KV1.3 and KCa3.1 play a role in the inflammation of UC and possibly of CD and represent new pharmacological targets.
Bojesen A.,Vejle Hospital |
Gravholt C.H.,Aarhus University Hospital
Acta Paediatrica, International Journal of Paediatrics | Year: 2011
Klinefelter syndrome (KS) (47,XXY) is the most common sex chromosome disorder in man and is a relatively common cause of male infertility and hypogonadism. The syndrome has been known since 1942, and many reports of different diseases associated with KS have been reported since that, but a more systematic knowledge about the long-term outcome was not described until the last decade, where nation-wide epidemiological studies were reported from Britain and Denmark. We here review the epidemiological data from two cohorts of patients with KS in Denmark and Britain, showing a significant increase in both mortality and morbidity from a variety of different causes. Mortality was increased by 50% (SMR 1.5 or HR 1.4) corresponding to a median loss of approximately 2 years. The risk of being admitted to hospital with any diagnosis was increased by 70%. The underlying reason for the poorer health in KS may be caused by interaction of genetic, hormonal and socio-economic factors. Conclusion: Both morbidity and mortality are significantly increased in Klinefelter syndrome with a 50% increase in mortality risk and a 70% increase in risk of being admitted to hospital. © 2011 The Author(s)/Acta Pædiatrica © 2011 Foundation Acta Pædiatrica.
Moller J.K.,Vejle Hospital
Methods in Molecular Biology | Year: 2012
Rapid clinical and laboratory diagnoses are the foundation for a successful management of serious infections with Neisseria meningitidis. A species-specific multiplex polymerase chain reaction (PCR) coupled with fluidic microarrays using microbeads (the Luminex xMAP™ Technology) can detect pathogens most frequently found in the cerebrospinal fluid of patients. The Luminex suspension array system uniquely combines flow cytometry, microspheres, laser technology, digital signal processing, and traditional chemistry. In this method, the reaction is carried out in one vessel, in which distinctly color-coded bead sets, each conjugated with a different specific nucleic acid reactant, are hybridized with the PCR products, and a reporter molecule is used to quantify the interaction. The flow-based Luminex array reader identifies each reaction (bead set) after excitation by a red classification laser. Reporter signals from each reaction are simultaneously quantified by fluorescence generated by a green reporter laser. This nonculture, multiplex assay may prove to be an important tool for optimal laboratory diagnosis, not only of meningococcal meningitis, but also of meningitis caused by other bacterial or viral pathogens. © 2012 Springer Science+Business Media, LLC.
News Article | February 27, 2017
BEERSE, Belgio--(BUSINESS WIRE)--Janssen-Cilag International NV ha oggi annunciato che il Comitato per i medicinali per uso umano (CHMP) dell'Agenzia europea per i medicinali (EMA) ha raccomandato l'ampliamento della autorizzazione all'immissione in commercio già esistente per DARZALEX®▼ (daratumumab).1 In caso di approvazione da parte della Commissione europea, daratumumab potrà essere utilizzato in combinazione con lenalidomide e desametasone, o bortezomib e desametasone, per il trattamento dei pazienti adulti affetti da mieloma multiplo (MM) già precedentemente sottoposti ad almeno una terapia.1 Il parere positivo del CHMP si basa su un riesame dei dati dello studio clinico di fase 3 MMY3003 (POLLUX), pubblicato sulla rivista The New England Journal of Medicine nel mese di ottobre 2016,3 e sul riesame dei dati dello studio clinico di fase 3 MMY3004 (CASTOR), anch'esso pubblicato sulla rivista The New England Journal of Medicine nel mese di agosto 2016.4 Il profilo di sicurezza di daratumumab in combinazione con i trattamenti di cura standard era coerente con gli studi in monoterapia. In combinazione con lenalidomide e desametasone (POLLUX), gli eventi avversi più comuni di grado 3 o 4 nel corso del trattamento sono stati neutropenia (51,9%), trombocitopenia (12,7%) e anemia (12,4%).3 Nel 47,7% dei pazienti si sono verificate reazioni correlate all'infusione associata con daratumumab, soprattutto di grado 1 o 2.3 In combinazione con bortezomib e desametasone (CASTOR), tre degli eventi avversi riportati più comuni di grado 3 o 4 erano trombocitopenia (45,3%), anemia (14,4%) e neutropenia (12,8%).4 Le reazioni correlate all'infusione associate al trattamento