186 research outputs found

    Biosimilars in rare diseases: a focus on paroxysmal nocturnal hemoglobinuria

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    Biologics, a class of medicines grown in and purified from genetically engineered cell cultures, have transformed the management of many cancers and rare diseases, such as paroxysmal nocturnal hemoglobinuria. As prescription drug spending has increased and exclusivity periods have expired, manufacturers have developed biosimilarsā€“biologics that may be more affordable and highly similar to a licensed biological therapeutic, with no clinically meaningful differences in terms of safety or efficacy. With biosimilars gaining regulatory approval around the globe and broadening patient access to biologics, this review aims to help rare disease healthcare providers familiarize themselves with biosimilars, understand their development and regulatory approval process, and address practical considerations that may facilitate their use

    Plain language summary of RACE study results: addition of eltrombopag to standard treatment of severe aplastic anemia

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    What is this summary about?Severe aplastic anemia (SAA) and very severe aplastic anemia (vSAA) are blood diseases of the bone marrow. If a suitable donor for bone marrow transplant as initial treatment is unavailable, standard immunosuppression is used. Standard immunosuppression treatment includes horse antithymocyte globulin (hATG) and cyclosporin A (CsA). This summary investigated the results of standard immunosuppression treatment (Group A) versus standard immunosuppression treatment with a medication called eltrombopag (Group B) in participants with SAA and vSAA. Eltrombopag is a medicine that improves the blood platelet level and is taken by mouth (orally).What were the results of the study?Compared to Group A, more participants in Group B showed increased blood cell level to a normal range without SAA or vSAA and faster treatment response. Side effects were similar in both groups even with the addition of eltrombopag for Group B. Participants in both groups reported feeling well after 6, 12 and 24 months. Differences in the participant-reported scores (overall health, physical, emotional, and social) between Group A and Group B were minimal.What do the results of the study mean? Immunosuppression treatment (hATG plus CsA) with eltrombopag benefited participants with SAA and vSAA and could be the new standard for SAA in persons who cannot undergo bone marrow transplant. At this time, eltrombopag is only approved in specific countries to treat the condition under study that is discussed in this summary. Clinical Trial Registration: NCT02099747 (RACE study)What do the results of the study mean?Immunosuppression treatment (hATG plus CsA) with eltrombopag benefited participants with SAA and vSAA and could be the new standard for SAA in persons who cannot undergo bone marrow transplant. At this time, eltrombopag is only approved in specific countries to treat the condition under study that is discussed in this summary. Clinical Trial Registration: NCT02099747 (RACE study

    Tissue iron distribution assessed by MRI in patients with iron loading anemias

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    Bone marrow, spleen, liver and kidney proton transverse relaxation rates (R2), together with cardiac R2* from patients with sickle cell disease (SCD), paroxysmal nocturnal hemoglobinuria (PNH) and non-transfusion dependent thalassemia (NTDT) have been compared with a control group. Increased liver and bone marrow R2 values for the three groups of patients in comparison with the controls have been found. SCD and PNH patients also present an increased spleen R2 in comparison with the controls. The simultaneous measurement of R2 values for several tissue types by magnetic resonance imaging (MRI) has allowed the identification of iron distribution patterns in diseases associated with iron imbalance. Preferential liver iron loading is found in the highly transfused SCD patients, while the low transfused ones present a preferential iron loading of the spleen. Similar to the highly transfused SCD group, PNH patients preferentially accumulate iron in the liver. A reduced spleen iron accumulation in comparison with the liver and bone marrow loading has been found in NTDT patients, presumably related to the differential increased intestinal iron absorption. The correlation between serum ferritin and tissue R2 is moderate to good for the liver, spleen and bone marrow in SCD and PNH patients. However, serum ferritin does not correlate with NTDT liver R2, spleen R2 or heart R2*. As opposed to serum ferritin measurements, tissue R2 values are a more direct measurement of each tissue's iron loading. This kind of determination will allow a better understanding of the different patterns of tissue iron biodistribution in diseases predisposed to tissue iron accumulation

    Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria

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    Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis due to the absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D inhibitor. Therapeutic factor D inhibition was designed to control intravascular hemolysis and prevent C3-mediated extravascular hemolysis. In this open-label, phase II, dose-finding trial, ten untreated PNH patients with hemolysis received danicopan monotherapy (100-200 mg thrice daily). Endpoints included changes in the concentrations of lactate dehydrogenase (LDH) at day 28 (primary endpoint), of LDH at day 84, and of hemoglobin. Safety, pharmacokinetics/ pharmacodynamics, and patient-reported outcomes were assessed. Ten patients reached the primary endpoint; two later discontinued treatment: one because of a serious adverse event (elevated aspartate aminotransferase/ alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. Intravascular hemolysis was inhibited, as demonstrated by a mean decrease of LDH (5.7 times upper limit of normal [ULN] at baseline vs. 1.8 times ULN at day 28 and 2.2 times ULN at day 84; both P<0.001). Mean baseline hemoglobin, 9.8 g/dL, increased by 1.1 (day 28) and 1.7 (day 84) g/dL (both P<0.005). No significant C3 fragment deposition occurred on glycosylphosphatidylinositol- deficient erythrocytes. Mean baseline Functional Assessment of Chronic Illness Therapyā€“Fatigue score, 34, increased by 9 (day 28) and 13 (day 84) points. The most common adverse events were headache and upper respiratory tract infection. These phase II, monotherapy data show that proximal inhibition with danicopan provides clinically meaningful inhibition of intravascular hemolysis and increases hemoglobin concentration in untreated PNH patients, without evidence of C3-mediated extravascular hemolysis. This trial was registered at www.clinicaltrials.gov (#NCT03053102)

    Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria

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    Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease of uncontrolled terminal complement activation leading to intravascular hemolysis, thrombotic events and increased morbidity and mortality. This phase 3, open-label, single-arm, multicenter study evaluated ravulizumab treatment in eculizumab-naive or -experienced pediatric patients (aged <18 years) with PNH over a 26-week primary evaluation period (PEP) and 4-year extension period (EP). Patients included in the study received weightā€“based intravenous ravulizumab dosing. Primary end points were pharmacokinetic and pharmacodynamic parameters to confirm complement component 5 (C5) inhibition by ravulizumab; secondary end points assessed the efficacy (including percentage change in lactate dehydrogenase levels over time) and safety of ravulizumab. Thirteen patients, 5 (38.5%) eculizumab-naive and 8 (61.5%) eculizumab-experienced, were enrolled. Ravulizumab Ctrough levels were above the pharmacokinetic threshold of 175 Ī¼g/mL in the PEP and EP except in 1 patient. At the end of the study, pre- and post-infusion mean Ā± standard deviation serum ravulizumab concentrations were 610.50 Ā± 201.53 Ī¼g/mL and 518.29 Ā± 109.67 Ī¼g/mL for eculizumab-naive and eculizumab-experienced patients, respectively. After the first ravulizumab infusion, serum-free C5 concentrations were <0.5 Ī¼g/mL in both cohorts until the end of the study (0.061 Ā± 0.021 Ī¼g/mL and 0.061 Ā± 0.018 Ī¼g/mL for eculizumab-naive and eculizumab-experienced patients, respectively). Compared with baseline, ravulizumab improved and maintained efficacy outcomes in both groups. Ravulizumab had an acceptable safety profile with no new safety signals identified, and provided immediate, complete, and sustained terminal complement inhibition, translating to clinical benefit for pediatric patients with PNH

    A functional assay for microRNA target identification and validation

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    MicroRNAs (miRNA) are a class of small RNA molecules that regulate numerous critical cellular processes and bind to partially complementary sequences resulting in down-regulation of their target genes. Due to the incomplete homology of the miRNA to its target site identification of miRNA target genes is difficult and currently based on computational algorithms predicting large numbers of potential targets for a given miRNA. To enable the identification of biologically relevant miRNA targets, we describe a novel functional assay based on a 3ā€²-UTR-enriched library and a positive/negative selection strategy. As proof of principle we have used mir-130a and its validated target MAFB to test this strategy. Identification of MAFB and five additional targets and their subsequent confirmation as mir-130a targets by western blot analysis and knockdown experiments validates this strategy for the functional identification of miRNA targets
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