con daratumumab, riportate nel 45,3% dei pazienti, erano per lo più di grado 1 o 2 (grado 3 nell 8,6% dei pazienti); nel 98,2% di questi pazienti si sono verificate nel corso della prima infusione.4 "Questo parere positivo riconosce i progressi compiuti nel trattamento del mieloma multiplo e, potenzialmente, offre nuove opzioni terapeutiche per i pazienti idonei", ha dichiarato il Dott. Torben Plesner, del Vejle Hospital di Vejle, in Danimarca, ricercatore dello studio clinico su daratumumab. "Daratumumab ha già dimostrato la propria efficacia come agente monoterapico nei pazienti altamente refrattari. A conferma di questi dati, sono incoraggianti anche i risultati derivanti dall'uso combinato con trattamenti standard dopo una prima linea terapica". Daratumumab inizialmente ha ricevuto l'approvazione condizionale da parte della Commissione europea (CE) nel mese di maggio 2016, come indicazione sotto forma di monoterapia per il trattamento dei pazienti adulti affetti da mieloma multiplo recidivo e refrattario, precedentemente trattati con un inibitore del proteasoma (PI) e un agente immunomodulante, e con progressione della malattia nel corso dell'ultima terapia.5,6 Daratumumab è stato il primo anticorpo monoclonale anti-CD38 approvato per l'uso in tutto il mondo. Questo importante risultato fa seguito alla decisione dello scorso anno da parte della Food and Drug Administration (FDA) statunitense in data 21 novembre 2016, che ha approvato l'uso ampliato di daratumumab in combinazione con bortezomib/desametasone o lenalidomide/desametasone nei pazienti affetti da mieloma multiplo precedentemente sottoposti ad almeno 1 terapia.7 Il mieloma multiplo (MM) è un tumore del sangue incurabile che ha origine nel midollo osseo ed è caratterizzato da un'eccessiva proliferazione delle plasmacellule.2 Il mieloma multiplo è la seconda forma più comune di tumore del sangue, con circa 39.000 nuovi casi registrati in tutto il mondo nel 2012.8 Il mieloma multiplo colpisce più comunemente le persone oltre i 65 anni ed è più diffuso tra gli uomini che tra le donne.9 Secondo i dati più recenti sul tasso di sopravvivenza a 5 anni per il 2000-2007, in tutta Europa fino alla metà dei pazienti di recente diagnosi non sopravvive 5 anni.10 Quasi il 29% dei pazienti affetti da mieloma multiplo muore entro un anno dalla diagnosi.11 Anche se il trattamento può portare alla remissione della malattia, sfortunatamente per i pazienti vi sono alte possibilità di ricaduta perché attualmente non esiste una cura. Mentre in alcuni casi il mieloma multiplo è totalmente asintomatico, la maggior parte dei pazienti viene diagnosticata a causa di sintomi quali problemi alle ossa, emocromo basso, ipercalcemia, insufficienza renale o infezioni. 9 I pazienti che recidivano dopo il trattamento con le terapie standard, come inibitore del proteasoma e agenti immunomodulanti, hanno prognosi infausta e poche opzioni di trattamento disponibili.12 Daratumumab è un biologico innovativo mirato alla CD38, una proteina di superficie con espressione elevata in diverse cellule di mieloma, indipendentemente dalla fase della malattia.13-15 provoca la rapida morte delle cellule tramite apoptosi (morte cellulare programmata) 6,16 e meccanismi d'azione immunomediati, inclusa la citotossicità complemento-dipendente (CDC), la citotossicità cellulare anticorpo-dipendente (ADCC) e la fagocitosi cellulare anticorpo-dipendente (ADCP).6,17,18 Daratumumab ha dimostrato inoltre effetti immunomodulanti che contribuiscono alla morte cellulare del tumore grazie all'aumento delle cellule immunosoppressive come le cellule T-reg, B-reg e le cellule soppressive di derivazione mieloide.6,19 Attualmente è in corso di svolgimento un completo programma di sviluppo clinico articolato in cinque studi clinici di fase 3 con daratumumab su diverse opzioni di trattamento del mieloma multiplo. Sono in fase di programmazione o di svolgimento anche studi addizionali per valutare il potenziale di daratumumab in altri tumori maligni e pre-maligni con espressione della CD38. Per ulteriori informazioni visitare il sito www.clinicaltrials.gov. Nel mese di agosto 2012, Janssen Biotech, Inc. e Genmab A/S hanno sottoscritto un accordo mondiale che garantisce a Janssen i diritti di licenza esclusivi per lo sviluppo, la produzione e la commercializzazione di daratumumab. Le aziende Janssen Pharmaceutical Companies, del gruppo Johnson & Johnson, sono impegnate a creare un mondo senza malattie. Trasformare la vita delle persone con metodi innovativi e migliorati per prevenire, intercettare, trattare e curare le malattie è per noi fonte di ispirazione. Abbiamo raccolto le menti migliori per investigare le scienze più promettenti. Siamo Janssen: collaboriamo con il mondo per la salute di tutti. Per ulteriori informazioni visitare il sito www.janssen.com/emea oppure seguire l'azienda su www.twitter.com/janssenEMEA. Questo comunicato stampa contiene "dichiarazioni a carattere previsionale" in base alla definizione del Private Securities Litigation Reform Act del 1995 sui potenziali benefici e sulle indicazioni ampliate di DARZALEX® (daratumumab). Si avvisano i lettori di non fare affidamento su queste dichiarazioni a carattere previsionale, che si basano su aspettative correnti di eventi futuri. Se le ipotesi di fondo dovessero rivelarsi imprecise o si verificassero incertezze o rischi noti o sconosciuti, i risultati effettivi potrebbero differire materialmente dalle aspettative e previsioni di Janssen-Cilag International NV, di una delle altre case farmaceutiche Janssen e/o Johnson & Johnson. Tali rischi e incertezze includono, ma non a titolo esaustivo: le incertezze insite nello sviluppo del prodotto, compresa l'incertezza del successo clinico e dell'ottenimento delle approvazioni normative; l'incertezza del successo commerciale; difficoltà e ritardi nella produzione; la concorrenza, inclusi progressi tecnologici, nuovi prodotti e brevetti ottenuti dai competitor; le difficoltà nei brevetti; problemi nell'efficacia o nella sicurezza dei prodotti, con conseguente ritiro degli stessi o azioni normative; cambiamenti nei modelli di comportamento e di spesa o difficoltà finanziarie degli acquirenti dei prodotti e dei servizi di assistenza sanitaria; modifiche alle leggi e ai regolamenti applicabili, comprese le riforme sanitarie mondiali; e, infine, le tendenze verso il contenimento dei costi per l'assistenza sanitaria. Un ulteriore elenco con la descrizione di tali rischi, incertezze e altri fattori è consultabile nella Relazioni annuale di Johnson & Johnson presentata sul modulo 10-K per l'anno fiscale concluso il 3 gennaio 2016, incluso l'Exhibit 99 allegato, e nei documenti successivamente depositati dalla Società presso la Securities and Exchange Commission. Le copie di questi documenti sono consultabili online all'indirizzo www.sec.gov, www.jnj.com oppure dietro richiesta a Johnson & Johnson. Nessuna delle case farmaceutiche Janssen o del gruppo Johnson & Johnson si impegna ad aggiornare le dichiarazioni a carattere previsionale a seguito di nuove informazioni o di eventi o sviluppi futuri. 1. EMA. Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 20-23 February 2017. Consultabile tramite il link: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/document_listing/document_listing_000378.jsp. Ultimo accesso: febbraio 2017. 3. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide and dexamethasone for multiple myeloma. New Eng J Med. 2016;375:1319–1331. 4. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib and dexamethasone for relapsed and refractory multiple myeloma. New Eng J Med. 2016;375:754–766. 5. Janssen. Janssen’s Single-Agent DARZALEX® (daratumumab) Approved by European Commission for Treatment of Multiple Myeloma (MM). Consultabile tramite il link: http://www.janssen.com/janssen-s-single-agent-darzalex-daratumumab-approved-european-commission-treatment-multiple-myeloma. Ultimo accesso: novembre 2016. 10. De Angelis R, Minicozzi P, Sant M, et al. Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000-2007: results of EUROCARE-5 population-based study. Eur J Cancer. 2015;51:2254-68. 12. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26:149-57. 13. Fedele G, di Girolamo M, Recine U, et al. CD38 ligation in peripheral blood mononuclear cells of myeloma patients induces release of protumorigenic IL-6 and impaired secretion of IFNgamma cytokines and proliferation. Mediat Inflamm. 2013;2013:564687. 14. Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121:482-8. 15. Santoconito AM, Consoli U, Bagnato S et al. Flow cytometric detection of aneuploid CD38++ plasmacells and CD19+ B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res. 2004;28:469-77. 16. Overdijk MB, Jansen JH, Nederend M, et al. The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcy Receptor-Mediated Cross-Linking. J Immunol. 2016;197(3):807-13. 17. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186:1840-8. 18. Overdijk MB, Verploegen S, Bögels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7:311-21. 19. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384-94.